Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][CH:6]=1.BrCC1CCCCO1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]1([C:31]3=[CH:32][C:33]4[O:37][CH2:36][O:35][C:34]=4[CH:38]=[C:30]3[O:29][CH2:28]1)[C:21](=[O:27])[NH:22]2>>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]1([C:31]3=[CH:32][C:33]4[O:37][CH2:36][O:35][C:34]=4[CH:38]=[C:30]3[O:29][CH2:28]1)[C:21](=[O:27])[N:22]2[CH2:7][C:4]1[S:3][C:2]([Cl:1])=[CH:6][CH:5]=1
Reactant: O=C1Nc2cccc(Cl)c2C12COc1cc3c(cc12)OCO3
Reactant: ClCc1ccc(Cl)s1
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(Cl)s2)c2cccc(Cl)c2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-chloro-5-(chloromethyl)thiophene to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 4′-chlorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 4′-chloro-1′-[(5-chloro-2-thienyl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (67%) as a colorless solid: mp 167-168° C. (diethyl ether/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.36 (dd, J=8.0, 8.0 Hz, 1H), 7.20-7.18 (m, 2H), 7.08 (dd, J=8.0, 0.7 Hz, 1H), 6.77 (d, J=3.4 Hz, 1H), 6.66 (s, 1H), 6.12 (s, 1H), 5.94 (s, 2H), 5.09 (ABq, 2H), 4.92 (d, J=9.8 Hz, 1H), 4.75 (d, J=9.8 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 176.1, 156.2, 148.5, 143.3, 141.5, 137.5, 130.5, 129.8, 127.8, 127.7, 127.3, 126.5, 123.6, 116.5, 108.3, 102.4, 101.4, 92.9, 77.0, 57.8, 38.7; MS (ES+) m/z 446.2 (M+1), 448.2 (M+1).
Reaction SMILES: [C:1]([N:6]1[C:11](=[O:12])[CH:10]2[CH2:13][CH:7]1[CH:8]=[CH:9]2)(=[O:5])[CH:2]([CH3:4])[CH3:3].[BH4-].[Na+].Cl.[OH-].[Na+]>O.CC(O)CC>[C:1]([NH:6][CH:7]1[CH2:13][CH:10]([CH2:11][OH:12])[CH:9]=[CH:8]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)N1C(=O)C2C=CC1C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCC(C)O
Solvent: O
Product: CC(C)C(=O)NC1C=CC(CO)C1
Temperature: 20 °C
Reaction time: 3 h
Yield: 73.9 %

Procedure:
9 g of (±)-2-isobutyryl-2-azabicyclo[2.2.1]hept-5-en-3-one were dissolved in water (32 ml) and 2-butanol (84 ml) under nitrogen and cooled to 0° C. 1.37 g of sodium borohydride were added in portions over the course of 3.5 h. The mixture was stirred for a further 3 h at 20° C., and it was then adjusted to pH 2.5 with a mixture of conc. hydrochloric acid and water (1/1) and then neutralized with 2N NaOH. The solution was evaporated to 40 g. The residue was extracted with 3×80 ml of dichloromethane. The combined organic phases were completely evaporated. The resulting solid was crystallized in 25 ml of toluene. 6.8 g of title compound were obtained. The yield was 73.6%.
Reaction SMILES: [CH3:1][C:2]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]1=[O:10].[CH3:17]OC(C1OC(C(C)C)(C2C=CC=CC=2)C(=O)C=1)=O.COC(C1OC(C2C=CC(Cl)=CC=2)(C)C(=O)C=1)=O.COC(C1OC(C)(C)C(=O)C=1)=O.COC(C1OC(CCCC)(CC)C(=O)C=1)=O.COC(C1OC(C2C=CC=CC=2)(C2C=CC=CC=2)C(=O)C=1)=O.COC(C1OC(C2CCCCC2)(CCC)C(=O)C=1)=O.COC(C1OC(COCC)(C2C=CC=C(OC)C=2)C(=O)C=1)=O.COC(C1OC(C2C=CC(CC)=C(CC)C=2)(C2C=CC([N+]([O-])=O)=CC=2)C(=O)C=1)=O.COC(C1OC(C2CCCC2)(CCCOCC)C(=O)C=1)=O>>[CH3:17][O:8][C:7]([C:5]1[O:6][C:2]([CH3:1])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3](=[O:10])[CH:4]=1)=[O:9]
Reactant: CC1(c2ccccc2)OC(C(=O)O)=CC1=O
Reactant: COC(=O)C1=CC(=O)C(c2ccccc2)(C(C)C)O1
Agent: CCCC1(C2CCCCC2)OC(C(=O)OC)=CC1=O
Agent: CCCCC1(CC)OC(C(=O)OC)=CC1=O
Agent: CCOCC1(c2cccc(OC)c2)OC(C(=O)OC)=CC1=O
Product: COC(=O)C1=CC(=O)C(C)(c2ccccc2)O1

