Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22]C=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[N:25]1([C:31](OC(C)(C)C)=O)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCCl.CO.O1CCOCC1.ClCCl.O>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:31][N:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: O=CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCN2CCNCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 71.1 %

Procedure:
To a solution of 2-chloro-5-(2-oxoethyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.101 g, Example 66b) in anhydrous 1,2-dichloroethane (5 ml) was added 1-piperazinecarboxylic acid, 1,1-dimethylethyl ester (0.108 g) then sodium triacetoxyborohydride (0.086 g). The reaction mixture was stirred for 14 h at room temperature. Water (10 ml) and dichloromethane (10 ml) were added and the layers were partitioned. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane then by chromatography over silica gel eluting with ethyl acetate. The white powder obtained was dissolved in methanol (5 ml) and a solution of hydrochloric acid in dioxane (4N, 1 ml) was added. The mixture was stirred for 14 h at room temperature. Solvents were then removed under reduced pressure and the product obtained was triturated with diethyl ether to afford the title compound as a white powder (0.047 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].O.S([O-])([O-])=[O:11].[Na+].[Na+].[N+]([O-])([O-])=O.[Pb+2].[N+]([O-])([O-])=O>>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:11])[CH3:2]
Reactant: O=S([O-])[O-]
Reactant: CCc1ccccc1
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Agent: [Pb+2]
Solvent: O
Product: CC(=O)c1ccccc1
Yield: 95 %

Procedure:
Ten millimoles of ethylbenzene were heated at 400° C. for 1 hour with 1.35 ml of water containing 20 millimoles of sodium sulfite and 10 millimoles of lead nitrate. On cooling, a suspension of black precipitate was observed. The reaction product was extracted with ether and the ether layer was dried over Na2SO4 and concentrated to yield acetophenone in more than 95% yield. Acetophenone was confirmed by NMR and gas chromatographic techniques.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[NH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10](=O)[C:5]=2[S:4][CH:3]=1.P(Cl)(Cl)([Cl:19])=O>>[CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([Cl:19])=[C:5]2[S:4][CH:3]=1
Reactant: CCOC(=O)c1c[nH]c2c(C)csc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(C)csc2c1Cl

Procedure:
3-Methyl-6-ethoxycarbonylthieno[3,2-b]pyridin-7(4H)-one (7.0 g, 0.0295 mol) and phosphorus oxychloride (35 ml) were heated under reflux for 2 hours. The excess phosphorus oxychloride was removed by distillation under reduced pressure. The residue was poured onto ice, basified with 2N.NaOH and extracted with chloroform (3×100 ml). The combined chloroform extracts were washed with water, dried and evaporated to dryness to give a buff-coloured solid. This was collected, washed with petroleum ether (b.p. 40°-60°) and dried to give ethyl 3-methyl-7-chlorothieno[3,2-b]pyridine-6-carboxylate, 6.8 g, m.p. 113°-115°.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[N:4][C:5]([CH3:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F:13][C:14]([F:28])([F:27])[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OC(C)C)=O)(C(OC(C)C)=O)=[N-]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[N:4][C:3]=1[O:12][CH:15]([C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=1)[C:14]([F:28])([F:27])[F:13]
Reactant: Cc1nc(O)c(Br)cc1[N+](=O)[O-]
Reactant: OC(c1ccc(C(F)(F)F)cc1)C(F)(F)F
Agent: CC(C)OC(=O)[N+](=[N-])C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(OC(c2ccc(C(F)(F)F)cc2)C(F)(F)F)c(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 6 h
Yield: 36.6 %

