Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20]4=[N:21][CH:22]=[C:23]([C:25]([OH:27])=O)[CH:24]=[C:19]4[N:18]=[CH:17]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.[N:53]1([CH2:59][CH2:60][NH2:61])[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>C1COCC1>[F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20]4=[N:21][CH:22]=[C:23]([C:25]([NH:61][CH2:60][CH2:59][N:53]5[CH2:58][CH2:57][O:56][CH2:55][CH2:54]5)=[O:27])[CH:24]=[C:19]4[N:18]=[CH:17]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1cnc2c(c1)ncn2-c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCN1CCOCC1)c1cnc2c(c1)ncn2-c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 3-{4-[(4-(trifluoromethoxy)benzyl)oxy]phenyl}-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (42 mg, 0.1 mmol), CDI (32.4 mg, 0.2 mmol) and DIPEA (87 μL, 0.5 mmol) in dry THF (2 mL) was stirred at 60° C. for 2 h and then treated with 2-(morpholin-4-yl)ethylamine (26 μL, 0.2 mmol). After a further 2 h at 60° C. the mixture was concentrated in vacuo and the residue chromatographed over silica gel eluting with 5% MeOH/CHCl3 to give 3-{4-[(4-(trifluoromethoxy)benzyl)oxy]phenyl}-N-(2-morpholin-4-ylethyl)-3H-imidazo[4,5-b]pyridine-6-carboxamide. 1H NMR (400 MHz, D4-MeOH) δ 2.57 (br.s, 4H), 2.65 (t, J=8 Hz, 2H), 3.60 (t, J=8 Hz, 2H), 3.71 (t, J=8 Hz, 4H), 5.21 (s, 2H), 7.22 (dd, J=6.8 and 2 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.8 Hz, 2H), 7.71 (dd, J=6.8 and 2 Hz, 2H), 8.57 (d, J=1.6 Hz, 1H), 8.71 (s, 1H) and 8.90 (d, J=1.6 Hz, 1H); MS (ES+): m/z 542 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[CH2:22])[CH2:14][CH2:15][CH:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[H][H]>C(O)(=O)C.[Pt]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[C@H:13]([CH3:22])[CH2:14][CH2:15][C@H:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[C@H:13]([CH3:22])[CH2:14][CH2:15][C@@H:16]([C:18]([O:20][CH3:21])=[O:19])[CH2:17][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: C=C1CCC(C(=O)OC)Cc2onc(-c3ccc(Cl)cc3)c21
Agent: [Pt]
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CC[C@@H](C)c2c(-c3ccc(Cl)cc3)noc2C1
Product: COC(=O)[C@H]1CC[C@@H](C)c2c(-c3ccc(Cl)cc3)noc2C1

Procedure:
1 g (3.13 mmol) of methyl 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4-methylene-4H-cyclohept[d]isoxazole-7-carboxylate was dissolved in 60 ml of glacial acetic acid and 0.3 g of 5% platinum-on-carbon catalyst was added under a nitrogen atmosphere. The mixture was shaken in a hydrogen atmosphere at room temperature and under atmospheric pressure for 8 hours. The catalyst was removed by filtration and washed with glacial acetic acid. The filtrate was evaporated and the residue was chromatographed on silica gel using 20% ethyl acetate in hexane for the elution. There were obtained 0.47 g of methyl cis-3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4-methyl-4H-cyclohept[d]isoxazole-7-carboxylate of melting point 90°-91° C. and 0.45 g of methyl trans-3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4-methyl-4H-cyclohept[d]isoxazole-7-carboxylate of melting point 108° C.
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.C(N(CC)CC)C.[OH:25][N:26]=[C:27]([Cl:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[CH2:35]([N:38]1[C:50]2[C:49]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[N:43]=[C:42]([Cl:51])[C:41]=2[N:40]=[C:39]1[CH2:52][O:53][CH2:54][CH3:55])[CH:36]=[CH2:37]>CN(C=O)C.ClCCl>[OH:25][N:26]=[C:27]([Cl:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Cl:51][C:42]1[C:41]2[N:40]=[C:39]([CH2:52][O:53][CH2:54][CH3:55])[N:38]([CH2:35][CH:36]3[O:9][N:8]=[C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:37]3)[C:50]=2[C:49]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[N:43]=1
Reactant: ON=Cc1ccccc1
Reactant: C=CCn1c(COCC)nc2c(Cl)nc3ccccc3c21
Agent: O=C1CCC(=O)N1Cl
Agent: ON=C(Cl)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1CC1CC(c2ccccc2)=NO1
Reaction time: 8 h