Procedure:
Similarly, but replacing 4,5-dihydro-5-methyl-4-oxo-5-phenylfuran-2-carboxylic acid with an equivalent amount of another compound of formula I described in Example 4, the following compounds of formula I are obtained, respectively: 4,5-dihydro-5-(1-methylethyl)-4-oxo-5-phenylfuran-2-carboxylic acid methyl ester; 5-(4-chlorophenyl)-4,5-dihydro-5-methyl-4-oxofuran-2-carboxylic acid methyl ester; 4,5-dihydro-5,5-dimethyl-4-oxofuran-2-carboxylic acid methyl ester, mp 66° C., ir(CHCl3)1720, 1695 and 1575 cm-1 ; spiro[furan-5(4H),1'(2'H)-naphthalene]-3',4'-dihydro-4-oxo-2-carboxylic acid methyl ester; 5-butyl-5-ethyl-4,5-dihydro-4-oxofuran-2-carboxylic acid methyl ester; 4,5-dihydro-4-oxo-5,5-diphenylfuran-2-carboxylic acid methyl ester; 5-cyclohexyl-4,5-dihydro-4-oxo-5-propylfuran-2-carboxylic acid methyl ester; 4,5-dihydro-5-ethoxymethyl-5-(3-methoxyphenyl)-4-oxofuran-2-carboxylic acid methyl ester; 4,5-dihydro-5-(3,4-diethylphenyl)-5-(4-nitrophenyl)-4-oxofuran-2-carboxylic acid methyl ester; 1,7-dioxaspiro[4,4]non-2-ene-4-oxo-2-carboxylic acid methyl ester; 1-oxaspiro[4,5]dec-2-ene-4-oxo-2-carboxylic acid methyl ester; spiro[furan-5-(4H),1'-indan]-4-oxo-2-carboxylic acid methyl ester; and 5-cyclopentyl-4,5-dihydro-5-(3-ethoxypropyl)-4-oxofuran-2-carboxylic acid methyl ester.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](O)=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6]>ClCCl.CN(C=O)C>[C:5]([O:9][C:10](=[O:11])[NH:12][C@H:13]([C:14](=[O:15])[N:3]([CH3:4])[CH3:2])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@H](CCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Dimethylamine hydrochloride (1.0 mmol) and (S)-N-t-butoxycarbonyl-2-amino-4-phenylbutyric acid (0.84 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 3:1 dichloromethane/DMF reaction solvent) giving the product which was used without further purification. Yield 238 mg, 93%; HPLC (60/40) 5.98 minutes (97%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][N:8]=[C:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=3[F:25])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[CH3:26][N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:26][N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][N:1]1[CH2:6][CH2:5][CH:4]([O:7][N:8]=[C:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:17][C:16]=3[F:25])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1
Reactant: Cn1cccc1C=O
Reactant: CS(=O)(=O)c1ccc(N2CCC(=NOC3CCNCC3)CC2)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cccc1CN1CCC(ON=C2CCN(c3ccc(S(C)(=O)=O)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 63a (24 mg, 0.065 mmol) in 1 mL of DCM, was added 1-methyl-1H-pyrrole-2-carbaldehyde (10.6 g, 0.098 mmol), triethylamine (27 μL, 0.19 mmol) and sodium triacetoxyborohydride (27.6 mg, 0.13 mmol). The mixture was stirred overnight at room temperature, concentrated and purified on preparative HPLC to give 66-1: LC-MS 463.0 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[CH:6][CH:7]=1>CC1C=CC(C(C)C)=CC=1.[Pd]>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([OH:18])=[CH:13][CH:12]=[CH:11]3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCc2cc(-c3cccc(O)c3)ccc21
Agent: [Pd]
Solvent: Cc1ccc(C(C)C)cc1
Product: Oc1cccc(-c2ccc3c(O)cccc3c2)c1
Yield: 16 %