Procedure:
To a stirring suspension of 3-bromo-6-methyl-5-nitro-pyridin-2-ol (0.25 g, 1.07 mmol) in THF (7 mL), 2,2,2-trifluoro-1-[4-(trifluoromethyl)phenyl]ethanol (0.39 g, 1.61 mmol, 1.5 equiv) and triphenylphosphine (0.42 g, 1.61 mmol, 1.5 eq) were added at room temperature under inert atmosphere (Ar). To this mixture, DIAD (diisopropyl diazodicarboxylate) (0.33 mL, 1.61 mmol, 1.5 eq) was added dropwise over 10 minutes while keeping the temperature below 40° C. The reaction mixture was stirred for 6 h under heating at 60° C. After this time, TLC indicted that the starting material was consumed and the reaction mixture was allowed to reach room temperature before quenching with water (10 mL). The water phase was extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to give a brown residue, which was purified by combiflash column chromatography (silica gel, heptane/ethyl acetate, v/v=95/5). Fractions containing the pure compound were collected and concentrated in vacuo to give the title compound (0.18 g, 41% yield) as a yellow oil.
Reaction SMILES: C(CCC1C(CCCCCCOC2C=C(C3C=CC(F)=C(F)C=3)C=C(C(=O)N(C)C)C=2)=CC=CC=1OCCCC(O)=O)(O)=O.C([O:47][C:48](=[O:92])[CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:67]=[C:68]([C:77]3[CH:82]=[CH:81][C:80]([F:83])=[C:79]([OH:84])[CH:78]=3)[CH:69]=[C:70]([C:72](=[O:76])[N:73]([CH3:75])[CH3:74])[CH:71]=2)[C:54]=1[CH2:85][CH2:86][C:87]([O:89]CC)=[O:88])C.[OH-].[Na+]>C1COCC1.CCO>[C:87]([CH2:86][CH2:85][C:54]1[C:55]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:67]=[C:68]([C:77]3[CH:82]=[CH:81][C:80]([F:83])=[C:79]([OH:84])[CH:78]=3)[CH:69]=[C:70]([C:72](=[O:76])[N:73]([CH3:75])[CH3:74])[CH:71]=2)=[CH:56][CH:57]=[CH:58][C:53]=1[O:52][CH2:51][CH2:50][CH2:49][C:48]([OH:92])=[O:47])([OH:89])=[O:88]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N(C)C)cc(-c3ccc(F)c(O)c3)c2)c1CCC(=O)OCC
Agent: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(O)c2)c1
Yield: 92.4 %

Procedure:
The title compound was prepared by the same method as 4-{2-(2-carboxy-ethyl)-3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid starting from 4-{3-[6-(5-dimethylcarbamoyl-4′-fluoro-3′-hydroxy-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (142 mg, 0.213 mmol) and 1.0 N aqueous NaOH (5 mL) in THF (5 mL) and EtOH (5 mL) to afford 4-{2-(2-carboxy-ethyl)-3-[6-(5-dimethylcarbamoyl-4′-fluoro-3′-hydroxy-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid (120 mg, 92%) as a white amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:17])=[C:5]([CH3:16])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=O.Cl.[NH2:19][C:20]1([C:23](OCC)=[O:24])[CH2:22][CH2:21]1>N1C=CC=CC=1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[C:6]3[C:5]([CH3:16])=[C:4]([CH3:17])[S:3][C:2]=3[NH:1][C:23](=[O:24])[C:20]3([CH2:22][CH2:21]3)[N:19]=2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)C1(N)CC1
Reactant: Cc1sc(N)c(C(=O)c2ccc(Cl)cc2)c1C
Agent: Cl
Solvent: c1ccncc1
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC1(CC1)C(=O)N2
Temperature: 120 °C
Reaction time: 24 h
Yield: 17.7 %

Procedure:
A microwave vial was charged with (2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone (1.605 g, 6.04 mmol), ethyl 1-aminocyclo-propanecarboxylate hydrochloride (1 g, 6.04 mmol), and a stir bar. Pyridine (6 mL, 1.0 M) was added, and the mixture was stirred in the microwave at 120° C. for 24 h. The reaction mixture was purified by flash chromatography (hexane/EtOAc) and triturated from DMF with water to give 5′-(4-chlorophenyl)-6′,7′-dimethylspiro[cyclopropane-1,3′-thieno[2,3-e][1,4]diazepin]-2′(1′H)-one as a brown amorphous solid (354 mg). LRMS (M+H)+: 331 m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:17])=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[F:18].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>CN(C=O)C>[CH2:27]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([Cl:1])[CH:11]=2)[C:6](=[O:17])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8]1)[CH:26]=[CH2:25]
Reactant: CCOC(=O)c1cnc2cc(Cl)c(F)cc2c1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1cc(C(=O)OCC)c(=O)c2cc(F)c(Cl)cc21
Temperature: 110 °C
Yield: 77.4 %

