Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[CH:46]=[CH:45][C:7]([O:8][CH2:9][C:10]([NH:12][C@H:13]([C:18]([NH:20][C@@H:21]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:22]([OH:37])[C:23]([N:25]2[CH2:36][CH2:35][CH2:34][C@H:26]2[C:27]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:24])=[O:19])[CH2:14][C:15](=[O:17])[NH2:16])=[O:11])=[CH:6][CH:5]=1.[N+:47]([C:50]1[CH:59]=[CH:58][C:53]([O:54][C:55](Cl)=[O:56])=[CH:52][CH:51]=1)([O-:49])=[O:48]>>[N+:47]([C:50]1[CH:59]=[CH:58][C:53]([O:54][C:55]([N:3]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([NH:12][C@H:13]([C:18]([NH:20][C@@H:21]([CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C@H:22]([OH:37])[C:23]([N:25]3[CH2:36][CH2:35][CH2:34][C@H:26]3[C:27]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:24])=[O:19])[CH2:14][C:15](=[O:17])[NH2:16])=[O:11])=[CH:45][CH:46]=2)[CH3:2])=[O:56])=[CH:52][CH:51]=1)([O-:49])=[O:48]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNc1ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)N2CCC[C@H]2C(=O)NC(C)(C)C)cc1
Agent: Cl
Product: CN(C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)N2CCC[C@H]2C(=O)NC(C)(C)C)cc1
Yield: 20.2 %

Procedure:
Following a procedure similar to that described in Example 30, but using 500 mg (0.76 mmol) of 1-{(2S,3S)-3-[N2 -(p-methylaminophenoxy)acetyl-L-asparaginyl]amino-2-hydroxy-4-phenylbutyryl}-N-t-butyl-L-prolinamide hydrochloride (prepared as described in Example 20) and 236 mg (1.13 mmol) of 4-nitrophenoxycarbonyl chloride, 121 mg of the title compound were obtained as a colorless powder, melting at 116°-119° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH3:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1cccc([N+](=O)[O-])c1Cl
Reactant: C1CCNCC1
Product: Cc1cccc([N+](=O)[O-])c1N1CCCCC1
Yield: 35 %

Procedure:
Using a procedure similar to Example 8, step (a), 2-chloro-3-methylnitrobenzene (264 mg, 1.53 mmol) was heated to 110° C. overnight in 3 mL of piperidine to afford 128 mg (35%) of the title compound and an undetermined amount of starting material. 1H-NMR (CDCl3; 400 MHz): δ 7.41-7.34 (m, 2H), 7.02 (t, 1H, J=7.7 Hz), 2.96-2.93 (m, 4H), 2.36 (s, 3H), 1.65 (br s, 6H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:31]2[CH2:35][S:34][C:33](=[O:36])[N:32]=2)=[N:25]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:35]2/[C:31]([NH:30][CH2:29][C:26]3[CH:27]=[CH:28][O:24][N:25]=3)=[N:32][C:33](=[O:36])[S:34]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(NCc2ccon2)CS1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(NCc2ccon2)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (413 mg) in 2-propanol (5 mL) were added 4-[(isoxazol-3-ylmethyl)amino]thiazol-2(5H)-one (480 mg) and piperidinium acetate (90 mg). The reaction mixture was stirred at 80° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (454 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9](Cl)[C:8]=2[N:7]=[CH:6]1.[NH3:19]>CO>[NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:19])[C:8]=2[N:7]=[CH:6]1
Reactant: N
Reactant: NCCCn1cnc2c(Cl)nc3ccccc3c21
Solvent: CO
Product: NCCCn1cnc2c(N)nc3ccccc3c21

