Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([OH:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH:18](Br)([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH:18]([CH3:20])[CH3:19])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2ccc(Cl)c(O)c2c1C
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2ccc(Cl)c(OC(C)C)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To 5-chloro-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (110 mg) was added 2 mL of isopropylbromide, 150 mg of K2CO3 and 4 mL of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. Removal of the solvent in vacuo gave 134 mg of 5-chloro-4-isopropoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as a thick colorless oil (100% yield).
Reaction SMILES: C(O)C=C.[CH3:5][CH2:6][Mg+].[Br-].[CH2:9]([C:12]1[C:17]2[C:18](=[O:24])[O:19][C:20](C)(C)[O:21][C:16]=2[CH:15]=[CH:14][CH:13]=1)[CH:10]=[CH2:11].[NH4+].[Cl-]>C1COCC1.O.C(OCC)C>[CH2:9]([C:12]1[C:17]([C:18]([O:19][CH2:20][CH:6]=[CH2:5])=[O:24])=[C:16]([OH:21])[CH:15]=[CH:14][CH:13]=1)[CH:10]=[CH2:11]
Reactant: C=CCc1cccc2c1C(=O)OC(C)(C)O2
Reactant: CC[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C=CCO
Product: C=CCOC(=O)c1c(O)cccc1CC=C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.3 %

Procedure:
To a stirred solution of allyl alcohol (2.25 mL, 32.8 mL) in THF (10 mL) was added dropwise EtMgBr (1.0M in THF, 29.8 mmol) at 0° C. After stirring for 15 min at rt, a solution of 5-allyl-2,2-dimethyl-benzo[1,3]dioxin-4-one (iv) (1.3 g, 5.96 mmol) in THF (5 mL) was added and stirring was continued for 5 h at rt and 2.5 h at 60° C. Diethyl ether (50 mL) was added and the mixture was poured into saturated aqueous NH4Cl (20 mL) and water (50 mL). An extraction was performed with Et2O (3×) and the combined organics were dried over MgSO4 and concentrated in vacuo. The residue was purified by FC (2% Et2O/pentane) to give 1.2 g of allyl 6-allyl-2-hydroxybenzoate (v) (90%) as a colorless oil. v: IR 2918, 2850, 1663, 1607, 1450, 1248, 1219,909,733 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.33 (1H, app.t, J=7.3 Hz), 6.88 (1H, br d, J=7.3 Hz), 6.75 (1H, d, J=7.3 Hz), 5.92-6.09 (2H, m), 5.43 (1H, br d, J=14.0 Hz), 5.33 (1H, br d, J=8.3 Hz), 5.02 (1H, br d, J=10.0 Hz), 4.96 (1H, br d, J=16.5 Hz), 4.86 (2H, br d, J=6.7 Hz), 3.70 (2H, d, J=5.9 Hz); 13C NMR (75 MHz, CDCl3) o 171.0, 162.8, 143.0, 137.7, 134.6, 131.5, 122.6, 119.8, 116.3, 115.6, 112.2, 66.7, 40.6; MS (El) 218 (M+, 10), 177 (24), 159 (100).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([NH:21]C(=O)OC(C)(C)C)[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1>C(Cl)Cl>[CH3:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=1)[NH2:21]
Reactant: CSCc1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cc(N)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97.4 %

