Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:16](=O)[NH:15][CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][NH:29][C:28](=[O:32])[CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][N:29]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[CH2:16][NH:15][CH2:14][CH2:13][CH2:12][C:7]=4[N:8]([CH3:11])[C:9]=3[CH:10]=2)[C:28](=[O:32])[CH:27]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)C(=O)NCCC2
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCCC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 7 %

Procedure:
8-Bromo-6-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (0.20 g, 0.68 mmol), 4-benzyloxy pyridinone (0.18 g, 0.89 mmol), and Cs2CO3 (0.24 g, 0.75 mmol) were suspended in DMSO (4.0 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar and the process repeated. 8-Hydroxyquinoline (30 mg, 0.21 mmol) and copper iodide (0.17 g, 0.89 mmol) were added to the suspension, and the evacuation/Ar flushing process was repeated twice more. The reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5:1 MeOH/NH4OH (10 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH2Cl2 (75 mL). The solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was diluted with CH2Cl2 and washed with brine (3×25 mL). The organic solution was dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes) followed by flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes, increased to 70:30 over 20 column volumes and held for 4 column volumes; increased to 25:75 over 10 column volumes) followed by trituration in hot EtOH provided the title compound (19 mg, 7%) as an off-white powder: mp 178-181° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.29 (d, J=8.5 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.53 (t, J=5.5 Hz, 1H), 7.49-7.35 (m, 6H), 7.00 (dd, J=8.5, 2.0 Hz, 1H), 6.10 (dd, J=7.5, 2.5 Hz, 1H), 5.97 (d, J=2.5 Hz, 1H), 5.15 (s, 2H), 3.68 (s, 3H), 3.21-3.10 (m, 2H), 3.12 (t, J=6.5 Hz, 2H), 2.08-2.07 (m, 2H); ESI MS m/z 414 [M+H]+; HPLC (Method A) 97.2% (AUC), tR=16.5 min.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:15])[CH2:11][CH2:12][CH2:13]Cl)=[CH:6][CH:5]=1.C(O)(=O)C>O>[CH:11]1([C:10]([C:7]2[CH:8]=[CH:9][C:4]([OH:3])=[CH:5][CH:6]=2)=[O:15])[CH2:13][CH2:12]1
Reactant: O=C(CCCCl)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1ccc(O)cc1)C1CC1
Temperature: 25 °C
Yield: 119.9 %

Procedure:
A refluxing solution of sodium hydroxide in water (50% (w/w), 40.4 mL) was treated over a period of 15 minutes with para-hydroxy-4-chlorobutyrophenone (25.0 g, 137 mmol), followed by additional aqueous sodium hydroxide (25% (w/w), 177 mL). Additional para-hydroxy-4-chlorobutyrophenone (25.0 g, 137 mmol) was added portionwise to the reaction mixture, followed by solid sodium hydroxide (40.4 g). A yellow precipitate formed. After refluxing for 60 minutes, water (50 mL) was added and the resulting mixture was refluxed for another 60 minutes, cooled to room temperature, diluted with water (100 mL) and neutralized with acetic acid. The precipitate was collected by filtration, washed with water, air-dried, and triturated at 40° C. with chloroform (1.5 L). The chloroform solution was dried (MgSO4), filtered, and concentrated. The concentrate was recrystallized from chloroform/hexanes to afford 26.65 g (95%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:7]3[CH2:16][CH2:15][CH2:14][CH:8]3[C:9](=S)[NH:10][C:11]=2[CH:12]=1.[NH3:17]>>[NH2:17][C:9]1[CH:8]2[CH2:14][CH2:15][CH2:16][CH:7]2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:11]=2[N:10]=1
Reactant: N
Reactant: COc1ccc2c(c1)NC(=S)C1CCCC21
Product: COc1ccc2c(c1)N=C(N)C1CCCC21
Yield: 79 %

Procedure:
Analogously to Example 4, 7-methoxy-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (150 mg, 0.64 mmol) in 7N methanolic ammonia solution (25 ml) is reacted to form 110 mg (79%) of product.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([Br:12])[CH:6]=1.[C:13](=[O:15])=[O:14].Cl>CCOCC.O>[Br:12][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([F:11])[CH:8]=1)[C:13]([OH:15])=[O:14]
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: O=C=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1cc(F)cc(Br)c1
Reaction time: 1 h
Yield: 55.4 %

