Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3=[N:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:21](=[O:22])[C:11]3=[CH:10]2)=[N:6][CH:7]=1.[CH3:30][Zn]C.[Cl-].[NH4+]>O1CCCC1.[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>[CH3:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[C:21](=[O:22])[C:11]2=[CH:10][N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([CH3:30])=[CH:7][N:6]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]2=[N:19]1
Reactant: Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(Br)cn3)cc-2c1=O
Reactant: C[Zn]C
Agent: [Pd]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(Cn2cc3c(=O)n(-c4ccccc4C)nc-3c3ccccc32)nc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
5-[(5-Bromopyridin-2-yl)methyl]-2-(2-methylphenyl)-2,5-dihydro-3/1-pyrazolo[4,3-c]quinolin-3-one (Example 743, 40 mg, 0.090 mmol) was dissolved in tetrahydrofuran (2 mL), and the mixture was sparged under an atmosphere of nitrogen. Dimethyl zinc (0.49 mL, 2.0 Min toluene, 0.90 mmol, 10 equiv) and tetrakis(triphenylphosphine) palladium (0) (1.0 mg, 0.01 mmol, 0.1 equiv) were added and the mixture was placed into an oil bath preheated to 60° C. for 4 hours. Additional dimethyl zinc (0.49 mL, 2.0 M in toluene, 0.90 mmol, 10 equiv) and tetrakis(triphenylphosphine) palladium (0) (1.0 mg, 0.01 mmol, 0.1 equiv) were added and the mixture was heated at 70° C. for an additional 3 hours. The mixture was cooled to ambient temperature, treated with ammonium chloride (0.2 mL, aqueous saturated), and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (90:10 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the titled compound: 1H-NMR (400 MHz, CD3OD) δ 8.98 (1H, s), 8.39 (1H, s), 8.35-8.32 (1H, m), 7.78 (1H, d, J=8.5 Hz), 7.73 (1H, d, J=6.2 Hz), 7.66-7.56 (2H, m), 7.42-7.35 (5H, m), 5.86 (2H, s), 234 (3H, s), 2.28 (3H, s), ppm; low resolution mass spectrometry (ES+) m/z 381.0 (M+H)+; calculated for C24H20N4O: 381.2].
Reaction SMILES: NC1SC2C=C(OC)C=CC=2N=1.[OH-].[K+].BrC1C=C(C2SC3C=C(OC)C=CC=3N=2)C=CC=1C1OC=NC=1.[I:38][C:39]1[CH:44]=[C:43]([C:45]2[S:46][C:47]3[CH:53]=[C:52]([O:54]C)[CH:51]=[CH:50][C:48]=3[N:49]=2)[CH:42]=[CH:41][C:40]=1[C:56]1[O:60][CH:59]=[N:58][CH:57]=1.B(Br)(Br)Br.Cl>O.ClCCl.C(O)(=O)C>[I:38][C:39]1[CH:44]=[C:43]([C:45]2[S:46][C:47]3[CH:53]=[C:52]([OH:54])[CH:51]=[CH:50][C:48]=3[N:49]=2)[CH:42]=[CH:41][C:40]=1[C:56]1[O:60][CH:59]=[N:58][CH:57]=1
Reactant: COc1ccc2nc(-c3ccc(-c4cnco4)c(I)c3)sc2c1
Agent: BrB(Br)Br
Agent: COc1ccc2nc(-c3ccc(-c4cnco4)c(Br)c3)sc2c1
Agent: COc1ccc2nc(N)sc2c1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc2nc(-c3ccc(-c4cnco4)c(I)c3)sc2c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
2-Amino-6-methoxybenzothiazole (3.0 g) was added to a solution (100 mL) of potassium hydroxide (21.9 g) in water, followed by refluxing under heating for 15 hours. The mixture was neutralized with 5N aqueous acetic acid solution, and the precipitated crystals were recovered through filtration. The procedure of Referential Example 22 was repeated, except that the thus-recovered 2-amino-5-methoxy-1-benzenethiol (185 mg) and 3-bromo-4-(1,3-oxazol-5-yl)benzaldehyde (300 mg), which had been produced in Referential Example 26, were used, to thereby yield 5-[2-bromo-4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]-1,3-oxazole (450 mg). Subsequently, The procedure of Referential Example 12 was repeated, except that 5-[2-bromo-4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]-1,3-oxazole (450 mg) was used, to thereby yield 5-[4-(6-methoxy-1,3-benzothiazol-2-yl)-2-(1,1,1-tributylstannyl)phenyl]-1,3-oxazole (15 mg). Thereafter, the procedure of Example 12 was repeated, except that 5-[4-(6-methoxy-1,3-benzothiazol-2-yl)-2-(1,1,1-tributylstannyl)phenyl]-1,3-oxazole (15 mg) was used, to thereby yield 5-[2-iodo-4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]-1,3-oxazole. Under a stream of argon, boron tribromide (200 μL, 1M dichloromethane solution) was added dropwise to a solution (30 mL) of 5-[2-iodo-4-(6-methoxy-1,3-benzothiazol-2-yl)phenyl]-1,3-oxazole (20 mg) in dichloromethane, and the mixture was stirred at room temperature for 23 hours. 1N Aqueous hydrochloric acid solution was added to the reaction mixture, followed by extraction with ethyl acetate. The solvent was evaporated, and the residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby yield the title compound (10 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[F:20])[CH3:11].[S-:21][C:22]#[N:23].[K+].BrBr>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([F:20])=[CH:15][C:16]2[N:17]=[C:22]([NH2:23])[S:21][C:18]=2[CH:19]=1)[CH3:11]
Reactant: CC(Oc1ccc(N)cc1F)c1c(F)ccc(Cl)c1Cl
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Product: CC(Oc1cc2sc(N)nc2cc1F)c1c(F)ccc(Cl)c1Cl
Yield: 97.5 %

