Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:53])[C:7]([O:10]/[N:11]=[C:12](/[C:40]1[N:41]=[C:42]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[S:43][CH:44]=1)\[C:13]([NH:15][C@@H:16]1[C:23](=[O:24])[N:22]2[C@@H:17]1[S:18](=[O:39])[CH2:19][C:20]([CH2:37]Cl)=[C:21]2[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[I-:54].[Na+]>CC(C)=O>[C:1]([O:5][C:6](=[O:53])[C:7]([O:10]/[N:11]=[C:12](/[C:40]1[N:41]=[C:42]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[S:43][CH:44]=1)\[C:13]([NH:15][C@@H:16]1[C:23](=[O:24])[N:22]2[C@@H:17]1[S:18](=[O:39])[CH2:19][C:20]([CH2:37][I:54])=[C:21]2[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:26])=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS(=O)[C@@H]3[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N23)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(CI)CS(=O)[C@@H]3[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(=O)OC(C)(C)C)n4)C(=O)N23)cc1
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a solution of (6R,7R)-4-methoxybenzyl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 5-oxide (10.00 g, 12.56 mmol) in Acetone (100 mL) at rt was added sodium iodide (2.82 g, 18.84 mmol). The mixture was stirred at the same temperature over 2 h. LCMS indicated completion of the reaction. The solid was filtered off, the filtrate was concentrated under vacuum, and the residue was purified by Combiflash automated silica gel chromatography (120 g Gold column), eluting with ethyl acetate/hexanes (0-50%) to afford (6R,7R)-4-methoxybenzyl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxy carbonyl)amino)thiazol-4-yl)acetamido)-3-(iodomethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 5-oxide (10.86 g, 12.23 mmol, 97% yield) as a yellow solid. LCMS: (M+H)+: 887.9.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[C:22]([CH:23]=O)=[CH:21][C:11]3[C:12]([C:15]4[N:19]([CH3:20])[N:18]=[CH:17][N:16]=4)=[N:13][O:14][C:10]=3[C:9]=2[F:25])[CH2:5][C@@H:4]([CH3:26])[O:3]1.[NH:27]1[C:32](=[O:33])[CH2:31][C:30](=[O:34])[NH:29][C:28]1=[O:35]>CO>[F:25][C:9]1[C:10]2[O:14][N:13]=[C:12]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][N:16]=3)[C:11]=2[CH:21]=[C:22]2[C:8]=1[N:6]1[CH2:5][C@@H:4]([CH3:26])[O:3][C@@H:2]([CH3:1])[C@@H:7]1[C:31]1([C:30](=[O:34])[NH:29][C:28](=[O:35])[NH:27][C:32]1=[O:33])[CH2:23]2
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(-c4ncnn4C)noc3c2F)C[C@@H](C)O1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CO
Product: C[C@@H]1CN2c3c(cc4c(-c5ncnn5C)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 150 °C

Procedure:
A mixture of 6-((2R,6R)-2,6-dimethylmorpholino)-7-fluoro-3-(1-methyl-1H-1,2,4-triazol-5-yl)benzo[d]isoxazole-5-carbaldehyde (Intermediate 537, 124 mg, 0.35 mmol) and pyrimidine-2,4,6(1H,3H,5H)-trione (44.2 mg, 0.35 mmol) in methanol (3 ml) was heated at 150° C. for 1 hour in a microwave reactor. Solvent was removed and the residue was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% TFA). The solid was taken up in 9:1 CH2Cl2— MeOH and washed with NaHCO3 and brine. The aqueous layers were repeatedly extracted with additional 9:1 CH2Cl2-MeOH with each extract being washed with brine. The combined organic layers were dried (MgSO4) and concentrated and the residue was dissolved in THF. After removal of solvent, the solid residue was dried in vacuo at 50° C. overnight to afford desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Cl:14][C:15]1[C:23]2[CH2:22][CH2:21][NH:20][CH:19]([CH3:24])[C:18]=2[O:17][CH:16]=1>>[Cl:14][C:15]1[C:23]2[CH2:22][CH2:21][N:20]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH:19]([CH3:24])[C:18]=2[O:17][CH:16]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2c(Cl)coc21
Product: CC1c2occ(Cl)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-chloro-7-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridine to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10]O)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Cl:13][CH2:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1cc(F)cc(CO)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(F)cc(CCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
To a solution of (3-fluoro-5-methoxyphenyl)methanol (4.9 g, 30 mmol) in CCl4 (50 mL), PCl5 (13 g, 60 mmol) was added. The mixture was stirred at room temperature for 1 h. To this mixture, saturated Na2CO3 solution was slowly added until pH was adjusted to 7˜8. The mixture was extracted with DCM (3×15 mL), and the organic phase was concentrated to give a colorless oil, which was purified by silica-gel column chromatography (100% petroleum ether) to give 2.9 g of 1-(chloromethyl)-3-fluoro-5-methoxybenzene. 1H NMR (CDCl3): δ 6.68-6.72 (m, 2H), 6.54-6.59 (m, 1H), 4.51 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccncc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc(-c2ccncc2)cc1
Temperature: 80 °C
Yield: 60 %