Procedure:
TFA (2.5 ml) was added to a stirred solution of tert-butyl {3-[(methylsulfanyl)methyl]-5-(tri-fluoromethyl)phenyl}carbamate (502 mg; 1.56 mmol) in DCM (5 mL) at 0° C. The ice bath was removed and the mixture was stirred for 45 min at RT. The batch was concentrated and saturated aqueous sodium bicarbonate solution was added. The batch was extracted with ethyl acetate (2×). The combined organic phases were dried (sodium sulfate), filtered and concentrated to give the crude product (336 mg), that was used without further purification.
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][C:8]1[CH:33]=[CH:32][CH:31]=[CH:30][C:9]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:34]([O:36][C:37](=[O:59])[CH2:38][C:39]1([CH2:42][CH2:43][CH:44]([CH:57]=O)[CH2:45][CH2:46][C:47]2[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=2)[CH2:41][CH2:40]1)[CH3:35].[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH2:34]([O:36][C:37](=[O:59])[CH2:38][C:39]1([CH2:42][CH2:43][CH:44](/[CH:57]=[CH:10]/[C:9]2[CH:30]=[CH:31][CH:32]=[CH:33][C:8]=2[OH:7])[CH2:45][CH2:46][C:47]2[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=2)[CH2:41][CH2:40]1)[CH3:35]
Reactant: CCOC(=O)CC1(CCC(C=O)CCc2ccc(C(=O)OC)cc2)CC1
Reactant: Oc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC1(CCC(/C=C/c2ccccc2O)CCc2ccc(C(=O)OC)cc2)CC1
Reaction time: 0.75 h

Procedure:
At 0° C., 0.6 ml (1.5 mmol) of a 2.5 M solution of n-butyllithium in hexane is slowly added to a solution of 359 mg (0.799 mmol) of (2-hydroxybenzyl)triphenylphosphonium bromide in 5 ml of anhydrous THF, and the mixture is stirred for 45 min. At this temperature, 192 mg (0.53 mmol) of methyl 4-{5-[1-(2-ethoxy-2-oxoethyl)cyclopropyl]-3-formylpentyl}benzoate are then added slowly, and the mixture is stirred at 0° C. for 2 hours. After complete conversion, saturated ammonium chloride solution is added to the reaction solution, which is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is evaporated to dryness. The crude product obtained is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). This gives 178.5 mg (74% of theory) of a colorless oil.
Reaction SMILES: OC1O[N:5]=[N+:4]2[CH2:7][S:8][CH2:9][C:3]=12.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C:18]#[C:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([Cl:26])[N:21]=1>C1(C)C=C(C)C=C(C)C=1>[Cl:26][C:22]1[N:21]=[C:20]([C:19]2[C:18]([C:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=3[F:10])=[N:5][N:4]3[C:3]=2[CH2:9][S:8][CH2:7]3)[CH:25]=[CH:24][N:23]=1
Reactant: Oc1on[n+]2c1CSC2
Reactant: Fc1ccc(C#Cc2ccnc(Cl)n2)c(F)c1
Solvent: Cc1cc(C)cc(C)c1
Product: Fc1ccc(-c2nn3c(c2-c2ccnc(Cl)n2)CSC3)c(F)c1

Procedure:
A solution of 3-hydroxy-4H,6H-thiazolo[3,4-c][1,2,3]oxadiazol-7-ium, inner salt (0.63 g, 4.3 mmol) (prepared from thiazolidine-4-carboxylic acid by nitrosation and treatment with trifluoroacetic anhydride as described in Sutcliffe et al. Tetrahedron 2000, 24, 10011-10021) and 4-[2-(2,4-difluorophenyl)ethynyl)-2-chloropyrimidine (1.0 g, 4.0 mmol) in mesitylene (15 mL) was heated at 155-160° C. under nitrogen for 48 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by medium pressure liquid chromatography using 0 to 50% ethyl acetate in hexanes as eluant to give 0.09 g of the title compound as a white solid.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]([CH3:28])[CH3:27])[C:20]=2[S:29][CH2:30][CH3:31])[CH:11]=1>CO>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]([CH3:27])[CH3:28])[C:20]=2[S:29]([CH2:30][CH3:31])=[O:5])[CH:11]=1
Reactant: CCSc1c(CN(C)C)cccc1Oc1cc(Cl)ccc1C#N
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Product: CCS(=O)c1c(CN(C)C)cccc1Oc1cc(Cl)ccc1C#N
Reaction time: 17 h