Procedure:
6-[1-(2,3-Dichloro-6-fluorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-amine was prepared according to the method described in Example 20d but from 2 g of 4-[1-(2,3-dichloro-6-fluorophenyl)ethoxy]-3-fluoroaniline, 2.44 g of potassium thiocyanate and 0.322 cm3 of dibromine. We obtain 2.3 g of 6-[1-(2,3-dichloro-6-fluorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-amine in the form of a cream-coloured powder, which has the following characteristics:
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:7]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:6]2[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:45][CH2:46][O:47][C:48]([CH2:50][SH:51])=[O:49].[H-].[Na+]>CN(C)C=O.O1CCCC1>[C:21]([O:20][C:19]([NH:18][CH2:17][C:7]1[C:8]([CH2:13][CH:14]([CH3:16])[CH3:15])=[N:9][C:10]2[C:5]([C:6]=1[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)=[CH:4][C:3]([CH2:2][S:51][CH2:50][C:48]([O:47][CH2:46][CH3:45])=[O:49])=[CH:12][CH:11]=2)=[O:25])([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)CS
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(CO)cc23)cc1
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CSCc1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a mixture of tert-butyl [6-(hydroxymethyl)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methylcarbamate (1.1 g, 2.5 mmol), triethylamine (0.53 ml, 3.8 mmol) and tetrahydrofuran (50 ml) was added methanesulfonyl chloride (0.3 ml, 3.8 mmol) under ice-cooling, and the mixture was stirred for 30 min. A mixture of ethyl thioglycollate (0.42 ml, 3.8 mmol), sodium hydride (60% in oil, 0.15 g, 3.8 mmol) and N,N-dimethylformamide (3 ml) were added to the reaction mixture and the mixture was stirred at room temperature for 15 min. The reaction mixture was partitioned between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give ethyl ({[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]methyl}thio)acetate (1.1 g, yield 83%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:35])[N:9]3[CH2:34][CH2:33][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:20][N:19]=[C:18]([CH2:21][N:22]4C(=O)C5=CC=CC=C5C4=O)[N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.CN>C(O)C>[NH2:22][CH2:21][C:18]1[N:17]=[C:16]([C:15]2[N:14]=[CH:13][N:12]3[C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=4[C:8](=[O:35])[N:9]4[CH2:34][CH2:33][C@H:10]4[C:11]=23)[O:20][N:19]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)n1
Agent: CN
Solvent: CCO
Product: NCc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)n1
Reaction time: 2 h
Yield: 91.2 %

Procedure:
6.01 g (12.3 mmol) of (S)-8-chloro-12,12a-dihydro-1-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were placed in 60 ml of ethanol and treated dropwise with 120 ml of methylamine (33% in ethanol) at 60° within 30 min. The solution was stirred at 70° for 2 hours and subsequently concentrated. By chromatography of the residue on silica gel while eluting with ethyl acetate/methanol 8/2 there were obtained 4.0 g (91%) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 206°-208°.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C@@H:9]([CH:14]([CH3:16])[CH3:15])[C:10](OC)=[O:11])=[CH:6][CH:5]=1>C(O)C>[Br:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C@@H:9]([CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[CH:6][CH:5]=1
Reactant: COC(=O)[C@@H](Oc1ccc(Br)cc1)C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)[C@@H](CO)Oc1ccc(Br)cc1
Yield: 54.8 %