Procedure:
This Example was carried out in the same manner as Example 1, except that 5.0 g (0.032 mol) of 4-chloro-phenyl boronic acid, 10.0 g (0.064 mol) of 4-bromopyridine, 150□ of tetrahydrofuran and 2M potassium carbonate solution (20□) were added and then 0.37 g (3 mol %) of palladium tetrakistriphenylphosphine [(pd(PPh3)4] was used as a catalyst. Finally, after the resulting solution was heated to reflux at 80° C. for 24 hours, the 4-(4-chloro-phenyl)pyridine was isolated. The yield was 60%.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][N:8]([CH:18]1[CH:23]([CH3:24])[CH2:22][CH2:21][NH:20][CH2:19]1)[C:9]1[C:10]2[CH:17]=[CH:16][NH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>ClCCl>[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([N:20]2[CH2:21][CH2:22][CH:23]([CH3:24])[CH:18]([N:8]([CH3:7])[C:9]3[C:10]4[CH:17]=[CH:16][NH:15][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:19]2)(=[O:35])=[O:34])=[CH:31][CH:32]=1
Reactant: CC1CCNCC1N(C)c1ncnc2[nH]ccc12
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N2CCC(C)C(N(C)c3ncnc4[nH]ccc34)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
To a stirred solution of 1 mL of pyridine and 9 ml of dichloromethane was added 40 mg (0.163 mmol) of the product from Method H and 20 L of 4-methoxy-benzenesulfonyl chloride and the resulting mixture stirred at room temperature for 18 hours. The reaction was then quenched upon addition of saturated NaHCO3 (aq), the organic layer was removed and the aqueous layer extracted with dichloromethane. The dichloromethane layer was dried over Na2SO4 and concentrated to dryness in vacuo. The residue was purified by PTLC (silica; 10:1 dichloromethane/methanol) affording 22 mg (32%) of the title compound as a light yellow solid. LRMS: 416.5 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[CH3:29])[N:22]([CH3:30])[CH:21]=2)[C:11]1=[O:31].Cl>O1CCOCC1.O>[CH3:30][N:22]1[C:23]2[C:28](=[C:27]([CH3:29])[CH:26]=[CH:25][CH:24]=2)[C:20]([CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:32])=[O:2])[C:11]2=[O:31])=[CH:21]1
Reactant: COC(=O)c1ccccc1-n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc2c1c(Cn1c(=O)n(-c3ccccc3C(=O)O)c3ccccc31)cn2C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
To a solution of 2-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-benzoic acid methyl ester (45 mg, 0.11 mmol) in 1,4-dioxane (1.0 mL) is added LiOH monohydrate (5.6 mg, 0.13 mmol) in water (0.1 mL) at room temperature. The solution is stirred at the same temperature for 16 hours. Then another 1.0 mg of LiOH monohydrate is added and the reaction is continued for another 2 hr. Then 0.5 mL of 1.0 M HCl is added along with 10 mL of water. The mixture is extracted with EtOAc (3×15 mL) and the organic layers are combined, dried and concentrated to give crude product. Purification by preparative TLC affords 41 mg (95%) of 2-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-benzoic acid. LCMS (ESMS): m/z 412.17 (M+H+).
Reaction SMILES: O.C(O[C:7]([CH2:9][O:10][C:11]1[C:16]([N+:17]([O-])=O)=[CH:15][C:14]([C:20]2[C:21](=[O:31])[N:22]([CH3:30])[C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][N:25]=2)=[C:13]([F:32])[CH:12]=1)=[O:8])CCC>C(OCC)(=O)C.C(O)(=O)C.[Fe]>[F:32][C:13]1[C:14]([C:20]2[C:21](=[O:31])[N:22]([CH3:30])[C:23]([C:26]([F:27])([F:29])[F:28])=[CH:24][N:25]=2)=[CH:15][C:16]2[NH:17][C:7](=[O:8])[CH2:9][O:10][C:11]=2[CH:12]=1
Reactant: CCCCOC(=O)COc1cc(F)c(-c2ncc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cnc(-c2cc3c(cc2F)OCC(=O)N3)c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
Then, 2.8 g of iron powder was added to a mixture of 5 ml of acetic acid and 50 ml of water, and the mixture was heated to 50° C. To this was slowly added dropwise a solution of 2.8 g of 3-[4-(butoxycarbonylmethoxy)-2-fluoro-5-nitrophenyl]-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (the present compound obtained in step (3) above) in 25 ml of ethyl acetate and 25 ml of acetic acid. The mixture was stirred at an internal temperature of 60° to 70° C. for 1 hour. After completion of the reaction, the reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium hydrogencarbonate solution, water, and saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated, which afforded 1.22 g of 3-(7-fluoro-3-oxo-2H-1,4-benzoxazin-6-yl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 2-49; m.p., 182.5° C.).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[C:12]([O:16][C:17](=[O:42])[NH:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:29]2[N:28]=[CH:27][C:26]3[N:32]=[C:33]([CH2:38][O:39][CH2:40][CH3:41])[N:34]([CH2:35][CH2:36][CH3:37])[C:25]=3[C:24]=2[CH:23]=1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:40]([O:39][CH2:38][C:33]1[N:34]([CH2:35][CH2:36][CH3:37])[C:25]2[C:24]3[CH:23]=[C:22]([O:21][CH2:20][CH2:19][NH:18][C:17](=[O:42])[O:16][C:12]([CH3:13])([CH3:14])[CH3:15])[CH:31]=[CH:30][C:29]=3[N+:28]([O-:9])=[CH:27][C:26]=2[N:32]=1)[CH3:41]
Reactant: CCCn1c(COCC)nc2cnc3ccc(OCCNC(=O)OC(C)(C)C)cc3c21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCn1c(COCC)nc2c[n+]([O-])c3ccc(OCCNC(=O)OC(C)(C)C)cc3c21
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
mCPBA (60% pure, 12.76 g, 44.36 mmol) was added in one portion to a solution of tert-butyl[2-(2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-yloxy)ethyl]carbamate (14.4 g, 33.6 mmol) and chloroform (150 mL); the reaction mixture was stirred for 30 minutes. The reaction mixture was then poured into saturated aqueous sodium carbonate (100 mL) and stirred for 30 minutes. Chloroform (250 mL) was added, and the organic fraction was washed sequentially with 5% aqueous sodium carbonate, water, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure. The resulting red oil was triturated with ethyl acetate to provide 9.7 g of tert-butyl 2-[(2-ethoxymethyl-5-oxido-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl)oxy]ethylcarbamate as a peach-colored powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[I:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O.OOS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O.CCOC(C)=O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:23]1[C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[I:20])([CH3:16])([CH3:18])[CH3:17]
Reactant: O=Cc1ccccc1I
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)n1c(-c2ccccc2I)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.4 %