Procedure:
14 mg (0.0536 mmol) of 1-(3-aminopropyl)-4-chloro-1H-imidazo[4,5-c]quinoline, 5 ml of methanol and 3 ml of liquid ammonia were stirred in an autoclave overnight at 150° C. under heating. The reaction mixture was concentrated under reduced pressure and 0.3 ml of a 1N sodium hydroxide solution was added to the residue. The precipitate thus formed was collected by filtration to obtain 8 mg (0.0331 ml) of 1-(3-aminopropyl)-1H-imidazo[4,5-c]quinoline-4-amine shown below. ##STR38## The physicochemical data of this compound was in agreement with the compound of Example 5.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11]P(=O)(OCC)OCC.[H-].[Na+].[CH:22]([C:24]1[S:25][CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=1)=O.O>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:22]/[C:24]1[S:25][CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=1
Reactant: CCOP(=O)(Cc1ccc2ccccc2n1)OCC
Reactant: CCOC(=O)c1csc(C=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1csc(/C=C/c2ccc3ccccc3n2)n1
Reaction time: 0.17 h

Procedure:
Diethyl 2-quinolinylmethylphosphonate (0.580 g, 2.08 mmol; see Preparation 13(i) above) was dissolved in anhydrous THF (2 mL), NaH (0.273 g, 11 mmol) was then added in small portions and the resulting solution allowed to stir for 10 min. Ethyl 2-formyl-1,3-thiazole-4-carboxylate (0.387 g, 2.08 mmol; see step (v) above) in anhydrous THF (3 mL) was added dropwise and the solution allowed to stir for 16 h. Water (5 mL) was then added (dropwise initially), during which time the sub-title compound precipitated as a light brown/yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:12]OCC)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][N:27]=1>CC(N(C)C)=O>[Br:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][CH:12]=[C:11]([S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:10])=[O:9])[S:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:17])=[O:18])=[N:27][CH:28]=1
Reactant: CCOC=C(S(=O)(=O)c1ccccc1)S(=O)(=O)c1cccc(Cl)c1
Reactant: Nc1ccc(Br)cn1
Solvent: CC(=O)N(C)C
Product: O=S(=O)(C(=CNc1ccc(Br)cn1)S(=O)(=O)c1cccc(Cl)c1)c1ccccc1
Yield: 60.1 %

Procedure:
A solution of 1-(3-chlorophenylsulphonyl)-2-ethoxy-1-phenylsulphonylethene (3.13 g) and 2-amino-5-bromopyridine (1.4 g) in dimethylacetamide (20 ml) was heated at reflux for 3.5 hours. The solution was cooled and poured onto ice (200 g), and the resulting pale yellow solid was filtered off and recrystallised from aqueous ehtaol (95% v/v), to give 2-(5-bromopyrid-2-ylamino)-1-(3-chloropheylsulphonyl)-1-phenylsulphonylethene (2.5 g), m.p. 170°-172° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:39]=[CH:40][CH:41]=1)[CH2:11][N:12]1[C:16](=[O:17])[C:15]2([CH2:22][CH2:21][N:20](C(OCC3C=CC=CC=3)=O)[CH2:19][CH2:18]2)[N:14]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[O:17]=[C:16]1[C:15]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:14]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:13][N:12]1[CH2:11][C:10]1[CH:9]=[C:8]([CH:41]=[CH:40][CH:39]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A solution of benzyl 3-(3-(tert-butoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (5 g, 9.0 mmol, 1 equiv) in a mixture of ethyl acetate and ethanol was charged with 10% palladium on carbon (1 g, 20%/wt) and the resulting mixture was stabilized to a hydrogen atmosphere. The reaction was stirred as such for 2 h, filtered through Celite and the filtrate was concentrated in vacuo to afford the title compound as a grey foam (3.69 g, 97%); 1H NMR (400 MHz, DMSO-d6): δ 1.52 (s, 9H); 1.54-1.56 (m, 2H); 2.43-2.49 (m, 2H); 2.88-2.93 (m, 2H); 3.18-3.24 (m, 2H); 4.58 (s, 2H); 4.62 (s, 2H); 6.74 (t, 2H, J=6.8 and 7.6 Hz); 6.88 (d, 2H, J=8 Hz); 7.18-7.22 (m, 2H); 7.49-7.55 (m, 2H); 7.79-7.85 (m, 2H); MS for C25H31N3O3 m/z 422.24 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=O)[CH3:14]>CCOC(C)=O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([NH:6]/[N:7]=[C:13](/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)\[CH3:14])=[O:5]
Reactant: NNC(=O)c1cc(F)ccc1F
Reactant: CC(=O)c1ccccc1
Solvent: CCOC(C)=O
Product: C/C(=N\NC(=O)c1cc(F)ccc1F)c1ccccc1