Procedure:
4-Chloro-2-fluorobenzonitrile (0.567 g, 3.6 mmol), 3-dimethylaminomethyl-2-ethylsulfanyl-phenol hydrobromide (0.77 g, 2.6 mmol) and cesium carbonate (1.19 g, 3.6 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 17 h. More cesium carbonate (1.19 g, 3.6 mmol) was added. After 1 h, the reaction was complete by LC/MS analysis. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water (1×), 10% sodium carbonate solution (2×), water (2×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(3-dimethylaminomethyl-2-ethylsulfanyl-phenoxy)-benzonitrile (662 mg, 52%) as a clear oil. Fumaric acid (30 mg, 0.26 mmol) in methanol (5 mL) was added to 4-chloro-2-(3-dimethylaminomethyl-2-ethylsulfanyl-phenoxy)-benzonitrile (91 mg, 0.26 mmol). The solvent was removed in vacuo and diethyl ether (20 mL) was added with stirring. After 17 h, 4-chloro-2-(3-dimethylaminomethyl-2-ethylsulfanyl-phenoxy)-benzonitrile fumarate (41.4 mg, 34%) was filtered off as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([Mg]Br)C.Br[C:16]1[C:17]([N:19]([CH3:34])[C:20](=[O:33])[C:21]=1[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH3:31])[CH:29]=2)[N:24]([CH3:32])[CH:23]=1)=[O:18].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[CH3:32][N:24]1[C:25]2[C:30](=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[C:22]([C:21]2[C:20]([N:19]([CH3:34])[C:17](=[O:18])[C:16]=2[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:33])=[CH:23]1
Reactant: Cc1ccc2[nH]ccc2c1
Reactant: Cc1ccc2c(c1)c(C1=C(Br)C(=O)N(C)C1=O)cn2C
Agent: CC[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Product: Cc1ccc2[nH]cc(C3=C(c4cn(C)c5ccc(C)cc45)C(=O)N(C)C3=O)c2c1
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 86.9 %

Procedure:
To a solution of 5-methylindole (77 mg, 0.66 mmol) dissolved in toluene (1 mL) was added 0.95M ethylmagnesium bromide (0.7 mL, 0.66 mmol) at 40° C., and the whole was stirred at 40° C. for 45 minutes. Successively, a solution of 2-bromo-3-(1,5-dimethyl-1H-indol-3-yl)-N-methylmaleimide (100 mg, 0.3 mmol) dissolved in toluene (5 mL) was added thereto, followed by stirring under heating and refluxing for 3 hours. After 20% aqueous citric acid solution (1 mL) was added thereto under ice cooling and the whole was stirred, toluene was removed by concentration under reduced pressure and the resulting concentrate was extracted with ethyl acetate. The extract was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=1:2) to obtain 2-(1,5-dimethyl-1H-indol-3-yl)-3-(5-methyl-1H-indol-3-yl)-N-methylmaleimide (100 mg, 86.9%) as red solids.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[ClH:29].[CH3:30][N:31]([CH2:33][C:34]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=1)[CH3:32].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[ClH:29].[CH3:30][N:31]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]3[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)=[CH:36][CH:35]=1)[CH3:32]
Reactant: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(CN(C)C)cc2)cc2c1cnn2C(C)C
Yield: 85.2 %