Procedure:
13.5 g of 7-chloro-3-ethoxycarbonyl-6-fluoro-4-hydroxyquinoline and 13.8 g of potassium carbonate in 160 cm3 of DMF were stirred and heated at 110° C. for 1 hour in a round-bottomed flask equipped with a reflux condenser. After cooling to 60° C., the solution was treated with 24 g of allyl bromide. The mixture was stirred and heated at 100° C. until the medium was neutral (duration: about 6 hours). The solvent was evaporated off in vacuo, the residue was taken up in 300 cm3 of water and the reaction product was extracted with chloroform (3×100 cm3). The combined organic extracts were washed with water, dried (MgSO4) and evaporated to dryness. The residue was recrystallised from 72 cm3 of isopropanol. 12 g of 1-allyl-7-chloro-3-ethoxycarbonyl-6-fluoro-4-oxo-1,4-dihydroquinoline, m.p.=162°-164° C., were obtained.
Reaction SMILES: Cl.[C:2]1([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)=[CH:16][CH:15]=3)[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH2:32].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C([O-])(O)=O.[Na+]>CN(C)C=O.O>[C:2]1([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:32][O:31][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)=[O:24])=[CH:16][CH:15]=3)[CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc(N[C@@H]2CCN(c3ccccc3)C2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(/C=C/c1ccc(N[C@@H]2CCN(c3ccccc3)C2)nc1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a solution of (2E)-3-(6-{[(3R)-1-phenyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid hydrochloride (37 mg), O-tetrahydro-2H-pyran-2-ylhydroxylamine (19 mg), and 1-hydroxybenzotriazole (22 mg) in N,N-dimethylformamide (1 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (25 mg) at 4° C. The mixture was warmed to ambient temperature and stirred for 8 hours. The reaction mixture was added saturated NaHCO3 (1 mL) and water (4 mL). A resulting precipitate was collected by filtration, and washed with water to give (2E)-3-(6-{[(3R)-1-phenyl-3-pyrrolidinyl]amino}-3-pyridinyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (43 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]=[CH:7][C:8]([NH:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[H][H]>[Pd].O1CCCC1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][CH2:7][C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][CH:21]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C=Cc2ccc(Cl)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NC(=O)CCc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 30.0 g. of 4-(p-chlorocinnamamido)benzoic acid, ethyl ester, 500 mg. of 10% palladium on carbon, and 150 ml. of tetrahydrofuran is hydrogenated in a Parr apparatus, over a 2 hour period, repressurizing until hydrogen uptake is complete. The mixture is filtered, and the filtrate is evaporated. The solid is crystallized from 175 ml. of ethanol, giving 26.8 g. of the desired product as white crystals, m.p. 163°-165° C.
Reaction SMILES: [S:1]([N:11]1[CH2:16][CH2:15][N:14]2[CH:17]=[CH:18][CH:19]=[C:13]2[CH:12]1[CH2:20][C:21]([OH:23])=O)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][C@@H:58]([C:60]1[CH:71]=[CH:70][C:63]([CH2:64][NH:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[CH:62][CH:61]=1)[CH3:59]>C1COCC1.C(Cl)Cl>[C:66]([NH:65][CH2:64][C:63]1[CH:62]=[CH:61][C:60]([C@H:58]([NH:57][C:21](=[O:23])[CH2:20][CH:12]2[N:11]([S:1]([C:4]3[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=3)(=[O:3])=[O:2])[CH2:16][CH2:15][N:14]3[CH:17]=[CH:18][CH:19]=[C:13]23)[CH3:59])=[CH:71][CH:70]=1)([CH3:69])([CH3:67])[CH3:68]
Reactant: Cc1ccc(S(=O)(=O)N2CCn3cccc3C2CC(=O)O)cc1
Reactant: C[C@@H](N)c1ccc(CNC(C)(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCn3cccc3C2CC(=O)N[C@H](C)c2ccc(CNC(C)(C)C)cc2)cc1
Reaction time: 0.25 h
Yield: 29 %