Procedure:
N-Hydroxybenzenecarboximidoyl chloride (13.7 g) was prepared according to the method described in Part D of Example 1 by reacting benzaldehyde oxime (11.5 g, 94.9 mmol) in DMF (20 mL) with N-chlorosuccinimide (12.6 g, 94.9 mmol) and was obtained as a white solid. Triethylamine (0.69 mL, 4.97 mmol) was added to a solution of N-hydroxybenzenecarboximidoyl chloride (644 mg, 4.14 mmol) and 1-allyl-4-chloro-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline (prepared as described in Part C of Example 1, 1.00 g, 3.32 mmol) in dichloromethane (50 mL) at room temperature. The solution was stirred overnight and then was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel to afford 4-chloro-2-(ethoxymethyl)-1-[(3-phenyl-4,5-dihydroisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline as a pale yellow solid (1.19 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][C:16]=2[O:24][CH2:25][CH3:26])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH2:33])=[O:32].O.[C:38]([OH:42])(=[O:41])[CH:39]=O>>[C:31]([C:30]1[CH:29]=[C:28]([NH:27][CH:39]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][O:12][C:10](=[O:11])[NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)=[C:16]([O:24][CH2:25][CH3:26])[CH:17]=2)[C:38]([OH:42])=[O:41])[CH:36]=[CH:35][CH:34]=1)(=[O:32])[NH2:33]
Reactant: O=CC(=O)O
Reactant: CCOc1cc(B(O)O)ccc1CCOC(=O)Nc1cccc(C#N)c1
Reactant: NC(=O)c1cccc(N)c1
Solvent: O
Product: CCOc1cc(C(Nc2cccc(C(N)=O)c2)C(=O)O)ccc1CCOC(=O)Nc1cccc(C#N)c1

Procedure:
Using a procedure analogous to that used to prepare 2D, 62G (150 mg, 0.423 mmol) was reacted with 3-aminobenzamide and glyoxylic acid monohydrate to afford 62H (170 mg, 80%) as an oil. MS (ESI) m/z 503.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][C:29]([OH:31])=[O:30])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:32])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:37]O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][C:29]([O:31][CH3:37])=[O:30])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:32])[CH3:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CC(=O)O)(c2ccccc2)OC1=O
Solvent: O=S(Cl)Cl
Product: COC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3)cc2)C(=O)O1
Yield: 68 %

Procedure:
To a solution of 2-((S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetic acid (1 g, 2.3 mmol) in MeOH (15 mL) was added thionyl chloride (408 mg, 3.5 mmol) dropwise at 0° C. under N2 atmosphere. After refluxing overnight, the mixture was concentrated to give the crude product, which was purified by chromatography to give methyl 2-((S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetate (680 mg, 68%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.[W]>[Br:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc(F)c1
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)ccn1
Temperature: 25 °C
Yield: 28.4 %

Procedure:
The mixture of 2-Fluoro-4-methyl-pyridine (10 g, 90 mmol), N-bromosuccinimide (19.2 g, 108 mmol), and benzoyl peroxide (2.18 g, 9 mmol) in carbon tetrachloride (100 ml) was refluxed for 5 hr under a light of 500 W tungsten light. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated in vacuo to give a brown oil, which was purified by silica gel column chromatography (eluent, ether:hexane (1:9)) to afford 4.85 g (28%) of a pale brown oil; 1H NMR (200 MHz, CDCl3) δ: 4.40 (2H, s), 6.95 (1H, m), 7.19 (1H, m), 8.18 (1H, d, J=5.2 Hz); m/z (EI): 189 (M+), 191 (M+2+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:17]([O:19][C:20](=[O:30])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:30])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[O:13][C:9]([C:4]3[CH:3]=[CH:2][CH:7]=[C:6]([Cl:8])[CH:5]=3)=[CH:10][CH:11]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: CCOC(=O)CCc1cccc(N)c1
Reactant: O=C(O)c1ccc(-c2cc(Cl)cc(Cl)c2)o1
Product: CCOC(=O)CCc1cccc(NC(=O)c2ccc(-c3cccc(Cl)c3)o2)c1