Procedure:
6-(3-Hydroxyphenyl)-3,4-dihydronaphthalene-1(2H)-one (503 mg, 2.11 mmol, 1 eq) and Pd/C (505 mg) are suspended in p-cymene (15 ml). The reaction mixture is refluxed for 6 h, cooled, filtered over Celite and extracted with 1 M NaOH. The aqueous phase is acidified with 1 M HCl and extracted with ether. The combined organic phases are washed with water, dried over magnesium sulfate, filtered and concentrated in vacuum on a rotary evaporator. Purification by column chromatography with dichloromethane/ethyl acetate 9/1 as the eluent yields the desired product in a yield of 16%, 83 mg.
Reaction SMILES: [CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20](O)=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:25][N:26]1[CH:34]=[C:33]2[C:28]([CH2:29][CH2:30][CH:31]([NH2:35])[CH2:32]2)=[N:27]1>>[CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20]([NH:35][CH:31]2[CH2:30][CH2:29][C:28]3[C:33](=[CH:34][N:26]([CH3:25])[N:27]=3)[CH2:32]2)=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)O
Reactant: Cn1cc2c(n1)CCC(N)C2
Agent: Cl
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)NC1CCc2nn(C)cc2C1

Procedure:
The title compound was prepared from 2-[3-[(benzylsulfonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetic acid and 2-methyl-4,5,6,7-tetrahydro-2H-indazol-5-ylamine hydrochloride using the procedure of EXAMPLE 1 (STEP 6), and was obtained as a faint yellow solid compound.
Reaction SMILES: [OH:1][CH:2]([CH:8]([NH:16][C:17](=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[C:24]1[N:25]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:27][CH:28]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5]CC)=[O:4].C1COCC1>O>[OH:1][CH:2]([CH:8]([NH:16][C:17](=[O:35])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][C:19]=1[C:24]1[N:25]=[C:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[S:27][CH:28]=1)[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-c1csc(-c2ccccc2)n1
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-c1csc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of ethyl 2-hydroxy-4-phenyl-3-(2-(2-phenylthiazol-4-yl)nicotinamido)-butanoate (1.31 g, 2.69 mmol) in THF (40 ml) LiOH (0.14 g, 5.85 mmol) in water (10 ml) was added at 10° C., the mixture stirred for 1 hour at room temperature and then for 2 hours at 60° C. The mixture then was concentrated under reduced pressure, water and 3 ml of 2n HCl added, poured into 300 ml of a mixture of dichloromethane and 5% acetone. The organic layer was dried, filtered and concentrated under reduced pressure to give 1.19 g of the title acid;
Reaction SMILES: [CH3:1][N:2]([CH3:17])[NH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][C:5]=1[N+:14]([O-])=O>C(#N)C.[Pt]>[CH3:1][N:2]([CH3:17])[NH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][C:5]=1[NH2:14]
Reactant: CN(C)Nc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: CC#N
Product: CN(C)Nc1c(N)cnc2ccccc12
Reaction time: 5 h
Yield: 99.7 %

Procedure:
A suspension of 4-(2,2-dimethylhydrazino)-3-nitroquinoline (5.33 g, 23.0 mmol) in 125 mL of acetonitrile was treated with 5% platinum on carbon (0.45 g, 0.11 mmol) and the mixture was shaken under an atmosphere of hydrogen (3.8×105 Pa). After 5 h, the reaction mixture was filtered through a pad of CELITE filter agent and rinsed with 80:20 acetonitrile:MeOH. The filtrate was concentrated under reduced pressure. The resulting oil was dissolved in CH2Cl2, dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-(2,2-dimethylhydrazino)quinolin-3-amine (4.64 g) as a red foam.
Reaction SMILES: [N+](=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[O:5][CH2:4]1)=[N-].[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:15]([O:14][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][CH2:4][CH:3]([O:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]2=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [N-]=[N+]=C1COc2ccc(OCc3ccccc3)cc2C1=O
Reactant: Oc1ccccc1
Agent: [Rh]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1c2cc(OCc3ccccc3)ccc2OCC1Oc1ccccc1
Temperature: 25 °C
Yield: 12.4 %

