Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[N+:16]([O-:18])=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:6]=1.C(O)(=O)C.CS(C)=O.[BH4-].[Na+]>O>[CH3:1][C:2]1[O:3][C:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N+:16]([O-:18])=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(Cc2ccc(/C=C/[N+](=O)[O-])cc2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: Cc1ccc(Cc2ccc(CC[N+](=O)[O-])cc2)o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.4 %

Procedure:
To a mixture of 2-methyl-5-(4-((E)-2-nitro-vinyl)-benzyl)-furan (120 mg) described in Manufacturing Example 46-1-4, acetic acid (0.2 mL) and dimethyl sulfoxide (3.4 mL) was added sodium borohydride (29 mg, 0.77 mmol) at room temperature while cooling appropriately, which was stirred for 20 minutes at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by neutral silica gel column chromatography (ethyl acetate:heptane=1:5) to obtain the title compound (90 mg, 77%).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[C:5]([NH2:13])[NH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:20](OC)(=[O:23])[C:21]#[CH:22]>CCO>[NH2:13][C:5]1[C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[C:2]2[NH:1][C:20](=[O:23])[CH:21]=[CH:22][N:3]2[N:4]=1
Reactant: C#CC(=O)OC
Reactant: C=CCOC(=O)c1c(N)n[nH]c1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: C=CCOC(=O)c1c(N)nn2ccc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
To a mixture of allyl 3,5-diamino-1H-pyrazole-4-carboxylate 3 (1 g, 5.489 mmol) and Cs2CO3 (2.504 g, 7.685 mmol) in EtOH (10 mL) was added methyl prop-2-ynoate (553.8 mg, 586.0 μL, 6.587 mmol), dropwise, over 15 minutes. The reaction mixture was stirred overnight at room temperature. The deep red reaction mixture was then filtered, washing through with a small amount of ethanol. The filtrate was cooled on an ice-bath and ether (100 ml) was slowly added; the mixture stirred at 0° C. for 20 mins. A yellow solid precipitated out of solution and was filtered off to afford a solid which was triturated in ether and filtered (3 cycles) to yield pure product as a yellow solid (yield 54%) LC-MS (M+H)+=235.1
Reaction SMILES: [CH2:1]([N:3]([CH2:5][C:6]1[S:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=2)[NH:16][CH:15]=[C:14]3[CH:23]2[CH2:28][CH2:27][N:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[CH2:25][CH2:24]2)[CH:7]=1)[CH3:4])[CH3:2].[CH2:34](C1CCCN1)CC>>[CH2:32]([S:29]([N:26]1[CH2:27][CH2:28][CH:23]([C:14]2[C:13]3[C:17](=[C:18]([C:20]([NH2:22])=[O:21])[CH:19]=[C:11]([C:8]4[CH:7]=[C:6]([CH2:5][N:3]([CH3:4])[CH2:1][CH2:2][CH3:34])[S:10][CH:9]=4)[CH:12]=3)[NH:16][CH:15]=2)[CH2:24][CH2:25]1)(=[O:30])=[O:31])[CH3:33]
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Reactant: CCCC1CCCN1
Product: CCCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Yield: 63.7 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, substituting methyl(propyl)amine (73 mg, 1.0 mmol) for 2-propylpyrrolidine to afford 32.0 mg of the title compound (63.7%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6].[CH2:12]1COCC1.C[Mg+].[Br-]>CCOCC>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]([OH:6])[CH3:12]
Reactant: O=Cc1cc(F)cc(Br)c1F
Reactant: C1CCOC1
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CC(O)c1cc(F)cc(Br)c1F
Reaction time: 1 h

Procedure:
To a stirred mixture of 13.3 g of 3-bromo-2,5-difluorobenzaldehyde and 300 mL of THF cooled to -35°/-20° under an N2 atmosphere is added 30 mL of 2.85M of MeMgBr in Et2O over 10 minutes. The cooling bath is removed and the mixture stirred 1 hour and finally poured into 1 L of ice/H2O. 10% HCl is added to bring the pH to ~2 and the mixture extracted with 3×200 ml of CH2Cl2. The CH2Cl2 extracts are washed with H2O, saturated NaHCO3, H2O (250 mL each) and stripped to furnish 14.5 g of crude 3-bromo-2,5-difluoro-α-methylbenzyl alcohol. M+1 ions are observed at 236 and 238 in the mass spectrum. The crude material is used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]=[C:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])[CH:3]=1.C1(C)C(C)=CC=CC=1>C(O)(C(F)(F)F)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:11](=[O:15])[C:10]([CH2:14][CH2:13][OH:12])=[CH:9][N:8]=[C:4]2[CH:3]=1
Reactant: O=C1OCCC1=CNc1cc(Br)ccn1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1C
Product: O=c1c(CCO)cnc2cc(Br)ccn12
Temperature: 85 °C