Procedure:
To a suspension of 2-(2-tosyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid (S11) (405 mg, 1.2 mmol, 1.0 eq.) in THF (5 ml) were added DIPEA (1.0 ml, 6.0 mmol, 5.0 eq.) and HATU (547 mg, 1.4 mmol, 1.2 eq.) at 0° C. and the mixture was stirred for 15 min at the same temperature. A solution of (R)—N-(4-(1-aminoethyl)-benzyl)-2-methylpropan-2-amine (A54) (1.2 mmol, 1.0 eq.) in THF (3 ml) was added to the reaction mixture and it was stirred at RT for 16 h. The mixture was diluted with DCM (70 ml) and washed with sat. NH4Cl solution (25 ml), sat. NaHCO3 solution (25 ml), water (25 ml) and brine (25 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 3% MeOH/DCM) to yield the desired product as a light brown solid. Yield: 29% (180 mg, 0.334 mmol); MS, Rt=2.9 min; m/z=523.1 [M H]+
Reaction SMILES: C(O[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]C)=[O:28])=[CH:22][CH:21]=3)=[CH:14][C:13]=2[CH2:31][CH3:32])[CH2:11][CH2:10]1)C1C=CC=CC=1.[OH-:33].[Na+]>C(O)C.O1CCCC1>[CH2:10]([C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:24][CH:25]=3)=[CH:14][C:13]=2[CH2:31][CH3:32])[CH2:11][O:33]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCc1cc(C#Cc2ccc(CC(=O)OC)cc2)ccc1C1(OCc2ccccc2)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1cc(C#Cc2ccc(CC(=O)O)cc2)ccc1C1(Cc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure I; a solution of methyl {4-[4-(1-benzyloxycyclopropyl)-3-ethyl-phenylethynyl]-phenyl}-acetate (Compound 92, 130.0 mg, 0.31 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up and purification by HPLC (Partisil 10-pac, 10% H2O/CH3CN) afforded the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]C(=O)C)=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O>O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)c1ccc(N)c([N+](=O)[O-])c1

Procedure:
N-(4-acetyl-2-nitrophenyl)acetamide (26.5 g, 11.94 mmol) was added to a mixture of water and concentrated sulfuric acid, 150 ml (1:2). After 15 minutes the mixture was poured into water. The product was filtered off, washed with water and dried.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH:6]([CH2:9][NH:10]C(=O)OCC3C=CC=CC=3)[CH2:5][CH2:4]2)[CH2:2]1.[ClH:21]>CO.[Pd]>[ClH:21].[CH2:2]1[C:3]2([CH2:8][CH2:7][CH:6]([CH2:9][NH2:10])[CH2:5][CH2:4]2)[CH2:1]1
Reactant: O=C(NCC1CCC2(CC1)CC2)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCC1CCC2(CC1)CC2
Yield: 98.5 %

Procedure:
Compound 8-5 (2.85 g, 10.4 mmol) was dissolved in 30 mL of methanol, added 0.2 g of palladium on carbon and 1 mL of concentrated hydrochloric acid, and subjected to catalytic hydrogenation reaction overnight and filtered to remove insolubles, then concentrated to give Compound 8-6 (1.8 g, yield 98.5%).
Reaction SMILES: C(OC1N=C2C(N=C(OC)N2CCCC2CCCCN2)=C(N)N=1)CCC.[NH2:27][C:28]1[N:36]=[C:35]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])[N:34]=[C:33]2[C:29]=1[N:30]=[C:31]([O:62][CH3:63])[N:32]2[CH2:42][CH2:43][CH2:44][CH2:45][CH:46]1[CH2:51][CH2:50][CH2:49][N:48](C(OCC2C=CC=CC=2)=O)[CH2:47]1>>[CH2:38]([O:37][C:35]1[N:34]=[C:33]2[C:29]([N:30]=[C:31]([O:62][CH3:63])[N:32]2[CH2:42][CH2:43][CH2:44][CH2:45][CH:46]2[CH2:51][CH2:50][CH2:49][NH:48][CH2:47]2)=[C:28]([NH2:27])[N:36]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCN(C(=O)OCc4ccccc4)C3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCNC3)c2n1

Procedure:
Prepared similarly to Intermediate 32 from phenylmethyl 3-{4-[6-amino-2-(butyloxy)-8-(methyloxy)-9H-purin-9-yl]butyl}-1-piperidinecarboxylate.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1.[H-].[Na+].[CH3:12]I>C1COCC1.CCOC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][CH3:12])[CH:3]=1
Reactant: CI
Reactant: OCc1cc(I)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1cc(I)ccn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of (4-iodo-pyridin-2-yl)-methanol 6AN (0.51 g, 2.16 mmol) in THF (7.5 ml) was added in a dry NaH (0.17 g, 4.32 mmol). Reaction mixture was stirred for 20 min at r.t. It was cooled to 0° C. and CH3I 0.16 ml, 2.59 mmol) was added drop wise. After 30 mins at 0° C., it was warmed up to r.t. and stirred further for 2 hr. Then it was diluted with EtOAc (50 ml) and washed with water (2×10 ml) and brine (1×15 ml). Organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified on silica gel eluting with 1/2 EtOAc/Hexane to give the desired product 4-Iodo-2-methoxymethyl-pyridine 7AN (0.39, 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[OH-].[K+:25].CO>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)=[C:11]([CH2:13][C:14]([O-:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[K+:25]
Reactant: CCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])Cc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 80 %