Procedure:
Carboxylic acid (67) (58 mg, 0.26 mmol) was coupled to aniline (124) (50 mg, 0.26 mmol) using Method C. The residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: C([Li])(C)(C)C.[Si:6]([C:10]#[CH:11])([CH3:9])([CH3:8])[CH3:7].[C:12]([Si:16]([CH3:23])([CH3:22])[O:17][CH2:18][C@@H:19]1[CH2:21][O:20]1)([CH3:15])([CH3:14])[CH3:13].B(F)(F)F>C1COCC1>[Si:16]([O:17][CH2:18][C@@H:19]([OH:20])[CH2:21][C:11]#[C:10][Si:6]([CH3:9])([CH3:8])[CH3:7])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:23])[CH3:22]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CO1
Agent: FB(F)F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H](O)CC#C[Si](C)(C)C
Temperature: -78 °C
Reaction time: 4.5 h

Procedure:
tert-Butyl lithium (2 eq) is added to a solution of TMS-acetylene (2 eq) in THF at −78° C. and the reaction mixture stirred for an additional 30 min. (S)-tert-butyldimethyl(oxiran-2-ylmethoxy)silane (1 eq) and BF3.EtO2 (2 eq) are added and stirred at −78° C. for 4.5 hours. The reaction is quenched by addition of aqueous ammonium chloride solution and extracted with ethyl acetate (3×). The combined organic layers are washed with brine, dried (MgSO4) and concentrated under reduced pressure to afford (S)-1-(tert-butyldimethylsilyloxy)-5-(trimethylsilyl)pent-4-yn-2-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:12]([O:17][CH3:18])(=[O:16])[C:13]([CH3:15])=O>>[CH3:18][O:17][C:12](=[O:16])[C@H:13]([CH3:15])[NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: COC(=O)C(C)=O
Reactant: Nc1ccc2ccccc2c1
Product: COC(=O)[C@H](C)Nc1ccc2ccccc2c1

Procedure:
Following reductive amination General Procedure AA above and using 2-aminonaphthalene (Aldrich) and methyl pyruvate (Aldrich), the title compound was prepared. The reaction was monitored by silica gel tlc (Rf=0.50 in 25% EtOAc/hexanes). Purification was by flash chromatography with silica gel using 25% EtOAc/hexanes as the eluant.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].Cl[CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([O:17][CH2:23][C:24]2[N:25]=[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:27][C:28]=2[CH3:29])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc(O)c2c1CCCC2)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c2c1CCCC2)OCC

Procedure:
In analogy to the procedure described in example 108 c], [rac]-2-ethoxy-3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester was treated with 4-chloromethyl-5-methyl-2-phenyloxazole and sodium hydride in N,N-dimethylformamide to yield [rac]-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-propionic acid as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:15])[N:11]([CH2:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:25])=[O:26])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)CCl)cc1
Reactant: O=c1[nH]cccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)Cn2cccc(OCc3ccccc3)c2=O)cc1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
To a suspension of 3-benzyloxy-1H-pyridin-2-one (0.22 g, 1.1 mmol) from step A and Cs2CO3 (0.72 g, 2.2 mmol) in dry DMF (5 mL) was added 1-chloromethanesulfonyl-4-methyl-benzene (0.31 g, 1.54 mmol). The reaction mixture was heated at 95° C. overnight and then additional 1-chloromethanesulfonyl-4-methyl-benzene (0.22 g, 1.1 mmol) was added. The reaction mixture was stirred for another 18 h. After the usual work-up, the crude material was purified by chromatography (silica gel, 40% EtOAc/hexanes) to give the product. MS (EI) 370 (M+H)+.
Reaction SMILES: [CH3:1]/[C:2](=[CH:11]\[N:12]1[CH2:17][CH2:16][CH2:15]CC1)/[C:3]([NH:5][C:6](=[O:10])OCC)=[S:4].Cl.[C:19]([C:23]1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32](CCCN)[CH2:31][CH2:30]2)[CH:26]=[C:25]([C:39]([F:42])([F:41])[F:40])[N:24]=1)([CH3:22])([CH3:21])[CH3:20].CN1CCOCC1>CO>[C:19]([C:23]1[N:28]=[C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH2:15][CH2:16][CH2:17][N:12]3[CH:11]=[C:2]([CH3:1])[C:3]([SH:4])=[N:5][C:6]3=[O:10])[CH2:33][CH2:34]2)[CH:26]=[C:25]([C:39]([F:40])([F:41])[F:42])[N:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)NC(=S)/C(C)=C/N1CCCCC1
Reactant: CC(C)(C)c1nc(N2CCN(CCCN)CC2)cc(C(F)(F)F)n1
Agent: Cl
Solvent: CO
Solvent: CN1CCOCC1
Product: Cc1cn(CCCN2CCN(c3cc(C(F)(F)F)nc(C(C)(C)C)n3)CC2)c(=O)nc1S
Yield: 40.9 %