Procedure:
A solution of 2,5-difluorobenzohydrazide (1-2, 90 mg, 0.52 mmol, 1 equiv) and acetophenone (61 μL, 0.52 mmol, 1.0 equiv) was heated in EtOAc (10 mL) at 75° C. for 3 d. The reaction mixture was concentrated to give 2,5-difluoro-N′-[(1E)-1-phenylethylidene]benzohydrazide (2-1); LRMS m/z (M+H) 275.1 found, 275.1 required. A solution of 2-1 in acetic anhydride (5 mL) was heated at reflux for 1.5 h. The reaction mixture was concentrated and the residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide 3-acetyl-5-(2,5-difluorophenyl)-2-methyl-2-phenyl-2,3-dihydro-1,3,4-oxadiazole (2-2) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.56 (m, 2H), 7.48 (m, 1H), 7.39 (m, 3H), 7.14 (m, 2H), 2.35 (s, 3H), 2.30 (s, 3H). LRMS m/z (M+H) 317.2 found, 317.1 required.
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:26]([Sn](CCCC)(CCCC)CCCC)=[CH2:27]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH:26]=[CH2:27])[C:11]([C@@H:12]([N:14]1[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]1=[O:23])[CH3:13])=[CH:10]2
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1nc2c(Cl)cccc2cc1[C@H](C)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C

Procedure:
To a stirred solution of (S)-2-(1-(2,8-dichloroquinolin-3-yl)ethyl)isoindoline-1,3-dione (1 g, 2.7 mmol) in dioxane (25 mL) under a nitrogen atmosphere was added vinyl tributyltin (1.28 mL, 4.04 mmol) and tetrakis(triphenylphosphine)palladium (156 mg, 0.13 mmol). The reaction was heated at 100° C. for 3 hours and then the solvent was evaporated in vacuo. The resulting black residue was purified by column chromatography (40 g SiO2, Hexanes:Ethyl acetate, 1:0 to 3:1) to give (S)-2-(1-(8-chloro-2-vinylquinolin-3-yl)ethyl)isoindoline-1,3-dione as a white solid. 1H-NMR (400 MHz, CDCl3) δ ppm 8.53 (1H, s), 7.76-7.81 (4 H, m), 7.68-7.72 (2H, m), 7.41 (1H, dd, J=7.8, 7.8 Hz), 7.26-7.33 (1H, m), 6.71 (1H, dd, J=16.4, 2.3 Hz), 6.00 (1H, q, J=7.3 Hz), 5.64 (1H, dd, J=10.6, 2.3 Hz), 2.00 (3H, d, J=7.0 Hz). Mass Spectrum (ESI) m/e=362.8 (M+1).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:58][CH2:59][CH3:60])[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:9]=1[C:10]([O:12][CH2:13][O:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[O:11])([CH3:4])[CH3:3]>C(O)(=O)C>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:58][CH2:59][CH3:60])[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:24][CH:23]=2)[C:9]=1[C:10]([O:12][CH2:13][O:14][C:15]([O:17][CH:18]([CH3:19])[CH3:20])=[O:16])=[O:11])([CH3:4])[CH3:3]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)OC(C)C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)OC(C)C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 88 %

Procedure:
Following a procedure similar to that described in Example 61(b), 0.78 g of isopropoxycarbonyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] was detritylated by heating it with 75% v/v aqueous acetic acid to give 0.48 g of the title compound as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH2:16]([N:13]1[CH2:12][CH:11]=[C:10](/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:15][CH2:14]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Fc1ccc(/C=C/c2ccncc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Fc1ccc(/C=C/C2=CCN(Cc3ccccc3)CC2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 43.4 %