Procedure:
In a small flask, 3-((4-bromopyridin-2-ylamino)methylene)dihydrofuran-2(3H)-one (250 mg, 0.93 mmol) and CF3COOH (8 drops) was added into a solution of xylene. The suspension was warmed to 85° C. and maintained at that temperature for 30 min. After the upper layer of suspension was poured out, the residue was diluted with water (30 mL) and adjusted to pH 8. Then the mixture was extracted with ethyl acetate (3×50 mL). The organic layer was dried over Na2SO4 and concentrated to give the crude product, which was purified by column chromatography. MS (ESI): 269, 271 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[CH:6][CH:7]=1.[Cl:11][C:12]1[C:13]([C:18](O)=O)=[N:14][CH:15]=[CH:16][CH:17]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[Cl:11][C:12]1[C:13]([C:18]2[N:8]([CH3:9])[C:5]3[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=3[N:10]=2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: CNc1ccc(I)cc1N
Reactant: O=C(O)c1ncccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: Cn1c(-c2ncccc2Cl)nc2cc(I)ccc21
Temperature: 100 °C
Reaction time: 12 h
Yield: 73.4 %

Procedure:
A mixture of 4-iodo-N1-methyl-benzene-1,2-diamine (850 mg), 3-chloro-pyridin-2-carboxylic acid (590 mg), WSC (790 mg), HOBt (46 mg), and pyridine (10 ml) was stirred at 100° C. for 12 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2-(3-chloro-pyridin-2-yl)-5-iodo-1-methyl-1H-benzimidazole (930 mg), which is hereinafter referred to as “intermediate compound (M6-21)”.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:35])[C@H:20]2[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([SH:47])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:52][NH:51][C:50]1=[O:53])=[O:41])[CH:37]=[CH2:38].C(N(CC)C(C)C)(C)C>>[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47][C:18]2[C@H:19]([CH3:35])[C@@H:20]3[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]3[C:22]=2[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH2:44][C@H:43]1[CH2:48][CH:49]1[CH2:52][NH:51][C:50]1=[O:53])=[O:41])[CH:37]=[CH2:38]
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CC1CNC1=O
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@H]2[C@@H]([C@@H](C)O)C(=O)N12
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC3CNC3=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 36.4 %

Procedure:
The same procedure as in Example 8-1 was carried out by using allyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (331 mg, 0.66 mmol), (2R,4S)-N-allyloxycarbonyl-2-(2-azetidinon-3-ylmethyl)-4-mercaptopyrrolidine (180 mg, 0.66 mmol) and N,N-diisopropylethylamine (0.12 ml, 0.66 mmol) to obtain allyl (1R,5S,6S)-2-[(2R,4S)-N-allyloxycarbonyl-2-(2-azetidinon-3-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (125 mg, yield: 36.3%) in the form of foam.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:33])[NH:29][CH:30]([CH3:32])[CH3:31])[CH:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:33])[NH:29][CH:30]([CH3:31])[CH3:32])[CH:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: CC(C)NC(=O)c1cccc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)c1cccc(-c2cnc3[nH]cc(C(=O)N[C@H](C)C(=O)N4CC(C#N)C4)c3n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
To a solution of 2-(3-isopropylcarbamoyl-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (52 mg, 0.088 mmol) in CH2Cl2 (4 mL) was added TFA (1.5 mL). The reaction mixture was stirred at room temp for 3 h then concentrated. The residue was redissolved in CH2Cl2 (4 mL) and ethylenediamine (0.5 mL) was added. The reaction mixture was stirred at room temp for 0.5 h then concentrated. The residue was purified by silica gel chromatography (50% to 100% EtOAc/hexanes to 5% MeOH) then triturated with Et2O to isolate 30 mg (70%) of 2-(3-isopropylcarbamoyl-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a white powder. MS: (M+H)+=460.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[C:16]([Cl:18])[C:15]([Cl:19])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=C(C)C(C)=C[C:29]=1[C:30]([OH:32])=[O:31])(=O)C1C=CC=CC=1>>[Cl:18][C:16]1[CH:17]=[C:9]2[C:10](=[CH:14][C:15]=1[Cl:19])[C:11](=[O:12])[O:13][C:29]([C:30]([OH:32])=[O:31])=[C:1]2[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1C(=O)c1ccccc1
Reactant: Cc1cc(C(=O)O)c(C(=O)c2ccccc2)cc1C
Product: O=C(O)c1oc(=O)c2cc(Cl)c(Cl)cc2c1-c1ccccc1