Procedure:
In a glass pressure tube was added 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (200 mg, 0.449 mmol), 4-(N,N-dimethylaminomethyl)phenylboronic acid pinacol ester hydrochloride (170 mg, 0.571 mmol), potassium phosphate (300 mg, 1.413 mmol), dioxane (12 mL) and water (3 mL). The suspension was stirred and purged with N2 then PdCl2(dppf)-CH2Cl2 adduct (50 mg, 0.061 mmol) was added. The reaction mixture was capped and stirred at 110° C. for 4 hr. The dark black reaction mixture was evaporated to dryness. The crude product was purified by silica gel chromatography (eluent: 0 to 70%, 20% (5% NH4OH in MeOH)/CH2Cl2) in CH2Cl2). The pure fractions were combined and evaporated to dryness to give the product as a very dark brown-black solid. The solid was taken up in CH2Cl2 and treated with Silicycle Si-Thiol (2 g, 1.46 mMol/g). After stirring for 30 minutes on a rotary evaporator (no vacuum) the mixture was filtered through a pad of Celite, washed with CH2Cl2, and evaporated to dryness. The light yellow colored solid was taken up in a small volume of MeOH and treated with 6 N HCl (200 uL) and re-evaporated to dryness. The residue was dissolved in a small volume of MeOH, ppt. with Et2O, triturated, filtered and dried under vacuum to give the product 6-{4-[(dimethylamino)methyl]phenyl}-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide hydrochloride salt as a light tan solid (205 mg, 85% yield). 1H NMR (400 MHz, DMSO-d6) δ=11.60 (br. s., 1H), 10.81 (br. s., 1H), 8.69 (t, J=4.9 Hz, 1H), 8.40 (s, 1H), 8.19 (s, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.90 (d, J=1.0 Hz, 1H), 7.71 (d, J=8.3 Hz, 2H), 5.94 (s, 1H), 5.18 (dt, J=6.7, 13.2 Hz, 1H), 4.43 (d, J=4.8 Hz, 2H), 4.34 (d, J=5.3 Hz, 2H), 2.72 (d, J=5.1 Hz, 6H), 2.58-2.52 (m, 2H), 2.14 (s, 3H), 1.59-1.52 (m, 2H), 1.51 (d, J=6.6 Hz, 6H), 0.89 (t, J=7.3 Hz, 3H); LC-MS (ES)+m/e 500.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.CN1CCOCC1>C(Cl)(Cl)Cl>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])=[CH:24][CH:23]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCc3ccc(F)cc3)cc2s1
Yield: 8.3 %

Procedure:
the title compound (8 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (75 mg, 0.23 mmol), 4-fluorobenzylamine (29 μL, 0.25 mmol) and PS-NMM (0.22 g, 0.45 mmol) in 4 mL of chloroform. MS (m/z, ES+): 418.3 (M+1, 100%). Yield=9%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1.[Br:11]N1C(=O)CCC1=O.O>ClCCl>[Br:11][C:10]1[CH:9]=[N:8][N:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[N:3][C:4]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccn2nccc2n1
Solvent: ClCCl
Solvent: O
Product: Clc1ccn2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 5-chloropyrazolo[1,5-a]pyrimidine (2.30 g, 15.0 mmol) in dichloromethane (100 mL) was added N-bromosuccinimide (2.67 g, 15.0 mmol) and the mixture allowed to stir at ambient temperature for 1 hour. The reaction mixture was poured into water, extracted with dichloromethane, and dried over sodium sulfate. The crude product was purified by column chromatography, eluting with 1% MeOH/dichloromethane and afforded 1.50 g (45%) of 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine as a light yellow solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([NH:26][C:27](=[NH:80])[C:28]1[S:32][C:31]([S:33][CH3:34])=[C:30]([S:35]([C:38]2[CH:39]=[C:40]([C:44]3[C:49]([CH3:50])=[CH:48][C:47]([NH:51]C(OCC[Si](C)(C)C)=O)=[CH:46][C:45]=3[NH:61][C:62](=[O:79])[NH:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][O:69][C:70]3[CH:78]=[CH:77][C:73]([C:74]([OH:76])=[O:75])=[CH:72][CH:71]=3)[CH:41]=[CH:42][CH:43]=2)(=[O:37])=[O:36])[CH:29]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[NH2:51][C:47]1[CH:48]=[C:49]([CH3:50])[C:44]([C:40]2[CH:41]=[CH:42][CH:43]=[C:38]([S:35]([C:30]3[CH:29]=[C:28]([C:27]([NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])=[NH:80])[S:32][C:31]=3[S:33][CH3:34])(=[O:37])=[O:36])[CH:39]=2)=[C:45]([NH:61][C:62](=[O:79])[NH:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][O:69][C:70]2[CH:71]=[CH:72][C:73]([C:74]([OH:76])=[O:75])=[CH:77][CH:78]=2)[CH:46]=1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=O)OCC[Si](C)(C)C)cc2NC(=O)NCCCCCOc2ccc(C(=O)O)cc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(N)cc2NC(=O)NCCCCCOc2ccc(C(=O)O)cc2)c1
Yield: 128.7 %