Procedure:
To a round bottom flask are added 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (430 mg, 1.67 mmol) in DMF (10 mL) and water (3 mL), followed by the addition of 2-iodobenzaldehyde (445 mg, 1.92 mmol) and oxone (1180 mg, 1.92 mmol). The reaction mixture is stirred at room temperature for 1 hour. Saturated sodium thiosulfate (10 mL) is added. The reaction mixture is diluted with EtOAc (50 mL). The organic layer is washed with water, brine, dried under anhydrous Na2SO4, filtered and concentrated. The residue is purified by silica gel flash column chromatography with 0-5% MeOH/CH2Cl2 as the eluent. The product fractions are collected and concentrated to afford 5-[1-tert-butyl-2-(2-iodo-phenyl)-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine (270 mg, 34%) as a light brown solid. LCMS (ESMS): m/z 470.58 (M++1)
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:19])[C:6](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][O:8]C(=O)C>CO.O>[CH:12](=[C:6]([CH2:7][OH:8])[C:5]([OH:19])=[O:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)C(=Cc1ccccc1)COC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(=Cc1ccccc1)CO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product (143.9 g) in Reference Example 2, namely 2-benzylidene-3-acetoxypropionate methyl ester, is dissolved in methanol (400 ml), followed by addition of an aqueous solution of sodium hydroxide (96.0 g; 2.40 mol; purity of 97%) in water (800 ml). The resulting mixture is stirred at ambient temperature for 90 minutes. The reaction solution is concentrated under reduced pressure to distill off methanol, followed by addition of water (100 ml) and 36% hydrochloric acid (250 ml) for adjusting the resulting mixture to neutrality and subsequent extraction into ethyl acetate (600 ml). The resulting organic phase is washed with saturated saline (300 ml). After filtering off insoluble matters, the resulting solution is concentrated under reduced pressure. To the resulting residue is added toluene (250 ml×4), and the mixture is concentrated under reduced pressure to remove acetic acid to give a crude product of the title compound (107.8 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:22][C:23]1[C:28](=[O:29])[CH:27]=[CH:26][NH:25][C:24]=1[CH3:30])[CH3:21].[CH2:31]([O:33][CH2:34][CH2:35]O)[CH3:32].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:20]([O:22][C:23]1[C:24]([CH3:30])=[N:25][CH:26]=[CH:27][C:28]=1[O:29][CH2:32][CH2:31][O:33][CH2:34][CH3:35])[CH3:21]
Reactant: CCOc1c(C)[nH]ccc1=O
Reactant: CCOCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOCCOc1ccnc(C)c1OCC
Yield: 43.9 %