Procedure:
0.7 g (2.7 mmol) of ethyl (2E)-2-methyl-3-piperidin-1-ylprop-2-enethioylcarbamate (WO 00/61579), 0.9 g (2.6 mmol) of 3-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}propan-1-amine hydrochloride from Example 1.2 and 0.6 g (5.5 mmol) of N-methylmorpholine in 20 ml of methanol were stirred at room temperature under a nitrogen atmosphere for 12 hours. Insolubles were removed by filtration, washed three times with methanol and water and then recrystallized from ethyl acetate. Drying in vacuo at 50° C. resulted in 0.5 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=S)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:18]([NH:21][NH2:22])([CH3:20])[CH3:19].C(N(CC)CC)C.O>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[N:21]([CH:18]([CH3:20])[CH3:19])[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(=S)OCc1ccccc1
Reactant: CC(C)NN
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)c1cc(OCc2ccccc2)nn1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a suspension of 4-methyl-3-oxothiopentanoic acid O-benzyl ester (0.84 g) and isopropylhydrazine hydrochloride (0.52 g) in acetonitrile (4 mL) was added triethylamine (1.4 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The solvent of the organic layer was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane/dichloromethane=1/1-2/3) to give the title compound (0.44 g).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Br:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1Nc1ccccc1)c1ccc(Br)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Temperature: 100 °C
Yield: 90.3 %

Procedure:
To a suspension of amide 1 (9.6 g, 26 mmol) in anhydrous 1,4-dioxane (100 mL) was added phosphorus oxychloride (POCl3) (9.2 mL, 100 mmol) slowly. The whole was then heated at 100° C. overnight. After cooling to RT, the mixture was poured into ice (200 g) with stirring. Filtration, followed by recrystallization in DCM/hexanes gave a pale grey solid 2 (8.2 g, in 90% yield).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=O)[CH2:8][CH:9]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)[CH2:10][C:5]=2[O:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:7]1[C:6]2[C:2]([CH3:1])=[CH:3][O:4][C:5]=2[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[CH2:8]1)[C:19]([NH2:21])=[NH:20]
Reactant: Cc1coc2c1C(=O)CC(c1ccc(Br)cc1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1coc2c1C(=NNC(=N)N)CC(c1ccc(Br)cc1)C2
Yield: 63.9 %

Procedure:
A mixture of 3-methyl-6-(4-bromophenyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.30 g), aminoguanidine hydrochloride (0.11 g), concentrated hydrochloric acid (0.049 ml), water (0.049 ml) and ethanol (30 ml) was refluxed for 2 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 4-guanidinoimino-3-methyl-6-(4-bromophenyl)-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 35) (0.25 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN(C)C=O>[F:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH:11]=[CH:10]2
Reactant: C1CNCCN1
Reactant: Fc1ccc2nc(Cl)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc2nc(N3CCNCC3)ccc2c1
Temperature: 130 °C
Yield: 52 %

Procedure:
To a solution of 2-chloro-6-fluoroquinoline (6.8 g, 37.4 mmol) in N,N-dimethylformamide (200 ml) in a round-bottomed flask was added potassium carbonate (10.4 g, 75.2 mmol) and piperazine (19.2 g, 222.9 mmol) at room temperature. After heating the contents to 130° C. for 5 hours, the reaction mixture was concentrated under vacuum to a minimum volume and then quenched with water (300 ml) and extracted with dichloromethane (3×200 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 1-2.5% methanol in dichloromethane to elute. The product containing fractions were combined and concentrated to afford 6-fluoro-2-(piperazin-1-yl)quinoline as a brown solid (4.5 g, 52%); (ES, m/z): [M+H]+ 232; 1H NMR (300 MHz, CDCl3): δ 7.86 (d, J=9.3 Hz, 1H), 7.62-7.72 (m, 1H), 7.32-7.36 (m, 1H), 7.24-7.29 (m, 1H), 7.01 (d, J=9.3 Hz, 1H), 3.73 (t, J=5.1 Hz, 4H), 3.05 (t, J=5.1 Hz, 4H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:20]=1[NH2:21].Cl.[OH-].[Na+]>O.C(O)C>[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Yield: 25.8 %