Procedure:
Magnesium turnings (1.97 g) and iodine (catalytic amount) were added to ether (150 ml), and 1,3-dibromo-5-fluorobenzene (19.6 g) in ether (20 ml) was added dropwise under nitrogen atmosphere at such a rate that gentle reflux occurred. The mixture was refluxed for 3 hours, and left to cool. Crushed dry ice was added thereto, and the mixture was stirred for 1 hour. The reaction mixture was poured into water, and acidified with hydrochloric acid. The mixture was extracted with ether (200 ml), and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=100:1), to thereby yield 9.37 g of the target compound (yield: 55.4%).
Reaction SMILES: [N+:1]1([O-:19])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](OC2C=CC([N+]([O-])=O)=CC=2)=[O:8])[CH:2]=1.[CH3:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][C:28]2[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=2)[O:31][CH2:32][CH2:33][CH2:34][NH2:35])[CH2:22]1>CO>[CH3:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][C:28]2[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=2)[O:31][CH2:32][CH2:33][CH2:34][NH:35][C:7]([C:3]2[CH:2]=[N+:1]([O-:19])[CH:6]=[CH:5][CH:4]=2)=[O:8])[CH2:22]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc[n+]([O-])c1
Reactant: CC1CCCN(Cc2cccc(OCCCN)c2)C1
Solvent: CO
Product: CC1CCCN(Cc2cccc(OCCCNC(=O)c3ccc[n+]([O-])c3)c2)C1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To the active ester thus obtained there is added a solution of 3.8 g of 3-[3-(3-methylpiperidinomethyl)phenoxy]propylamine in 70 ml of methanol and the mixture is stirred 3 hours at 50° C. The solvent is evaporated, the residue is taken up with 30 ml of N hydrochloric acid and the acid solution is washed 3 times with 20 ml of ethyl acetate. The pH is adjusted to 7.8, then the solution is salted out with sodium chloride and extracted 6 times with 30 ml of ethyl acetate. The organic extracts are collected and dried over anhydrous sodium sulfate and the solvent in evaporated to dryness. The product is purified by chromatography on silica as described in Example 7. Thus, the N-[3-[3-(3-methylpiperidinomethyl)phenoxy]propyl]-3-pyridinecarboxamide 1-oxide is obtained, identical to the product of Example 8.
Reaction SMILES: [CH2:1]([N:8]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[C:9]1[C:17]([O:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:34](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].[OH-].[Na+].Cl>CN(C=O)C.O.CCOC(C)=O>[CH2:1]([N:8]([S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[C:9]1[C:17]([O:18][CH2:19][CH2:20][CH2:21][O:22][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(OCCCO)cccc2C(=O)O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(OCCCO[Si](C)(C)C(C)(C)C)cccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
To a solution of 0.145 g (0.308 mmol) of the product of Example 172 in 5.0 mL of DMF was added 0.105 g (1.539 mmol) of iidazle and 0.111 g (0.739 mmol) of t-butyidimethylsilyl chloride. The reaction was stirred at room temperature for 18 h and then 0.40 mL of 1N sodium hydroxide solution was added and the resulting mixture was sired for 1 h. The reaction mixture was then diluted with water, acidified with 5% HCl solution and extted with EtOAc. The combined organics were washed with water, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc/Hexanes to provide 0.089 g (50%) of the desired product as a white foam. Electrospray Mass Spec: 586 (M+H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH:14]=[C:13]([C:27]([F:30])([F:29])[F:28])[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][CH:48]=1)(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1.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>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=4)[CH:14]=[C:13]([C:27]([F:29])([F:28])[F:30])[N:12]=3)[CH:10]=2)=[N:49][CH:48]=1)(=[O:45])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (Example G.12) (0.570 g, 0.88 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.265 g, 0.99 mmol), tetrakis(triphenylphosphine)palladium (0.061 g, 0.046 mmol) in toluene (6 mL) was heated under reflux conditions for 16 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (220 mg, 43%). MS (ISP) 576.3 [(M+H)+]; mp 252° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]([Sn](CCCC)(CCCC)CCCC)=[CH2:14])[CH3:11].[F-].[K+]>C(#N)C.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>[CH2:13]([O:12][C:10]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1)=[CH2:11])[CH3:14]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: C=C(OCC)c1ccc(C#N)cn1
Temperature: 25 °C
Yield: 190.5 %

Procedure:
Slurry 6-bromo-nicotinonitrile (8.0 g, 43.7 mmol), 1-ethoxyvinyl-tributylstannane (17.4 g, 48 mmol), and dichlorobis(triphenylphosphine)-palladium (1.5 g, 2.2 mmol) in acetonitrile (680 mL) at room temperature. Stir the mixture at reflux for 16 h under a nitrogen atmosphere. Cool the mixture to room temperature, add aqueous saturated potassium fluoride (100 mL), stir 30 min then filter and wash with EtOAc (200 mL). Wash the organic phase with water (250 mL). Dry the organic layer over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (14.5 g) that was used without further purification. MS (ES+) m/z: 175 (M+H)+.
Reaction SMILES: C1([Li])C=CC=CC=1.[CH2:8]([N:12]1[C:16]2[CH:17]=[C:18](Br)[CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH2:22])[CH:9]([CH3:11])[CH3:10].C([Li])(C)(C)C.[Cl-].[NH4+].[O:30]1CCC[CH2:31]1>CN(C)C=O>[CH2:8]([N:12]1[C:16]2[CH:17]=[C:18]([CH:31]=[O:30])[CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH2:22])[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Cn1c(N)nc2ccc(Br)cc21
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [Li]c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)Cn1c(N)nc2ccc(C=O)cc21
Reaction time: 0.67 h