Procedure:
Triphenylphosphine (2.93 g, 11.2 mmol) was added to a stirred solution of 3-ethoxy-2-methylpyridin-4(1H)-one (1.42 g, 9.3 mmol, obtained from Example 4(b)) in THF (15 mL). 2-Ethoxy ethanol (2.93 g, 11.2 mmol) was added dropwise, followed by dropwise addition of DEAD (1.76 mL, 11.2 mmol). The reaction mixture was then stirred under reflux overnight. The solvent was evaporated in vacuo and the residue was dissolved in water (15 mL). The aqueous solution was adjusted to pH 1 with 2M hydrochloric acid, then extracted with ethyl acetate (3×20 mL). The combined organic phases were dried (MgSO4) and concentrated, and the crude product was purified by flash chromatography (CHCl3/MeOH; 9:1), giving the title compound (0.92 g, 44%).
Reaction SMILES: [CH:1]12[CH2:7][CH:6]1[CH2:5][CH2:4][C@H:3]([C:8]([O:10]CC)=[O:9])[N:2]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O1CCOCC1.O[Li].O>O>[C:16]([O:15][C:13]([N:2]1[CH:3]([C:8]([OH:10])=[O:9])[CH2:4][CH2:5][CH:6]2[CH:1]1[CH2:7]2)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)[C@H]1CCC2CC2N1C(=O)OC(C)(C)C
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1C(C(=O)O)CCC2CC21
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.2 %

Procedure:
(3R)-2-tert-butyl 3-ethyl 2-azabicyclo[4.1.0]heptane-2,3-dicarboxylate (D21) (600 mg, 2.22 mmol) was partitioned between dioxane (10 ml) and water (5 ml) prior addition of LiOH H2O (370 mg, 8.9 mmol). The mixture was stirred at RT for 18 hrs. Water (10 ml) and LiOH H2O (740 mg, 18 mmol) were added and the mixture left at RT for 66 h. Dioxane was evaporated off and remaining aqueous was washed with Et2O (3×20 ml). Aqueous solution was acidified with acetic acid up to pH 4 and extracted with EtOAc (3×30 ml). Collected organics were washed with NaCl sat., dried over Na2SO4 and evaporated in vacuo to afford the title compound (D22) (210 mg).
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:32]3[C:31](=[O:33])[NH:30][C:29]([C:34]([O:36]CC)=O)=[N:28][C:27]=3[S:26][CH:25]=2)=[CH:20][CH:19]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:82]2[CH:86]=[N:85][C:84]([O:87][CH2:88][CH2:89][O:90][C:91]3[CH:92]=[C:93]([CH2:97][NH2:98])[CH:94]=[CH:95][CH:96]=3)=[N:83]2)C=CC=CC=1>>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:32]3[C:31](=[O:33])[NH:30][C:29]([C:34]([NH:98][CH2:97][C:93]4[CH:94]=[CH:95][CH:96]=[C:91]([O:90][CH2:89][CH2:88][O:87][C:84]5[N:85]=[CH:86][NH:82][N:83]=5)[CH:92]=4)=[O:36])=[N:28][C:27]=3[S:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2scc(-c3ccc(Br)cc3)c2c(=O)[nH]1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: O=C(NCc1cccc(OCCOc2nc[nH]n2)c1)c1nc2scc(-c3ccc(Br)cc3)c2c(=O)[nH]1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-(4-bromophenyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 79 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (147.7 mg, 71%).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[H-].[Na+].O>C(Cl)(Cl)Cl>[CH2:26]([NH:33][CH2:11][CH:12]1[S:24][C:16]2=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]2[CH2:14][CH2:13]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: c1ccc(CNCC2CCn3c(nc4ccccc43)S2)cc1
Yield: 31.3 %