Procedure:
Using 2-benzoyl-4,5-dichlorobenzoic acid in lieu of 2-benzoyl-4,5-dimethylbenzoic acid, the procedure of Step 1 of Reference Example 1 was otherwise repeated to provide 6,7-dichloro-4-phenylisocoumarin-3-carboxylic acid [m.p. 243°-244° C. (recrystallized from ethyl acetate-isopropyl ether)]. This compound was reacted and treated in the same manner as in Step 2 of Reference Example 1 to provide the title compound as colorless crystals.
Reaction SMILES: OCC(CO)(C)C[O:5][C:6](=[O:28])[CH2:7][C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[CH:21]=3)[N:14]=2)=[CH:11][CH:12]=1.[OH-].[Na+]>C1COCC1>[OH:27][CH2:26][C:22]1[CH:21]=[C:20]([NH:19][C:15]2[N:14]=[C:13]([C:10]3[S:9][C:8]([CH2:7][C:6]([OH:28])=[O:5])=[CH:12][CH:11]=3)[CH:18]=[CH:17][N:16]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CC(CO)(CO)COC(=O)Cc1ccc(-c2ccnc(Nc3cccc(CO)c3)n2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-c2ccnc(Nc3cccc(CO)c3)n2)s1
Reaction time: 8 h
Yield: 90.6 %

Procedure:
{5-[2-(3-Hydroxymethyl-phenylamino)-pyrimidin-4-yl]-thiophen-2-yl}-acetic acid 3-hydroxy-2-hydroxymethyl-2-methyl-propyl ester (717 mg, 1.6 mmol) was dissolved in 30 mL of THF and 1N sodium hydroxide solution (3.5 mL, 3.5 mmol). The mixture was stirred overnight, quenched with acetic acid, and concentrated. The crude product was triturated with water to give 496 mg of {5-[2-(3-Hydroxymethyl-phenylamino)-pyrimidin-4-yl]-thiophen-2-yl}-acetic acid as an orange solid (1.45 mmol, 90%).
Reaction SMILES: [OH:1][CH:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:30])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1)=[O:6].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(OCC)C.[Na]>[O:1]=[C:2]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:30])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:27])([F:29])[F:28])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1)=[O:6]
Reactant: O=C(NCC(O)c1ccccc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(CNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)c1ccccc1
Reaction time: 2 h
Yield: 50.9 %

