Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][C:17]=1[N:25]1[CH:29]=[N:28][CH:27]=[N:26]1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:6]3[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:18][C:17]=1[N:25]1[CH:29]=[N:28][CH:27]=[N:26]1
Reactant: OB(O)c1ccc(F)c(-n2cncn2)c1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)cnn23)cc1-n1cncn1

Procedure:
7-Bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine was coupled with 4-fluoro-3-([1,2,4]triazol-1-yl)phenylboronic acid as described in Example 3, step f, final paragraph, to give the title compound: 1H NMR (360 MHz, DMSO-d6) δ 7.82 (1H, dd, J 8.7, 10.5 Hz), 8.34-8.39 (1H, m), 8.39 (1H, s), 8.71 (1H, dd, J 2.4, 7.4 Hz), 9.02 (1H, s), 9.13 (1H, d, J 2.4 Hz); MS (ES+) m/z 350 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[N:14][NH:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]#[N:27])#[N:2].[ClH:28].[CH2:29]([N:31]([CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])[CH3:30]>C(Cl)Cl>[ClH:28].[CH2:29]([N:31]([CH2:32][CH2:33][CH2:34][C:35]([N:13]([C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2])[N:14]=[N:15][C:16]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:17]=1[C:26]#[N:27])=[O:36])[CH2:38][CH3:39])[CH3:30]
Reactant: N#Cc1ccc(C(F)(F)F)cc1N=NNc1cc(C(F)(F)F)ccc1C#N
Reactant: CCN(CC)CCCC(=O)O
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)CCCC(=O)N(N=Nc1cc(C(F)(F)F)ccc1C#N)c1cc(C(F)(F)F)ccc1C#N

Procedure:
A solution of 10.0 g. (0.026 mol.) of 1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene, 6.0 g. (0.029 mol.) of N,N-dicyclohexylcarbodiimide and 5.1 g. (0.026 mol.) of 4-diethylaminobutyric acid hydrochloride in 800 ml. of methylene chloride is stirred at 25° for 12 hours. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure to give a residue which is washed with ether and recrystallized from benzene to give 3-[4-(N,N-diethylamino)butyryl]-1,3-bis(2-cyano-5-trifluoromethylphenyl)-triazene hydrochloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1)(=[O:20])=[O:19]
Reactant: Cn1cccc1CCN
Reactant: COc1ccccc1S(=O)(=O)Cl
Product: COc1ccccc1S(=O)(=O)NCCc1cccn1C

Procedure:
Prepared from 2-(2-aminoethyl)-1-methylpyrrol and 2-methoxybenzenesulphonylchloride analogously to Example A.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.C(O)(=O)C.O.[N+:16]([CH:19]([CH:22]=O)[CH:20]=O)([O-:18])=[O:17].[Na]>C(O)(=O)C.O>[CH3:2][O:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[N:10]=[CH:22][C:19]([N+:16]([O-:18])=[O:17])=[CH:20]2
Reactant: COc1ccc(N)cc1
Reactant: O=CC(C=O)[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2ncc([N+](=O)[O-])cc2c1
Temperature: 4 °C
Yield: 59.6 %

Procedure:
p-Anisidine hydrochloride (35.0 g, 219.4 mmol) was weighed into a dry 300 mL three-necked round-bottomed flask, equipped with a magnetic stirring bar, a pressure-equalizing addition funnel, a solid addition funnel and a thermometer. Glacial acetic acid (150 mL) was added to the solid, with vigorous stirring to maintain a homogeneous suspension. To this suspension was added sodium nitromalonaldehyde monohydrate (12.0 g, 76.4 mmol) and the mixture stirred for 1.0 h at 25° C. A short-path distillation head was placed on the flask and approximately 120 mL of acetic acid/water removed under reduced pressure at 40° C. To the residue (imine 13) was added glacial acetic acid (40 mL) and sulfolane (75 mL). The resulting solution was flushed with argon to :remove air and the flask immersed in an oil bath preheated to 195° C. The mixture was vigorously stirred while acetic acid was removed by distillation. When the temperature reached 184°-185° C. the mixture was stirred for a further 15 min at 185° C. and then poured (while still at ca. 180° C.) onto crushed ice (750 g). The resulting solution was allowed to stand in a refrigerator (overnight) until precipitation was complete. The dark brown solid precipitate was filtered and transferred to a round-bottomed flask (500 mL) containing 2M hydrochloric acid (250 mL). The mixture was heated at reflux for 50-60 min and the boiling; solution filtered through a preheated Buchner funnel to remove an insoluble brown gum. The hot filtrate was cooled to ca. 4° C. and extracted with chloroform (4×50 mL). The combined extracts were dried (MgSO4) and the chloroform removed on a rotatory evaporator to give the crude 3-nitro-6-methoxyquinoline 14 (9.3 g, brown solid).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>>[CH2:23]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CCCCCCCCCCCCCBr
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCCCCCCN1CCC(C(N)=O)CC1
Yield: 101.2 %