Procedure:
A solution of 17 g of 3-diazo-6-benzyloxy-4-chromanone and 17 g of phenol in 100 ml of toluene was heated to 110° C. in an oil bath. Rhodium (II) acetate dimer (50 mg) was added in one portion. After nitrogen evolution ceased (5 minutes), the reaction was allowed to cool to room temperature, diluted with ethyl acetate and washed with 10% sodium hydroxide to remove excess phenol. The organic layer was dried over sodium sulfate and evaporated in vacuo to give the crude product, which was purified by column chromatography on silica gel eluting with dichloromethane to give 2.6 g of product, m p. 100°-102° C. 1H-NMR(CDCl3)delta(ppm): 4.4 (m, 2H), 4.84 (m, 1H), 4.88 (s, 2H), 6.82-7.40 (m, 13H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]2[S:22][CH:23]([CH2:26][C:27]([OH:29])=O)[CH2:24][N:25]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>CN(C)C=O.CCCCCC.C(OCC)(=O)C.CO.O>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]2[S:22][CH:23]([CH2:26][C:27]([N:53]4[CH2:58][CH2:57][O:56][CH2:55][CH2:54]4)=[O:29])[CH2:24][N:25]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C4=NCC(CC(=O)N5CCOCC5)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.9 %

Procedure:
To a solution of [2-(5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (150 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (80 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg), and morpholine (61 mg), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (methanol:ethyl acetate:hexane=0:0:100 to 10:90:0, volume ratio) and crystallized from acetonitrile to give the title compound (106 mg, yield 61%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18]C)=[O:17])=[N:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[CH:6][N:7]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[NH2:1][C:2]1[C:3]([C:16]([OH:18])=[O:17])=[N:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(-c2c(F)cccc2F)cnc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncc(-c2c(F)cccc2F)nc1C(=O)O
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A solution of methyl 3-amino-6-(2,6-difluorophenyl)pyrazine-2-carboxylate (258 mg, 0.973 mmol) and lithium hydroxide monohydrate (200 mg, 4.8 mmol) in THF (4.0 mL) and water (2.0 mL) was heated at 60° C. in a sealed vial for 2 h. The reaction mixture was allowed to cool to ambient temperature and neutralized by the addition of 1.0 M hydrogen chloride in water (4.8 mL, 4.8 mmol) to form a precipitate. The precipitate was collected by filtration, washed with EtOAc (5 mL), and dried under vacuum to afford the sub-title compound (170 mg). The filtrate was diluted with EtOAc (15 mL) and the layers were separated. The organic layer was washed with H2O (3 mL) and the combined aqueous phases were extracted with EtOAc (3 mL). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to provide additional sub-title compound. The crude product was used in the subsequent reaction without further purification (70 mg). LC/MS (ESI) calc. for C11H8F2N3O2(M+H)+: m/z=252.1. found: 251.9.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:27])=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:28][CH2:29][O:30][C:5]2=[CH:4][CH:3]=1.[F:31][CH2:32][CH2:33]O>>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH2:33][CH2:32][F:31])=[CH:16][C:17]=3[O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:12]=[CH:11][N:10]=2)=[C:6]2[O:28][CH2:29][O:30][C:5]2=[CH:4][CH:3]=1
Reactant: CN1CCC(Oc2cc(O)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Reactant: OCCF
Product: CN1CCC(Oc2cc(OCCF)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1