Procedure:
To a solution of 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl)amide (0.517 g, 1.03 mmol) in dichloromethane (10 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.53 g) was added in one portion under stirring in a cold water bath. After stirred in a cold water bath for 15 minutes and then at ambient temperature for 2 hours, the reaction mixture was diluted with diethyl ether (20 mL). The mixture was poured into a solution of sodium thiosulfate (1.176 g, 7.44 mmol) in saturated aqueous sodium biocarbonate (29 mL). The mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated aqueous NaHCO3 (2×15 mL) and water (2×15 mL). The combined aqueous washes were then extracted with ethyl acetate (2×80 mL). The combined organic phases were dried over Na2SO4 and filtered, the solvent was then removed in vacuo. The crude product was purified by column chromatography, which was sequentially eluted with hexane:ethyl acetate (1:1), hexane:ethyl acetate (1:2) and pure ethyl acetate. The product was obtained as a white powder (0.261 g, 51% yield). m.p. 196-198° C. 1H NMR (300 MHz, CDCl3) δ 8.72, 7.97-8.06, 7.74, 7.47-7.66, 7.36, 6.99, 4.96, 4.02-4.11, 3.70-3.92, 3.27-3.42. 13C NMR (CDCl3) δ 193.4, 167.7, 163.4, 160.0, 145.1, 134.6, 134.2, 134.0, 132.4, 129.6, 128.9, 128.0, 127.2, 126.9, 126.8, 112.3, 46.4, 44.7, 44.4, 41.3. MS (ES+) m/z 498 (M+1).
Reaction SMILES: [I-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7].[C:14](#[N:16])C>>[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6]([C:14]#[N:16])=[O:7]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CC#N
Agent: [I-]
Agent: [Na+]
Product: N#CC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The reaction was carried out under Argon. Cuprous cyanide (5.0 g, 56.0 mmol) and anhydrous sodium iodide (15.6 g, 104 mmol) were stirred for 2 minutes in anhydrous acetonitrile (100 ml). The resulting solution was mixed with 2,4-dichlorobenzoyl chloride (10.96 g, 52.3 mmol) whereupon an orange precipitate formed. The mixture was stirred for 30 minutes at room temperature, filtered and concentrated in vacuo. The residue was taken up in dichloromethane and the resulting precipitate was filtered off. Concentration of the filtrate under reduce pressure gave a yellow solid which was recrystallised from 60°-80° C. b.p.t. petroleum ether to give 2,4-dichlorobenzoyl cyanide as cream coloured crystals (8.36 g, 80%), melting point 73°-74° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[O:24][CH3:25].COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[OH:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:18][C:17]=1[O:24][CH3:25]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: COc1cc(C=O)ccc1O
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(O)c(OC)c3)nc2c1
Yield: 36 %

Procedure:
2-(4-Hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-hydroxy-3-methoxybenzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-Hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (90 mg, 36%) was isolated as a white solid. Selected data: MS (m/z): 329.06; MP 294-296° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([OH:26])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:46][N:47]([CH2:51][CH2:52]O)[CH2:48][C:49]#[CH:50]>C(Cl)Cl>[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:52][CH2:51][N:47]([CH3:46])[CH2:48][C:49]#[CH:50])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1
Reactant: C#CCN(C)CCO
Reactant: COc1cc2c(Cl)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C#CCN(C)CCOc1cc2ncnc(Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
Diethyl azodicarboxylate (0.297 g, 1.71 mmol) was added to a solution of 4-chloro-7-hydroxy-6-methoxyquinazoline (0.3 g, 1.42 mmol), (prepared as described for the starting material in Example 4), triphenylphosphine (0.485 g, 1.85 mmol) and 2-(N-methyl-N-prop-2-yn-1-ylamino)ethanol (0.177 g, 1.56 mmol) in methylene chloride (8 ml). The mixture was stirred for 2 hours at ambient temperature and poured onto a column of silica and eluted with increasingly polar mixtures of methylene chloride and ethyl acetate followed by ethyl acetate to give 4-chloro-6-methoxy-7-[2-(N-methyl-N-prop-2-yn-1-ylamino)ethoxy]quinazoline (0.341 g, 78%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1([C:43]2[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=2)[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[F:37])[C:24]([O:26]CC)=[O:25])[C:13]2[C:8](=[CH:9][C:10]([OH:42])=[CH:11][CH:12]=2)[S:7][CH2:6]1)[CH3:4].Cl>O.C(O)C>[CH2:3]([C:5]1([C:43]2[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=2)[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([F:41])([F:40])[C:36]([F:38])([F:37])[F:39])[C:24]([OH:26])=[O:25])[C:13]2[C:8](=[CH:9][C:10]([OH:42])=[CH:11][CH:12]=2)[S:7][CH2:6]1)[CH3:4]
Reactant: CCOC(=O)C(CCCCCCCCC1c2ccc(O)cc2SCC1(CC)c1ccc(O)cc1)CCCCCCC(F)(F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Yield: 89.9 %