Procedure:
Prepared from isonipecotamide (2.0 g, 15.6 mmol), 1-bromotridecane (4.0 mL, 15.6 mmol) and potassium carbonate (2.16 g, 15.6 mmol) of according to procedure used for Example 8 (Step A) to give 4.9 g of the title compound as a white solid.
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][C@H:3]1[OH:18].[H-].[Na+].[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[N:26]=[C:25]2[C:37]1[CH:42]=[C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[N:40]=[C:39](S(C)(=O)=O)[N:38]=1>C1COCC1>[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[N:26]=[C:25]2[C:37]1[CH:42]=[C:41]([O:43][CH2:44][C:45]2[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=2)[N:40]=[C:39]([O:18][C@H:3]2[C@H:2]([F:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:9])[CH2:4]2)[N:38]=1
Reactant: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)nc(S(C)(=O)=O)n2)cc1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](F)[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)nc(O[C@@H]3CN(C(=O)OCc4ccccc4)CC[C@H]3F)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of benzyl trans-4-fluoro-3-hydroxypiperidine-1-carboxylate (racemic) (0.486 g, 1.92 mmol) in dry THF (10 mL) at 0° C. was added NaH (0.126 g, 5.24 mmol) and the reaction was stirred at RT for 30 min. A solution of 5-bromo-3-(6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1 g, 1.74 mmol) in dry THF (5 mL) was added drop wise to the above mixture and the reaction was stirred for 2 h. The reaction was quenched with ice cold water (10 mL) and extracted with EtOAc (2×20 mL) and the combined organic layers were dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 35% EtOAc in petroleum ether) to give benzyl 3-((4-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-6-((4-methoxybenzyl)oxy)pyrimidin-2-yl)oxy)-(trans)-4-fluoropiperidine-1-carboxylate (racemic) (1 g, 77%) as a off white solid. MS (ESI, pos. ion) m/z: 745.7 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Cl[CH2:22][C:23]1[C:24]([CH3:29])=[N:25][O:26][C:27]=1[CH3:28]>>[CH3:29][C:24]1[C:23]([CH2:22][N:15]2[CH2:16][C:17](=[O:18])[N:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:20])[CH:12]=3)[C:14]2=[O:19])=[C:27]([CH3:28])[O:26][N:25]=1
Reactant: Cc1noc(C)c1CCl
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1CN1CC(=O)N(c2cnn(Cc3c(C)noc3C)c2)C1=O
Yield: 50 %