Procedure:
Tetrabutyl ammonium fluoride solution (2.38 mL, 1M in THF) was added to a solution of 4-(5-{3-[3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilanyl-ethoxycarbonylamino)-biphenyl-2-yl]-ureido}-pentyloxy)-benzoic acid (276 mg, 0.298 mmol, Example 283: step d) in THF (10 mL) over 2 days at 35° C. The solvents were removed in vacuo. The residue was diluted in EtOAc, washed with water and brine, and dried over magnesium sulfate. The solvents were removed in vacuo to afford the title compound as a brown solid (300 mg, quantitative). ESI-MS (m/z): Calcd. for C37H44N5O8S3: 782.2 (M+1); found: 781.8.
Reaction SMILES: O[C@H](C)C([N:5]1[CH2:8][CH:7]([C:9]2[CH:30]=[CH:29][C:12]3[C:13]4[N:14]=[C:15]([C:21]5[N:22]([CH:26]([CH3:28])[CH3:27])[N:23]=[CH:24][N:25]=5)[S:16][C:17]=4[CH2:18][CH2:19][O:20][C:11]=3[CH:10]=2)[CH2:6]1)=O.[C:32]([NH:39][C:40]1([C:43]([OH:45])=O)[CH2:42][CH2:41]1)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>CN(C=O)C>[C:35]([O:34][C:32](=[O:33])[NH:39][C:40]1([C:43]([N:5]2[CH2:8][CH:7]([C:9]3[CH:30]=[CH:29][C:12]4[C:13]5[N:14]=[C:15]([C:21]6[N:22]([CH:26]([CH3:28])[CH3:27])[N:23]=[CH:24][N:25]=6)[S:16][C:17]=5[CH2:18][CH2:19][O:20][C:11]=4[CH:10]=3)[CH2:6]2)=[O:45])[CH2:41][CH2:42]1)([CH3:36])([CH3:37])[CH3:38]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)[C@@H](C)O)C3)ccc1-2
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)C4(NC(=O)OC(C)(C)C)CC4)C3)ccc1-2

Procedure:
The title compound was prepared by a similar procedure to (R)-2-hydroxy-1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-propan-1-one using 1-(Boc-amino)cyclopropane carboxylic acid and DMF to give (1-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carbonyl}-cyclopropyl)-carbamic acid tert-butyl ester isolated as a white solid (228 mg, 66%). LCMS: RT=4.72 min, [M+H]+=551
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][N:8]=2)=[C:4]([CH3:17])[CH:3]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:27]=1[C:28](Cl)=[O:29]>C(Cl)Cl>[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:27]=1[C:28]([N:13]([C:10]1[CH:9]=[N:8][C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:17])=[CH:12][CH:11]=1)[CH3:14])=[O:29]
Reactant: CNc1ccc(Oc2ccc(Cl)cc2C)nc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1Oc1ccc(N(C)C(=O)c2c(Cl)cccc2Cl)cn1
Temperature: 22 °C
Reaction time: 18 h

Procedure:
2-(4-Chloro-2-methyl-phenoxy)-5-(N-methylamino)pyridine (32 mg, 0.13 mmol) dissolved in methylene chloride (0.25 mL) was treated with triethylamine (0.026 mL, 0.18 mmol) followed by a solution of 2,6-dichlorobenzoyl chloride (31 mg, 0.15 mmol) dissolved in methylene chloride (0.15 mL). The reaction mixture was shaken at 22° C. for 18 hours followed by quenching with saturated aqueous NH4Cl and stirring for an additional 5 hours. The organic layer was separated and dried over Na2SO4 then concentrated in vacuo. The crude product was purified by chromatography on SiO2 using 1:1 ethyl acetate/hexane as eluent. MS (m/z): 422/424 (M+H)+; C20H15N2O2Cl3 requires 422.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].[N:10]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[C:14]=2[CH:13]=[CH:12][CH:11]=1.C([O-])(=O)C.[K+].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[CH:13]=[CH:12][CH:11]=[N:10]3)=[CH:4][C:3]=1[F:9]
Reactant: OB(O)c1cccc2ncccc12
Reactant: Fc1cc(I)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: Fc1cc(-c2cccc3ncccc23)ccc1Br
Yield: 104 %