Procedure:
Solid sodium borohydride (11.8 g) was added with cooling in three portions over 3 days to a stirred solution of (2S)-2-(4-bromophenoxy)-3-methylbutanoic acid, methyl ester (27.7 g) in ethanol (400 ml). The reaction was concentrated under reduced pressure and the residue partitioned between 2M hydrochloric acid (400 ml) and ether. The organic layer was dried over anhydrous magnesium sulfate filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluting with dichloromethane:isohexane (1:1) to give the sub-title compound as an oil (13.7 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][C:11](Br)=[CH:12][N:13]=2)[CH:5]=[CH:4][CH:3]=1.[C:15]([C:18]1[CH:19]=[C:20]([SH:25])[CH:21]=[CH:22][C:23]=1[CH3:24])([OH:17])=[O:16].C[O-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][C:11]([S:25][C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[C:18]([CH:19]=3)[C:15]([OH:17])=[O:16])=[CH:12][N:13]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S)cc1C(=O)O
Reactant: Brc1cccc(Nc2ncc(Br)s2)n1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(Sc2cnc(Nc3cccc(Br)n3)s2)cc1C(=O)O
Temperature: 54 °C
Yield: 81.3 %

Procedure:
A suspension of 2-[(6-bromo-2-pyridinyl)amino]-5-bromothiazole (100 mg, 0.3 mmol), 3-carboxy-4-methylthiophenol (170 mg, 0.98 mmol) and sodium methoxide (210 μL, 25% w/w solution in methanol, 0.9 mmol) in methanol (4.9 mL) and THF (2 mL) was heated to 54° C. for 5.5 h. Supplemental sodium methoxide solution (1.42 mL) was added in portions over a period of 5 h. The mixture was heated to 54° C. for 16 h and concentrated. The residue was diluted with 1 N aqueous HCl solution at 0° C. and stirred for several minutes. The precipitated solid was filtered, washed several times with water and ether, and dried in vacuo over P2O5. Trituration with ether afforded the titled compound (103 mg, 81%) as an off-white solid.
Reaction SMILES: [OH-].[Na+].[C:3]([CH:7]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][N:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]2[CH3:28])=[CH:11][C:10]=1[CH2:29][CH2:30][CH3:31])([O:5]C)=[O:4].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.C(Cl)Cl>[C:3]([CH:7]([C:32]1[CH:37]=[CH:36][C:35]2[O:38][CH2:39][O:40][C:34]=2[CH:33]=1)[O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[CH:13][C:12]([CH2:18][N:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]2[CH3:28])=[CH:11][C:10]=1[CH2:29][CH2:30][CH3:31])([OH:5])=[O:4]
Reactant: CCCc1cc(Cn2c(C)nc3ncccc32)cc(CCC)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCc1cc(Cn2c(C)nc3ncccc32)cc(CCC)c1OC(C(=O)O)c1ccc2c(c1)OCO2
Yield: 48.7 %

Procedure:
A 5N sodium hydroxide solution (0.2 mL) was added to a stirred mixture of the product of Step A (27 mg, 0.0524 mmol) in methanol (2 mL). A few drops of methylene chloride were added to allow stirring then the mixture was stirred at room temperature for 2 h. The solution volume was reduced to ~10% in vacuo then 5% citric acid solution added. The mixture was extracted with ethyl acetate (3 times). The combined organic phase was washed with water, brine, dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by flash-chromatography using silica gel (8, 10% methanol/methylene chloride) to give the titled compound (12.8 mg) as a white solid.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[CH2:17][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([OH:16])[C:10]=3[C:8](=[O:9])[C:4]2=[C:5]([OH:7])[CH:6]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>C1(C)C=CC=CC=1>[OH:16][C:15]1[C:10]2[C:8](=[O:9])[C:4]3[C:3](=[CH:2][CH:1]=[CH:6][C:5]=3[OH:7])[CH:17]([C:24](=[O:27])[CH2:25][CH3:26])[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: O=C1c2c(O)cccc2Cc2cccc(O)c21
Reactant: CCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCC(=O)C1c2cccc(O)c2C(=O)c2c(O)cccc21
Temperature: 85 °C