Procedure:
Prepared as in Example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione and 4-(chloromethyl)-3,5-dimethylisoxazole. Yield: 50%. 1H NMR (CDCl3, 400 MHz): 2.19 (s, 3H), 2.27 (s, 3H), 2.43-2.42 (d, J=5.2 Hz, 6H), 3.82 (s, 2H), 4.40 (s, 2H), 5.05 (s, 2H), 7.92 (s, 1H), 8.05 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.04 μM.
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].CC1C=CC(S(O[CH2:21][CH2:22][CH2:23][C:24]2[C:32]3[C:27](=[C:28]([C:33]4[N:37]=[C:36]([C:38]5[CH:43]=[CH:42][C:41]([O:44][CH:45]([CH3:47])[CH3:46])=[C:40]([Cl:48])[CH:39]=5)[O:35][N:34]=4)[CH:29]=[CH:30][CH:31]=3)[N:26]([CH3:49])[CH:25]=2)(=O)=O)=CC=1>CN(C=O)C>[Cl:48][C:40]1[CH:39]=[C:38]([C:36]2[O:35][N:34]=[C:33]([C:28]3[CH:29]=[CH:30][CH:31]=[C:32]4[C:27]=3[N:26]([CH3:49])[CH:25]=[C:24]4[CH2:23][CH2:22][CH2:21][O:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:37]=2)[CH:43]=[CH:42][C:41]=1[O:44][CH:45]([CH3:46])[CH3:47]
Reactant: CCOC(=O)CO
Reactant: Cc1ccc(S(=O)(=O)OCCCc2cn(C)c3c(-c4noc(-c5ccc(OC(C)C)c(Cl)c5)n4)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COCCCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
To a stirred solution of ethyl hydroxyacetate (90 mg) in DMF (4 mL) at 20° C. was added NaH (69 mg), the mixture was stirred for 15 mins. Then a solution of 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propyl 4-methylbenzenesulfonate (D129) (100 mg) in DMF (4 mL) was added dropwise during 1 min. The reaction was stirred at 20° C. for 48 h. The reaction mixture was quenched with water, partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was washed with water and brine, dried over sodium sulphate and evaporated to give the crude product ethyl ({3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propyl}oxy)acetate (D105) (80 mg). MS (ES): C27H30ClN3O5 requires 511; found 512.2 (M+H+).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[CH2:31]([N:34]=[C:35]=[O:36])[CH:32]=[CH2:33]>>[CH2:31]([N:34]1[CH:11]([C:13]([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:19][CH2:20]2)=[O:14])[CH2:12][N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:35]1=[O:36])[CH:32]=[CH2:33]
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Reactant: C=CCN=C=O
Agent: [I-]
Agent: [Na+]
Product: C=CCN1C(=O)N(S(=O)(=O)c2ccccc2)CC1C(=O)N1CCN(c2cc(C)ccc2C)CC1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and allyl isocyanate to give the title compound as a colorless solid. MS: 483.2 ([M+H]+)
Reaction SMILES: [OH:1][CH:2]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=N)[CH2:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1.S(=O)(=O)(O)[OH:26]>>[OH:26][C:9]1[C:8]2[C:13](=[CH:14][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:6][CH:7]=2)[O:12][C:11](=[O:15])[CH:10]=1
Reactant: N=C1CC(=O)Oc2cc(OCC(O)COc3ccccc3)ccc21
Reactant: O=S(=O)(O)O
Product: O=c1cc(O)c2ccc(OCC(O)COc3ccccc3)cc2o1
Reaction time: 4.5 h
Yield: 34.6 %

Procedure:
A solution of 3,4-dihydro-7-(2-hydroxy-3-phenoxypropoxy)-4-iminocoumarin (6.5 g; 0.02 mole) in 50% w/v sulphuric acid (80 g) was stirred at 100° for 3-6 hours. The initial pale red solution precipitated a yellow solid which after cooling and dilution with water was separated by decantation. After several decantations with water the oily solid as taken up in hot ethanol, charcoaled, filtered and the filtrate gradually diluted with water. The precipitated oily solid crystallised overnight to give 2.934 of buff solid of m.p. 145°-175°. Recrystallisation from aqueous methanol gave 2.275 g (34%) of material of m.p. 181°-183°, νmax (mull) 3250, 3060, 1705, 1610 cm-1 ; τ(DMSO); 5.85 (5H, m); 4.75 (1H broad exchangeable); 4.50 (1H, sharp exchangeable singlet); 3.19-2.50 (7H, complex m); 2.22 (1H, d, J 9.0 Hz); 1 low field exchangeable singlet. (Found; C, 65.48; H, 5.19; C18H16O6 requires; C, 65.85; H, 4.91%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]([C@@H:30]1[CH2:34][N:33]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)=[O:36])[C@H:32]([C:48]([C:50]2[N:51]=[CH:52][N:53]3[CH:57]=[C:56]([Sn](CCCC)(CCCC)CCCC)[S:55][C:54]=23)=[O:49])[CH2:31]1)=[N+:28]=[N-:29]>>[N:27]([C@@H:30]1[CH2:34][N:33]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)=[O:36])[C@H:32]([C:48]([C:50]2[N:51]=[CH:52][N:53]3[CH:57]=[C:56]([C:8]4[C@H:9]([CH3:10])[C@@H:5]5[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]5[C:7]=4[C:12]([O:14][CH2:15][C:16]4[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=4)=[O:13])[S:55][C:54]=23)=[O:49])[CH2:31]1)=[N+:28]=[N-:29]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)[C@@H]3C[C@H](N=[N+]=[N-])CN3C(=O)OCc3ccc([N+](=O)[O-])cc3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)[C@@H]5C[C@H](N=[N+]=[N-])CN5C(=O)OCc5ccc([N+](=O)[O-])cc5)c4s3)[C@H](C)[C@H]12