Procedure:
A solution of sodium hydroxide (325 mg) in water (4 ml) was added to a solution of ethyl 10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)decanoate (558 mg, 0.81 mmol) in ethanol (8 ml). The reaction mixture was heated under reflux for 12 hours. Dilute hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=2/1) to give 10-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(7,7,8,8,8-pentafluoro-octyl)decanoic acid (480 mg, Yield 89%).
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C@@H:7]([C:9]1[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=1)[OH:8].O=[C:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([N:37]3[CH2:41][C:40](=[O:42])[NH:39][C:38]3=[O:43])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[O:43]=[C:38]1[NH:39][C:40](=[O:42])[CH2:41][N:37]1[S:34]([C:31]1[CH:30]=[CH:29][C:28]([N:25]2[CH2:26][CH2:27][CH:22]([NH:5][CH2:6][C@@H:7]([C:9]3[CH:10]=[CH:11][C:12]([OH:20])=[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=3)[OH:8])[CH2:23][CH2:24]2)=[CH:33][CH:32]=1)(=[O:36])=[O:35]
Reactant: O=C1CCN(c2ccc(S(=O)(=O)N3CC(=O)NC3=O)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(S(=O)(=O)N4CC(=O)NC4=O)cc3)CC2)ccc1O
Reaction time: 0.33 h
Yield: 67.2 %

Procedure:
Acetic acid (0.15 mL, 2.6 mmol) was added dropwise into a mixture N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (320 mg, 1.3 mmol), 1-[[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl}-2,4-imidazolidinedione (440 mg, 1.3 mmol) and N,N-dimethylformamide (5 mL). The mixture was stirred for 20 minutes and then, sodium triacetoxyborohydride (331 mg, 1.56 mmol) was added, and the new mixture was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the residue was purified by flash chromatography (dichloromethane/methyl alcohol 4/1) to produce a white solid (496 mg, 67% yield): mp 200-202° C.; c 1.35-1.42 (m, 2H), 1.81-1.97 (m, 2H), 2.83-2.97 (m, 6H), 3.95-3.97 (m, 2H), 4.22 (s, 2H), 4.57-4.6 (m, 1H), 7.1 (M, 3H), 7.2 (m, 1H), 7.75 (m, 2H), 8.4 (brs, 2H); MS m/e 566 (M−H)+; Analysis for: C23H29N5O8S2 Calc'd: C, 48.67; H, 5.11; N, 12.34 Found: C, 47.64; H, 5.2; N, 11.26.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([CH3:12])=[N:4]1)[CH3:2].[B-](F)(F)(F)[F:14].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.CCOC(C)=O>C(#N)C.O>[CH2:1]([N:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([F:14])[C:5]([CH3:12])=[N:4]1)[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CCn1nc(C)cc1C(=O)OC
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCn1nc(C)c(F)c1C(=O)OC
Yield: 26.9 %

Procedure:
To a flask, methyl 1-ethyl-3-methylpyrazol-5-ylcarboxylate (1.70 g, 0.010 mol, Ref. CN1626520A) was dissolved in 30 mL of acetonitrile and the selectfluor (1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanium bis(tetrafluoroborate)) (5.30 g, 0.015 mol) was added in batches. After heating to reflux for 1.5 h, the mixture was diluted with 50 mL of water, and then extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with 150 mL of saturated aqueous sodium bicarbonate solution and 150 mL of saturated brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. Column chromatography (EtOAc:P.E.=1:20 as eluent) gave 0.50 g of the title compound as a yellow oil (yield 26%).
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4]([C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:3]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:35]3[C:30](=[N:31][CH:32]=[CH:33][CH:34]=3)[NH:29][C:28]2=[O:36])[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].CN1C(=O)CCC1>O>[F:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([C:9]([C:4]1[CH:3]=[C:2]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:25][CH2:26]3)[C:7]([I:8])=[CH:6][N:5]=1)=[O:10])[CH2:12][CH2:13]2
Reactant: O=C(c1cc(Cl)c(I)cn1)N1CCc2cc(F)ccc21
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)c(I)cn1)N1CCc2cc(F)ccc21
Temperature: 130 °C
Reaction time: 10 h

Procedure:
0.50 g (1.2 mmol) (4-chloro-5-iodo-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone, 0.27 g (1.2 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 0.26 g (1.9 mmol) potassium carbonate and 3.5 mL NMP were combined and stirred at 130° C. for 10 h. After the addition of water the precipitate formed was suction filtered and dried.