Procedure:
4-Bromo-3-fluoroiodobenzene (250 mg, 0.8 mmol, 1.2 eq.), quinoline-5-boronic acid (120 mg, 0.7 mmol), potassium acetate (70 mg, 1 eq.), Pd(dppf)Cl2 (70 mg, 0.1 eq.), and Cs2CO3 (700 mg, 3.0 eq.) in DMSO (5 mL) were heated under argon at 80° C. during 1 h. The reaction mixture was extracted from water into ether, dried over Na2SO4, concentrated, and chromatographed on silica gel (5→20% EtOAc/hexanes) to give 5-(4-bromo-3-fluorophenyl)quinoline (220 mg, quant.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[NH:11][C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1.Cl[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:7]([O:8][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[NH:11][C:10]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(Oc2ccccc2[N+](=O)[O-])c(Cl)cc1F

Procedure:
A mixture of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (2.2 g), 2-chloronitrobenzene (1.3 g) and potassium carbonate (1.4 g) in N,N-dimethylformamide (100 ml) was heated at reflux for 3 hours under an atmosphere of nitrogen. The resulting mixture was poured into water (200 ml) and acidified by the addition of a small portion of conc. hydrochloric acid. The solution was extracted with a mixed solvent (ethyl acetate:hexane, 1:1, 400 ml) and the organic phase dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue chromatographed on silica gel eluting with ethyl acetate:hexane, 1:1, to give 3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (Intermediate 11-18) as an amorphous solid (1.0-g).
Reaction SMILES: N#N.C(O)C.Cl.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1B(O)O.[CH3:17][O:18][C:19](=[O:27])[CH2:20][C:21]1[S:22][C:23](Br)=[CH:24][CH:25]=1>O.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:17][O:18][C:19](=[O:27])[CH2:20][C:21]1[S:22][C:23]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH2:7])=[CH:24][CH:25]=1
Reactant: Nc1ccccc1B(O)O
Reactant: COC(=O)Cc1ccc(Br)s1
Agent: [Pd]
Agent: Cl
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)Cc1ccc(-c2ccccc2N)s1
Temperature: 100 °C
Reaction time: 22 h
Yield: 51.3 %

Procedure:
(The following reaction is carried out in an N2 atmosphere.) Ethanol (3.7 mL), tetrakis-(triphenylphosphine)-palladium(0) (289 mg, 0.25 mmol) and Na2CO3 decahydrate (4.0 g, 14.0 mmol) dissolved in water (5.2 mL) are subsequently added to a solution of 2-amino-benzeneboronic acid hydrochloride (910 mg, 5.25 mmol) in toluene (52 mL). Degas the reaction mixture carefully (5 times) and flush with N2 again. A solution of (5-bromo-thiophen-2-yl)-acetic acid methyl ester (1.17 g, 5.0 mmol) in toluene (4.5 mL) is added. Degas the mixture again (5 times) and stir for 22 h at 100° C. Partition the reaction solution between EtOAc and brine and extract the separated aqueous layer with EtOAc (3 times). Wash combined organic layer with water and brine and dry it with Na2SO4. Purify the crude product by preparative radial chromatography (CyH/EtOAc 5+1] to obtain [5-(2-amino-phenyl)-thiophen-2-yl]-acetic acid methyl ester (87) as a brown oil (634 mg, 51%). 1H NMR (400 MHz, CDCl3): 3.73 (s, 3H); 3.83 (s, 2H); 3.92-4.07 (br.s, 2H); 6.74 (d, 1H); 6.76 (td, 1H, J1=7.6 Hz, J2=1.3 Hz); 6.92 (d, 1H, J=3.5 Hz); 7.02 (d, 1H, J=3.5 Hz); 7.11 (td, 1H, J1=7.6 Hz, J2=1.5 Hz); 7.23 (dd, 14H, J1=7.6 Hz, J2=1.5 Hz).