Procedure:
A mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (1 g, 3.90 mmol), 2-methyl-5-nitroaniline (890 mg, 5.90 mmol), and 2N HCl (3 ml) in water:ethanol (1:1, 200 ml) was refluxed for 48 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10–12. The mixture was extracted with ethyl acetate (200 ml), washed with water (2×100 ml), with aqueous saturated NaCl (1×100 ml) and dried over anhydrous sodium sulfate. The ethyl acetate solution was rotary evaporated to dryness to give a tan solid (377 mg, 30%). 1H NMR (CDCl3): 8.90 (s, 1H), 8.80 (dd, J=1.8, 4.8 Hz, 2H), 8.30 (dd, J=1.5, 4.5 Hz, 2H), 8.09 (dd, J 2.4, 8.1 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 6.99 (s, 1H), 6.87 (s, 1H), 2.47 (s, 3H).
Reaction SMILES: [OH:1][C:2]12[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[C:6]1([OH:15])[C:5]1[CH:16]=[CH:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:19][C:4]=1[O:3]2.[C:26]([OH:29])(=O)[CH3:27].N1C=CC=CC=1.C1C[O:39][CH2:38][CH2:37]1>>[C:38]([O:3][C:4]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][C:5]=1[C:6]1([O:15][C:26](=[O:29])[CH3:27])[C:2](=[O:1])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:14])(=[O:39])[CH3:37]
Reactant: C1CCOC1
Reactant: O=C1c2ccccc2C2(O)Oc3cc(-c4ccccc4)ccc3C12O
Reactant: CC(=O)O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(-c2ccccc2)ccc1C1(OC(C)=O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 11 %

Procedure:
4b,9b-Dihydroxy-7-phenyl-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (2.00 g, 6.0 mmol) was dissolved in anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (1.24 ml, 12.1 mmol), pyridine (0.48 ml, 6.0 mmol), and 4-dimethyl aminopyridine (0.2 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (0.41 g, 11%).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:11]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([OH:24])=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2)(=[O:10])[CH3:9].[CH3:25][O:26][C:27](Cl)=[O:28]>O1CCCC1>[C:8]([C:11]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([O:24][C:27]([O:26][CH3:25])=[O:28])=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(O)c2ncccc12
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Oc1c([N+](=O)[O-])cc(C(C)=O)c2cccnc12

Procedure:
10.5 g of triethylamine are added to a solution of 23 g of 5-acetyl-7-nitro-8-hydroxyquinoline in 150 ml of tetrahydrofurane and 9.5 g of chloroformic acid methyl ester are slowly added dropwise to this mixture.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([C:10]#[N:11])=[CH:8][N:7]=[C:6]([Cl:12])[N:5]=1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[N:21]=[C:22]=[O:23].Cl>C(OCC)(=O)C.CN(C)C=O>[Cl:12][C:6]1[N:5]=[C:4]2[NH:3][C:22](=[O:23])[N:21]([C:15]3[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:20])[C:10](=[NH:11])[C:9]2=[CH:8][N:7]=1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: N#Cc1cnc(Cl)nc1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.1 %

Procedure:
1.12 g of sodium hydride was added to an N,N-dimethylformamide (35 mL) solution of 3.0 g of 4-amino-2-chloropyrimidine-5-carbonitrile, and stirred at room temperature for 5 minutes. 4.38 g of 2,6-dichlorophenyl isocyanate was added to the reaction liquid, and stirred at room temperature for 1 hour. Ethyl acetate and aqueous 1 N hydrochloric acid solution were added to the reaction solution, and the organic layer was separated. This was washed with saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The precipitated solid was solidified with a mixed solvent of methanol/ethyl acetate and taken out through filtration to obtain 3.8 g of the entitled compound as a white solid.