Procedure:
A crude compound (261 mg) of 4-nitrobenzyl (1S,5R,6S)-2-[7-[(2S,4S)-4-azido-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate was prepared in the same manner as in Example, except that 157 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 321 mg of 7-[(2S,4S)-4-azido-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-2-yl]carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH2:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22](Cl)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Solvent: c1ccncc1
Product: CC(=O)NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Temperature: 25 °C

Procedure:
C-(6-Benzenesulfonyl-naphthalen-1-yl)-methylamine is dissolved in pyridine and acetyl chloride is added. The reaction mixture is stirred at room temperature and then quenched by addition of water. The mixture is extracted with EtOAc, and the organic layer is dried (MgSO4), filtered, and concentrated under reduced pressure to give N-(6-benzenesulfonyl-naphthalen-1-ylmethyl)-acetamide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH3:12][O:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][CH2:14][O:13][CH3:12])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCOc1ccc(O)c(C(C)=O)c1
Temperature: 25 °C
Yield: 50 %

Procedure:
To a solution (250 mL) of 1-(2,5-dihydroxyphenyl)ethanone (11.0 g) in acetonitrile were added 2-methoxyethylbromide (19.6 mL) and potassium carbonate (12.0 g) at room temperature, and the mixture was heated under reflux for 15 hr. The reaction mixture was allowed to cool to room temperature and filtered through celite, and the filtrate was concentrated under reduced pressure. Saturated aqueous ammonium chloride solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10, volume ratio) to give the title object compound (7.6 g, 50%) as a pale-yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[C:10]([CH3:24])([CH3:23])[C@H:11]([NH:15]C(OC(C)(C)C)=O)[C:12](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[C:32]([NH2:37])[CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[NH2:15][C@H:11]([C:12]1[NH:36][C:33]2[CH:34]=[CH:35][C:30]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:31][C:32]=2[N:37]=1)[C:10]([CH3:23])([CH3:24])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Product: CC(C)(C)c1ccc2[nH]c([C@@H](N)C(C)(C)C(=O)OCc3ccccc3)nc2c1

Procedure:
The title compound was prepared according to Method 1 Steps 1 and 2 using (2S)-4-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethyl-4-oxobutanoic acid (Preparation 44) and 4-tert-butyl-1,2-diaminobenzene.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9](/[CH:13]=[CH:14]/[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:16])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.[N:25]1[CH:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27][CH:26]=1>>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]([CH2:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[O:16])[C:31]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)=[O:32])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: O=Cc1ccncc1
Reactant: CON=C1CCc2cc(/C=C/C(=O)c3ccc(OC)cc3)ccc21
Product: CON=C1CCc2cc(C(CC(=O)c3ccc(OC)cc3)C(=O)c3ccncc3)ccc21
Yield: 86 %

Procedure:
The title compound (8.82 g, 86%) was prepared from the product of Step 1 and pyridine-4-carboxaldehyde fusing the method of Example 1 Step 4; MS(ES+) m/e 429 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[C:12]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>O>[C:12]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][CH:15]=[C:14]([C:2]2[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=2)[CH:13]=1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: CC(C)(C)c1ccnc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)c1ccnc(-c2cccc(-c3ccccc3)c2)c1
Yield: 8.9 %

Procedure:
15.0 g (0.7 mol) of 2-bromo-4-tert-butyl-pyridine was added to 13.8 g (0.7 mol) of 3-biphenylboronic acid, 2.4 g (0.002 mol) of Pd(Ph3)4, 26 g (0.188 mol) of K2CO3, 100 mL of DME and 100 mL of water. The reaction mixture was refluxed for 20 hours and separated on silica gel column with 10% ethyl acetate in hexane. ˜18.0 g (˜90% yield) 2-(biphenyl-3-yl)-4-tert-butylpyridine was obtained. MS confirmed the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][NH:13][C:14](=O)[CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[S:11])[CH:5]=[CH:6][C:7]=1[Cl:8].S(=O)(=O)(O)O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[S:11][C:14]([CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(COc1ccc2c(c1)CCC(=O)N2)NNC(=S)Nc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Product: O=C1CCc2cc(OCc3nnc(Nc4ccc(Cl)c(Cl)c4)s3)ccc2N1
Yield: 31.3 %