Procedure:
To a solution of (E)-4-[2-(4-fluorophenyl)ethenyl]pyridine (18.75 g, 94.2 mmol) in dimethylformamide (30 ml) at 90° C. was added benzyl bromide (11.9 ml, 100 mmol) and the reaction stirred at 90° C. for 1 hour. The reaction was cooled to room temperature, diluted with ethanol (400 ml) and sodium borohydride (4 g, 105 mmol) added in portions. The reaction was stirred at room temperature for 2 hours, after which time the solvent was evaporated to a slurry. Methanol was added, and the resultant solid filtered and dried to yield (E)-1-benzyl-4-[2-(4-fluorophenyl)ethenyl]-1,2,3,6-tetrahydropyridine (12 g, 44%) as a white solid. δH (CDCl3) 2.41 (2H, br s, tetrahydropyridinyl CH2), 2.68 (2H, t, J 5.8 Hz, tetrahydropyridinyl CH2), 3.14 (2H, br s, tetrahydropyridinyl CH2), 3.63 (2H, s, NCH2Ar), 5.80 (1H, br s, tetrahydropyridinyl 5-CH), 6.40 (1H, d, J 16.2 Hz, ArCHCHC), 6.69 (2H, d, J 16.2 Hz, ArCHCHC), 6.96-7.02 (2H, m, ArH) and 7.25-7.39 (7H, m, ArH).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][N:5]=1)([O-:3])=[O:2].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.[OH-].[Li+].CN(C=O)C>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:18][C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)=[CH:6][N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Reactant: Sc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Sc2ccc(Cl)cc2)cn1

Procedure:
2-Nitro-5-chloropyridine (9.5 grams), 4-chlorothiophenol (8.7 grams), and lithium hydroxide (4 grams) were mixed in 100 ml. of DMF and the reaction mixture was stirred overnight (about 18 hours) at room temperature. The reaction mixture was then poured into water and the product separated by filtration and crystallized from ethanol-hexanes, yield, 10.0 grams, m.p., 96°-98° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7](=[O:10])[S:8][CH:9]=1)=O.[OH-].[NH4+:12]>>[NH2:12][C:3]([C:5]1[NH:6][C:7](=[O:10])[S:8][CH:9]=1)=[O:2]
Reactant: COC(=O)c1csc(=O)[nH]1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1csc(=O)[nH]1
Reaction time: 24 h

Procedure:
48 g of 4-methoxycarbonyl-4-thiazoline-2-one were added to 600 ml of concentrated aqueous ammonium hydroxide and the mixture was stirred for 24 hours. The mixture was acidified and filtered to obtain 30 g of 4-aminocarbonyl-4-thiazoline-2-one in the form of white crystals melting at 261°C.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:29]=[N:28][C:10]3[N:11]([CH3:27])[C:12](=[O:26])[N:13]([CH2:16][CH2:17][CH2:18][O:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][O:21]4)[C:14](=[O:15])[C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[F:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]=[O:46])=[CH:43][CH:42]=1>C1COCC1>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:29]=[N:28][C:10]3[N:11]([CH3:27])[C:12](=[O:26])[N:13]([CH2:16][CH2:17][CH2:18][O:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][O:21]4)[C:14](=[O:15])[C:9]=3[C:8]=2[CH:45]([C:44]2[CH:47]=[CH:48][C:41]([F:40])=[CH:42][CH:43]=2)[OH:46])=[CH:4][CH:3]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3ccc(Cl)cc3)cnc21
Reactant: O=Cc1ccc(F)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(F)cc3)c(Oc3ccc(Cl)cc3)cnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
To a solution of 6-(4-chlorophenoxy)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (110 mg, 0.25 mmol) in THF (5 mL) at −78° C. was added LDA (2.0 M in THF, 0.63 mL, 1.25 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then a solution of 4-fluorobenzaldehyde (62 mg, 0.50 mmol) in THF (1 mL) was added dropwise. The reaction was stirred at −78° C. for 1 h, quenched with sat. aq. NH4Cl (5 mL) then diluted with EA (30 mL) and water (30 mL). The organic layer was dried over Na2SO4 and concentrated to give a residue which was purified by chromatography eluted with PE/EA (7:1) to give 6-(4-chlorophenoxy)-5-((4-fluorophenyl)(hydroxy)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (55 mg, 40% yield) as a solid. LCMS: [M++Na] 592 and TR=3.372 min.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]([C:7]1[CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=2[Cl:26])[C:9]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([CH3:14])[NH:11][C:12]=1[CH3:13])=[O:6].[F:27][C:28]1[CH:41]=[CH:40][C:31]([C:32]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[O:33])=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([CH:34]2[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][O:4][C:5]([C:7]3[CH:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=4[Cl:26])[C:9]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([CH3:14])[NH:11][C:12]=3[CH3:13])=[O:6])[CH2:36][CH2:35]2)=[O:33])=[CH:40][CH:41]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCl)C1c1cccc(Cl)c1Cl
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCC(C(=O)c3ccc(F)cc3)CC2)C1c1cccc(Cl)c1Cl
Reaction time: 1 h