Procedure:
To a suspension of 56.6 g (0.25 mole) of purified anthralin in 1750 cm3 of anhydrous toluene, there are added at ambient temperature 27.3 cm3 of anhydrous pyridine (0.34 mole) and then, slowly, over about a 20 minute period, 26.2 cm3 of propionyl chloride (0.3 mole) are added. The mixture is then heated to 85° C. for about 1 hour. After return to ambient temperature, there are added to the reaction mixture 27.3 cm3 of pyridine and 26.2 cm3 of propionyl chloride. This mixture is then heated for 1 hour at a temperature of about 85° C.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[H-].[Na+].CS(C)=O.C[O:13][C:14](=O)[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][CH2:24][CH3:25])=[C:17]([O:26][CH3:27])[CH:16]=1>O.C(O)(=O)C>[CH2:24]([NH:23][C:18]1[C:19]([O:21][CH3:22])=[CH:20][C:15]([C:14](=[O:13])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])=[CH:16][C:17]=1[O:26][CH3:27])[CH3:25]
Reactant: CS(C)(=O)=O
Reactant: CCNc1c(OC)cc(C(=O)OC)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: CCNc1c(OC)cc(C(=O)CS(C)(=O)=O)cc1OC
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A suspension of 58.4 g. of dimethylsulfone and 21.1 g. of sodium hydride (50% dispersion in oil) in 200 ml. of absolute dimethylsulfoxide was stirred at 50° C. under an atmosphere of nitrogen and the exclusion of moisture for a period of 4 hours. Then, 42.6 g. of 4-(ethylamino)-3,5-dimethoxy-benzoic acid methyl ester were added. The resulting mixture was stirred at 80° C. for 10 minutes and subsequently dissolved in 1 liter of water. The solution was neutralized with glacial acetic acid. The precipitate was removed by filtration with suction, washed with water, dried and recrystallized from ethyl acetate, whereby there was obtained 4'-(ethylamino)-3',5'-dimethoxy-2-(methylsulfonyl)-acetophenone having a melting point of 129°-130° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@:5]1([CH3:31])[C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1.COC[C@@H]1[C@@H](C=O)[C@@]1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1>>[CH3:1][O:2][CH2:3][C@@H:4]1[C@@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@:5]1([CH3:31])[C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1
Reactant: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@@H](COC)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: COC[C@@H]1[C@@H](C=O)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCOC(=O)/C=C(C)/C=C/[C@@H]1[C@@H](COC)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 75 %

Procedure:
Following a procedure similar to that for the preparation of Compound 16a but using Intermediate 15a as the starting material afforded the title compound (34 mg, 75% yield) as a white solid:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]2=3)(=[O:10])=[O:9])=[CH:4][C:3]=1[NH2:22].[NH2:23][C:24](N)=[O:25].CCOCC>ClCCCl.CC(O)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]2=3)(=[O:9])=[O:10])=[CH:4][C:3]=1[NH:22][C:24]([NH2:23])=[O:25]
Reactant: NC(N)=O
Reactant: Nc1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOCC
Product: NC(=O)Nc1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 100 °C
Reaction time: 24 h
Yield: 44.8 %

Procedure:
To 2-chloro-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenylamine (3.4 g, 10 mmol) in DCE (20 mL) and HOAc (20 mL) was added urea (1.2 g, 20 mmol). The mixture was stirred at 100° C. for 24 hrs and was then partitioned between DCM (150 mL) and sat. NaHCO3 solution (150 mL). Additional solid NaHCO3 was added until the aqueous layer pH value was 8. The organic layer was separated, washed with saturated NaHCO3 and brine, dried over MgSO4 and evaporated to obtain a yellow oil. The oil was re-dissolved in DCM (10 mL) and ether (50 mL) and stood at rt for 12 hrs to give [2-chloro-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-urea (1.7 g) as a white solid. MS: 379.7 (M+H)+; tR=6.67 min (method 2).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]#[C:13][Si](C)(C)C)=[N:10][CH:11]=2)[CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]#[CH:13])=[N:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)C#Cc1ccc(OCC2CC2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(OCC2CC2)cn1
Yield: 108.3 %

Procedure:
To a solution of 5-(cyclopropylmethoxy)-2-[(trimethylsilyl)ethynyl]pyridine (773 mg) in THF (15 mL) was added a THF solution (1.0 M, 4.1 mL) of tetrabutylammonium fluoride at room temperature, and the reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate and water, and the aqueous layer was separated from the organic layer. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a colorless oil (591 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[OH:14])([O-])=O>[C].[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[C:5]=1[OH:14]
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1O
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.5 %