Procedure:
N-(3,4-dichlorophenyl)-2-(2-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)oxy)acetyl)hydrazinecarbothioamide (0.15 g, 0.341 mmol) and concentrated sulfuric acid (1 mL) were placed in a reaction beaker and the mixture was subjected to ultrasonic irradiation for 15 min. The reaction contents were poured into ice cold water. The precipitate was filtered and basified with 10% sodium bicarbonate (30 mL). Crude product was crystallized with ethanol/DMSO to afford 6-((5-(3,4-dichlorophenylamino)-1,3,4-thiadiazol-2-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (0.045 g, 31%) as an off white solid. 1H NMR 400 MHZ, DMSO-d6: δ 2.42 (dd, J=7.20, 8.20 Hz, 2H), 2.85 (t, J=7.60 Hz, 2H), 5.37 (s, 2H), 6.79 (d, J=8.80 Hz, 1H), 6.88 (dd, J=2.40, 8.60 Hz, 1H), 6.95 (d, J=2.00 Hz, 1H), 7.48 (dd, J=2.40, 8.80 Hz, 1H), 8.08 (d, J=2.80 Hz, 1H), 9.96 (s, 1H), 10.75 (s, 1H). LCMS: RT 1.97 min, LCMS (ES-API), m/z 423.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].Cl.[OH-].[NH4+].[CH:13](O)=O>>[CH3:9][C:3]1[C:2]2[N:1]=[CH:13][NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=CO
Reactant: Cc1cccc(N)c1N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cccc2[nH]cnc12

Procedure:
To a flask were added 2.0 g 2,3-diaminotoluene, 1.0 g 90% formic acid and 30 ml 5M hydrochloric acid and the mixture was heated to 90 C under nitrogen for 4 hours. After cooling to 22 C, the mixture was basified with aqueous ammonium hydroxide and the product was removed by filtration and washed with water. The product was purified by column chromatography using pure ethyl acetate resulting in 1.0 g brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH2:22](Cl)[O:23][CH2:24][CH2:25][O:26][CH3:27]>C(Cl)Cl>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:7][CH:6]=1
Reactant: COCCOCCl
Reactant: COC(=O)Cc1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-hydroxyphenylacetate (200 mg, 1.20 mmol) in DCM (5 ml) is added DIPEA (0.315 ml, 1.81 mmol), and then MEMCl (0.204 ml, 1.81 mmol), and the resulting reaction mixture is stirred for 2 hours at room temperature. An additional portion of MEMCl (0.102 ml, 1 mmol) and of DIPEA (0.158 ml, 1 mmol) are added, and the reaction mixture is stirred for a further 16 hours. An additional portion of MEMCl (0.102 ml, 1 mmol) and of DIPEA (0.158 ml, 1 mmol) are added and the reaction mixture is stirred for 3 hours. The reaction mixture is diluted with DCM and washed with 0.5 M HCl, 1 M NaOH and then 0.5 M HCl, dried (MgSO4) and concentrated in vacuo to afford [4-(2-Methoxy-ethoxymethoxy)-phenyl]-acetic acid methyl ester
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:24]2[C:8]3[N:9]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:10]4[C:15]([C:16](=[O:17])[C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=1)=[CH:14][CH:13]=[CH:12][N:11]=4.[H][H]>[Pd].C(O)C>[OH:1][C:2]1[CH:26]=[CH:25][C:24]2[C:8]3[N:9]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:10]4[NH:11][CH2:12][CH2:13][CH2:14][C:15]=4[C:16](=[O:17])[C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: O=c1c2c(n(-c3ccccc3)c3ncccc13)-c1ccc(O)cc1CC2
Agent: [Pd]
Solvent: CCO
Product: O=c1c2c(n(-c3ccccc3)c3c1CCc1cc(O)ccc1-3)NCCC2

Procedure:
Charge a Paar bottle with 5,6-dihydro-3-hydroxy-12-phenyl-naphtho[1,2-b] [1,8]naphthyridin-7(12H)-one, an equal weight of 5% Pd on carbon, and ethanol. Pressurize the bottle with hydrogen to about 50 psi, and shake the contents in a Paar apparatus at 25° C. Monitor the progress of hydrogenation by pressure changes or by thin-layer chromatography. When hydrogen uptake ceases, remove catalyst by filtration and ethanol by evaporation. Crystallize the residue to obtain 5,6,8,9,10,11-hexahydro-3-hydroxy-12-phenyl-naphtho[1,2-b] [1,8]naphthyridin-7(12H)-one, m.p. >330° C. after crystallization from C2H5OH.