Procedure:
2.7 g of ethyl 2-[2-(4-fluorophenyl)-5-(3-thienyl)-4-oxazolyl]acetate are dissolved in 10 ml of 10% potassium hydroxide/methanol, and the solution is stirred at room temperature for 17 hours. After the reactioh, the crystalline precipitates are collected by filtration, and then washed with cold ethanol and ether. 2.4 g of potassium 2-[2-(4-fluorophenyl)-5-(3-thienyl)-4-oxazolyl]acetate are thereby obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH2:12][C:13]([O:15]CC)=[O:14])[OH:11])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH2:12][C:13]([OH:15])=[O:14])[OH:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1(O)CCc2ccc(F)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1(O)CCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 2-(6-fluoro-1-hydroxy-1-indanyl)acetate (44.0 g, 0.18 mol), 1N sodium hydroxide (180 mL) and absolute ethanol (280 mL) was stirred for 18 h at room temperature. The mixture was concentrated in vacuo, diluted with H2O and extracted with diethyl ether. The aqueous phase was acidified (pH 3) with dilute hydrochloric acid and extracted with diethyl ether. The diethyl ether layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 2-(6-fluoro-1-hydroxy-1-indanyl)acetic acid as an amber oil (37.7 g, 100%; Note: This compound spontaneously dehydrated upon standing at room temperature to a mixture of olefins unless immediately reacted with trifluoroacetic acid); NMR (DMSO-d6): d 11.60 (br s, 1H, COOH), 6.75-7.05 (m, 3H, Ar), 5.20 (br s, 1H, OH), 2.22-2.69, 1.77-1.95 (2m's, 6H, 3XCH2).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[CH:32]([CH3:34])[CH3:33]>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:31][CH:32]([CH3:34])[CH3:33])=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: CC(C)CBr
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCC(C)C)c1OCC1CC1
Temperature: 70 °C
Yield: 21.3 %

Procedure:
To a stirring solution of 5-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl) isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.745 mmol) and isobutylbromide (102 mg, 0.745 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 21%).
Reaction SMILES: [N:1]1([CH2:7][C:8]#[C:9][C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][C:33]([C:39]#[N:40])=[C:32]2[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([C:48]#[CH:49])[CH:43]=1.C(=O)(O)[O-].[Na+]>C1COCC1.N1C=CC=CC=1>[C:39]([C:33]1[CH:34]=[N:35][C:36]2[C:31]([C:32]=1[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([C:48]#[CH:49])[CH:43]=1)=[CH:30][C:29]([NH:28][C:10](=[O:12])[C:9]#[C:8][CH2:7][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[CH:38][CH:37]=2)#[N:40]
Reactant: O=C(O)C#CCN1CCCCC1
Reactant: C#Cc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Product: C#Cc1cccc(Nc2c(C#N)cnc3ccc(NC(=O)C#CCN4CCCCC4)cc23)c1
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
Partially dissolved 1.03 g (6.16 mmol) 4-piperidino-2-butynoic acid in 70 ml THF and chilled to 0° under N2. Added 812 μl (7.38 mmol) N-methylmorpholine and 640 μl (4.92 mmol) isobutyl chloroformate. After 0.5 hour stirring, added a solution of 700 mg (2.46 mmol) 6-amino-4-[(3-ethynylphenyl)amino)-3-quinolinecarbonitrile dissolved in 5 ml pyridine. At I hours poured onto ice bath and made basic with a saturated solution of sodium bicarbonate. Extracted with ethyl acetate, dried organics with sodium sulfate, reduced to a small volume and loaded onto a column of silica gel. Eluted with 8% methanol in ethyl acetate. Stripped solvent of desired fractions and dried in vacuo, giving 641 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=434.2.