Procedure:
A 10% palladium carbon catalyst (1.0 g) was added to a solution of the resulting nitro compound (2.0 g, 9.65 mmol) in ethanol (60 ml) and the mixture was stirred under hydrogen atmosphere at room temperature for 5 hours. After completion of the reaction, the reaction solution was filtered off through celite and the filtrate was concentrated to provide 1.70 g (yield 99%) of 2-amino-6-trifluoromethylphenol as pale yellow crystals.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:17]2[CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][CH2:22][CH2:23][Cl:24].[OH-].[Na+].O>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:21][CH2:22][CH2:23][Cl:24])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:17]2[CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCCBr
Reactant: CC(C)(C)c1nc(C2CC2)cc(N2CCNCC2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1nc(C2CC2)cc(N2CCN(CCCCl)CC2)n1
Yield: 62 %

Procedure:
19.2 g of 2-tert-butyl-4-piperazin-1-yl-6-cyclopropyl-pyrimidine (73.7 mmol) were dissolved in 50 ml of toluene. 14.6 ml of 1-bromo-3-chloropropane (147.4 mmol) and 3.4 g of sodium hydroxide (84.7 mmol) were added, followed by dropwise addition of 0.95 g of tetrabutylammonium bromide (2.95 mmol, dissolved in water). After stirring for 5 h at 60° C. additional 1-bromo-3-chloropropane was added to drive the reaction to completion. The reaction mixture was cooled, water was added and the product extracted 3 times with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated. The crude product was purified by chromatography on silica gel using dichloromethane/ethyl acetate (9:1). Fractions containing the product were combined, the solvent was evaporated to yield 15.4 g of the title compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[CH3:16][O:17][C:18]([C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH3:29])=[CH:25][NH:26]2)=[CH:22][CH:21]=1)=[O:19].O>C(Cl)Cl>[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([C:25]1[NH:26][C:27]2[C:23]([C:24]=1[CH3:29])=[CH:22][CH:21]=[C:20]([C:18]([O:17][CH3:16])=[O:19])[CH:28]=2)=[O:9]
Reactant: COC(=O)c1ccc2c(C)c[nH]c2c1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc2c(C)c(C(=O)c3ccc(Cl)cc3Cl)[nH]c2c1
Reaction time: 2.5 h
Yield: 77.3 %

Procedure:
Aluminium chloride (1.72 g) is suspended in methylene chloride (50 ml), to which are added 2,4-dichlorobenzoyl chloride (1.35 g) and then 6-(methoxycarbonyl)-3-methylindole (1.00 g), and stirred at room temperature for 16 hours and then at 40° C. for 2.5 hours. The reaction mixture is poured into water with ice, and then extracted with ethyl acetate (150 ml). The organic layer is washed three times with a saturated aqueous sodium hydrogencarbonate solution (50 ml) and then with a saturated saline solution, and thereafter dried with anhydrous sodium sulfate. The drying agent is removed through filtration, and the filtrate is concentrated under reduced pressure. The resulting crystal is washed with methyl t-butyl ether and dried to obtain 2-(2,4-dichlorobenzoyl)-6-(methoxycarbonyl)-3-methylindole (71) (1.48 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:6]([OH:15])[C:5](Br)=[CH:4][CH:3]=1.[CH:17]([C:19]1[O:20][CH:21]=[CH:22][C:23]=1B1OC(C)(C)C(C)(C)O1)=[O:18].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:1][C:2]1[C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:6]([OH:15])[C:5]([C:23]2[CH:22]=[CH:21][O:20][C:19]=2[CH:17]=[O:18])=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccoc2C=O)OC1(C)C
Reactant: CC(C)(C)OC(=O)c1c(N)ccc(Br)c1O
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)c1c(N)ccc(-c2ccoc2C=O)c1O
Temperature: 70 °C
Yield: 69.9 %

Procedure:
A mixture of tert-butyl 6-amino-3-bromo-2-hydroxybenzoate (Intermediate 62, 1.16 g), 2-formylfuran-3-boronic acid pinacol ester (1.073 g), tris-(dibenzylideneacetone)dipalladium (0.184 g), tri-tert-butylphosphonium tetrafluoroborate (0.117 g) and cesium carbonate (3.935 g) was suspended in dioxane (40 mL) and water (5 mL). The mixture was de-gassed and flushed with nitrogen then heated at 70° C. for 3 hours. After cooling, the mixture was concentrated in vacuo. The residue was partitioned between water and ethyl acetate and the combined organic layers were dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 2.5-25% to give tert-butyl 6-amino-3-(2-formylfuran-3-yl)-2-hydroxybenzoate (0.854 g) as a yellow oil.