Procedure:
To a solution of 1.12 g of 3,4-dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole in chloroform (20 ml) was added with 0.41 g of benzylamine and a catalytic amount of sodium hydride, and refluxed for 11 hours. The reaction mixture was cooled and then condensed under reduced pressure. Theresidue was added with water, extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure. The residue was chromatographed on silica gel and eluted with chloroform to obtain 0.29 g (Yield: 31%) of theintended product, m.p. 155°-156° C.; IR νmaxKBr cm-1 : 3260, 3100-2800, 1600, 1420; Anal. Calcd. for C18H19N3S: C, 69.87; H, 6.19; N, 13.58; S, 10.36; Found: C, 70.00; H, 6.21; N, 13.69; S, 10.10.
Reaction SMILES: Br[C:2]1[C:3]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[N:4][N:5]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=12.[CH3:25][S:26][C:27]1[N:32]=[C:31]([Sn](CCCC)(CCCC)CCCC)[CH:30]=[CH:29][N:28]=1>O1CCOCC1.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.[Ag-]=O>[F:14][C:11]([F:12])([F:13])[C:9]1[CH:8]=[CH:7][C:6]2[N:5]([N:4]=[C:3]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=3)[C:2]=2[C:31]2[CH:30]=[CH:29][N:28]=[C:27]([S:26][CH3:25])[N:32]=2)[CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2nn3cc(C(F)(F)F)ccc3c2Br)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[Ag-]
Solvent: C1COCCO1
Product: CSc1nccc(-c2c(-c3ccc(C(F)(F)F)cc3)nn3cc(C(F)(F)F)ccc23)n1

Procedure:
A mixture of 3-bromo-6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridine (0.82 g), 2-(methylthio)-4-(tributylstannyl)pyrimidine (0.83 g), dichlorobis(triphenylphosphine)palladium (0.14 g) and silver (I) oxide (0.43 g) in 1,4-dioxane (10 mL) was heated to reflux for 18 h. The mixture was cooled, filtered and the filtrate concentrated to dryness. The residue was purified by chromatography eluting with an increasing gradient from cyclohexane to cyclohexane-diethylether (94:6) to give, after concentration to dryness of the appropriate fractions, the title compound as a cream solid (0.46 g); 1H NMR (d6-DMSO) δ 9.58(1H, s), 8.50(1H, d), 8.46(1H, d), 7.90(2H, d), 7.84 (2H, d), 7.82(1H, dd), 6.94(1H, d), 2.43(3H, s); m/z 455 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[CH:11]([CH3:13])[CH3:12].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]=[C:21]=[O:22])[CH:15]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:21](=[O:22])[NH:20][C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[CH:11]([CH3:13])[CH3:12]
Reactant: O=C=Nc1cccnc1
Reactant: CC(C)c1cc2c(cc1Cl)NCC2
Product: CC(C)c1cc2c(cc1Cl)N(C(=O)Nc1cccnc1)CC2
Yield: 57 %

Procedure:
6-Chloro-5-isopropylindoline (D58) (0.4 g, 2.05 mmol) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The product was recrystallised from ethanol/diethyl ether to give the title compound (0.36 g, 57%) as a white crystalline solid m.p.=183°-185° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]2[C:25]([I:26])=[CH:24][C:19]3[C:20](=[O:23])[O:21][CH2:22][C:18]=3[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27].CC1C2COC(=O)C=2C=CC=1CCN1CCNCC1>O1CCOCC1>[ClH:27].[I:26][C:25]1[C:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:17][C:18]2[CH2:22][O:21][C:20](=[O:23])[C:19]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2cc3c(cc2I)C(=O)OC3)CC1
Agent: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C1OCc2cc(CCN3CCNCC3)c(I)cc21

Procedure:
6-Iodo-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride was prepared from tert-butyl-4-[2-(6-iodo-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate using 4N HCl in dioxane in an analogous fashion to that described for the synthesis of 4-methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride above. LC-MS (IE, m/z): 373 [M+1]+.