Procedure:
Using an analogous procedure to that described in Example 51, 4-(6-chloro-2,3-methylenedioxyanilino)-7-hydroxy-5-(N-methylpiperidin-4-yloxy)quinazoline was reacted with 2-fluoroethanol to give the title compound; NMR Spectrum: (CDCl3) 2.0–2.1 (m, 2H), 2.15–2.3 (m, 2H), 2.35 (s, 3H), 2.3–2.4 (m, 2H), 2.8 (br s, 2H), 4.32 (m, 1H), 4.4 (m, 1H), 4.65 (m, 1H), 4.8 (m, 1H), 4.9 (m, 1H), 6.05 (s, 2H), 6.6 (s, 1H), 6.75 (d, 1H), 6.85 (s, 1H), 7.0 (d, 1H), 8.55 (s, 1H), 9.3 (s, 1H); Mass Spectrum: M+H+ 475 and 477.
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH3:15][N:16]([CH:18]=O)C>>[C:2]1([C:1]2[NH:8][CH:4]=[C:3]([C:2]3[CH:7]=[CH:18][N:16]=[CH:15][CH:1]=3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)c1ccccc1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: c1ccc(-c2nc(-c3ccncc3)c[nH]2)cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
2-Bromo-1-(pyrindin-4-yl)ethanone hydrobromide (6.4 g, 23 mmol) was added portionwise to a solution of benzamidine (11.2 g, 93 mmol) in dry DMF (50 mL) at 0° C., maintaining an internal temperature of <5° C. The stirred reaction was allowed to warm to rt over 2 h and then heated to 40° C. for 16 h. The crude reaction was poured into saturated aqueous NaHCO3 solution (600 mL), and partition and extracted with EtOAc (3×300 mL). The combined organic layers were dried (Na2SO4) and evaporated. The resulting crude residue was purified by flash chromatography (SiO2, 100:0-90:10 DCM-MeOH) to give 3.68 g (72%) of 4-(2-phenyl-1H-imidazol-4-yl)pyridine: 1H NMR (CDCl3) δ 9.73 (broad s, 1H), 8.61 (d, J=6.0, 1.2 Hz, 2H), 7.91 (d, J=8.0, 1.6 Hz, 2H), 7.77 (d, J=6.0, 1.2 Hz, 2H), 7.57 (s, 1H), 7.48 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][C:29]=1[O:37][CH3:38]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([O:27][CH2:26][CH2:25][CH2:24][OH:23])=[C:29]([O:37][CH3:38])[CH:30]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: COc1cc(C(=O)O)ccc1OCCCO
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)c3ccc(OCCCO)c(OC)c3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example 26b) and 4-(3-hydroxypropoxy)-3-methoxybenzoic acid (Baraldi, P. G. et al. J. Med. Chem. 1999, 42, 5131.) as a brown solid. MS 512 (MH+).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[N:18][OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=Cc1cccc(C#Cc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: ON=Cc1cccc(C#Cc2ccccc2)c1

Procedure:
The procedure was the same as described in Example 1b, except there were used 16.5 g of 3-(phenylethynyl)-benzaldehyde, 8.3 g of hydroxylamine hydrochloride and 8.2 g of sodium acetate to give 16.8 g (94.8% of the theoretical yield) of the title compound in form of a yellowish powder (mixture of isomers).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]1([CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CO.CN(C)C=O>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: O=C(O)CCCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(CCCc1ccccc1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 32.3 %

Procedure:
Preparation of example 36 from the title compound of Example 7 (0.030 g, 0.11 mmol), 4-Phenyl-butyric acid (0.027 g, 0.16 mmol), triethylamine (0.077 mL, 0.44 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (63 mg, 0.16 mmol) and N,N-dimethylformamide (0.05 M, 2.0 mL) was carried out analogously to Example 11. Silica gel chromatography (95:5 CH2Cl2/methanol) afforded the title compound (15 mg) as a yellow powder in 33% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:12](=[O:13])[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C1C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:12](=[O:13])[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: c1ccccc1
Product: CCOC(=O)C1=CCN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 4.64 g (16.26 mmol) 5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (route 1 step a) in 200 mL benzene at room temperature was added 1.47 g (8.13 mmol) copper (II) acetate and the resulting reaction mixture was stirred at room temperature for 30 minutes. 7.21 g (16.26 mmol) lead (IV) tetraacetate was added and the reaction was stirred at room temperature for 3 hours. After evaporation of the solvent, the material was partitioned between 250 mL EtOAc and 150 mL H2O, the organic layer was separated and washed with H2O (150 mL) and saturated brine (150 mL) and dried over MgSO4. After filtration and evaporation of the solvent the resulting solid was used for the next step without further purification.