Procedure:
A mixture of 8.4 g of 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl ester 2-chloroethyl ester and 8.8 g of 4-(p-fluorobenzoyl)-piperidine is stirred under argon for 1 hour at a temperature of 145°. After working up, the resulting residue is chromatographed over 500 g of silica gel, yielding 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl ester 2-[4-(p-fluorobenzoyl)-piperidino]-ethyl ester in amorphous form which exhibits the following characteristic bands in th NMR spectrum: 1H-NMR (CDCl3): 2.3 and 2.4 [2S, 6H, 2 H3C--C (2 and 6)]; 3.6 [s, 3H, H3C--OOC]; 5.4 [s, 1H, H-c (4)], 7.1-8.1 (m, 7H, 7 arom. H). Rf value: 0.40 (hexane/ethyl acetate/methanol=4:2:1).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.C(O)(=O)C.[N:21]([O-])=[O:22].[Na+]>O>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([N:21]=[O:22])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: O=N[O-]
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(N2CCN(N=O)CC2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 52.6 parts of 1-(4-methoxyphenyl)piperazine dihydrochloride, 100 parts of acetic acid and 100 parts of water is added dropwise, during a 1.50 hours-period, a solution of 20.8 parts of sodium nitrite in 100 parts of water at a temperature between 0° and 5° C. Upon completion, stirring is continued for 30 minutes. The reaction mixture is diluted with water. The precipitated product is filtered off and crystallized from 2-propanol, yielding 22.5 parts of 1-(4-methoxyphenyl)-4-nitrosopiperazine, mp. 94.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[OH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]4[CH:31]=[CH:32][C:27]([CH2:26][OH:25])=[CH:28][CH:29]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccc(CO)cc4)cc32)N=C1N
Temperature: 120 °C
Yield: 5.4 %

Procedure:
Pd(PPh3)2Cl2 (5 mg, 0.007 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(hydroxymethyl)phenylboronic acid (17 mg, 0.104 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and HPLC to give 2′-amino-6-(4-(hydroxymethyl)phenyl)-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (1.16 mg, 5%). 1H-NMR (MeOD): 2.42 (m, 1H), 2.57 (m, 1H), 3.31 (m, 3H), 4.15 (s, 2H), 5.83 (m, 1H), 7.09 (m, 1H), 7.28 (m, 1H), 7.38 (m, 4H), 7.47 (m, 3H), 7.56 (m, 1H), 7.61 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.CC1(C)[O:25][C:24](=O)[C:21]2([CH2:23][CH2:22]2)[C:20](=[O:27])[O:19]1.C(OCC)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:23][CH2:22][CH:21]([C:20]([OH:27])=[O:19])[C:24]2=[O:25])=[CH:9][CH:8]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)C1CCN(c2ccc(OCc3cccc(F)c3)cc2)C1=O
Yield: 56.6 %

Procedure:
A solution of 561 mg (2.6 mmol) 4-(3-fluoro-benzyloxy)-phenylamine and 448 mg (2.6 mmol) 6,6-dimethyl-5,7-dioxa-spiro[2,5]octane-4,8-dione in 2 ml dichloromethane is refluxed for 16 hours. 5 ml of diethylether is added and the precipitate filtered off to yield 485 mg (57%) of a colorless solid. MS: m/e=330.2 (M+H)+.