Procedure:
Add phenyllithium (19.4 mL, 33 mmol, 1.7M in cyclohexane/diethyl ether) dropwise over 20 minutes to a solution of 1-isobutyl-2-amino-6-bromobenzimidazole (2.68 g, 10 mmol) in tetrahydrofuran (50 mL) at −78° C. Stir 40 minutes after addition is complete and then add tert-butyllithium (17.6 mL, 30 mmol, 1.7M in pentane) dropwise over 20 minutes. Stir 1.5 hours after addition is complete and then add dimethylformamide (5 mL) dropwise over 5 minutes. Warm reaction mixture to 0° C. over 1 hour, and then to room temperature over 20 minutes. Dilute reaction mixture with saturated aqueous ammonium chloride (100 mL), and then extract well with ethyl acetate. Combine ethyl acetate extracts, wash sequentially with water and saturated aqueous sodium chloride, dry over sodium sulfate and concentrate under reduced pressure. Slurry the residue in diethyl ether, filter and dry to provide 1.58 g of the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([CH:11]=[CH:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21]CC3C=CC=CC=3)=[C:17]([O:29][CH3:30])[CH:16]=2)=[O:10])[CH2:4][CH2:3]1.[H][H]>CO.[C].[Pd]>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:10])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:29][CH3:30])[CH:16]=2)[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: COc1cc(C=CC=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCCCC(=O)N[C@H]2CC[C@H](C)CC2)ccc1O

Procedure:
3.62 g of N-(trans-4-methylcyclohexyl)-4-(4-benzyloxy-3-methoxyphenyl)-l,3-butadiene-1-carboxamide (Example 117) was dissolved in 150 ml of methanol. 0.2 g of 10% palladium-carbon was added to the solution. The solution was stirred for 16 hours under normal-pressure hydrogen gas. After reaction, the catalyst was filtered out, and the solvent was removed in vacuo from the filtrate, yielding 2.3 g of N-(trans-4-methylcyclohexyl)-5-(4-hydroxy-3-methoxyphenyl)valeramide (a compound of the present invention) as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[CH2:20][CH2:19][N:18]([C:16]([O:15][CH2:14][CH:9]3[CH2:10][O:11][CH2:12][CH2:13][NH:8]3)=[O:17])[CH2:23][CH2:22]2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCOCC1COC(=O)N1CCN(c2ccc(F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCC1COCCN1)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
3-[4-(4-Fluorophenyl)-piperazine-1-carbonyloxymethyl]-morpholine-4-carboxylic acid tert-butyl ester (2.98 g, 7.04 mmol) was stirred in DCM (30 mL) at 0° C. TFA (6 mL) dissolved in DCM (24 mL) was added dropwise. The reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was partitioned between DCM (30 mL) and aqueous NaHCO3 (5 g in 30 mL). The aqueous layer was extracted with DCM (3×30 mL), dried (MgSO4) and the solvent removed in vacuo to give morpholin-3-ylmethyl 4-(4-fluorophenyl)piperazine-1-carboxylate (2.18 g, 96%) as a white solid.
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][C@@H:12]([CH2:22][CH3:23])[CH2:13][O:14]CC2C=CC=CC=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1>[OH-].[Pd+2].[OH-].C(O)C>[C:1]1([CH3:24])[CH:2]=[CH:3][C:4]([S:7]([O:10][CH2:11][C@@H:12]([CH2:22][CH3:23])[CH2:13][OH:14])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: CC[C@@H](COCc1ccccc1)COS(=O)(=O)c1ccc(C)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC[C@@H](CO)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
1.5 g (0.0043 mol) of 2-(S)-ethyl-3-benzyloxypropyl p-toluenesulfonate (XVIIId-1), 12 ml of ethanol and 0.29 g of 20% palladium hydroxide are introduced into a 100 ml round-bottomed flask. The mixture is vigorously stirred at ambient temperature under a slight hydrogen pressure. After reacting for one hour, the mixture is filtered through celite and the solid is washed with ethanol. The filtrate is concentrated under reduced pressure and the residue is purified by flash chromatography on silica gel (eluent: dichloromethane/cyclohexane=80:20). 1.02 g (0.0039 mol) of the title compound (XIXd-1) are recovered in the form of a colorless oil.
Reaction SMILES: [F:1]C1C(N)=NC(=O)NC=1.FC1C=CC(B(O)O)=CC=1.NC1C=CN(C2C=CC(F)=CC=2)C(=O)N=1.[Cl:35][CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][N:42]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=3)[C:41](=[O:52])[N:40]2[CH:53]=1>>[Cl:35][CH2:36][C:37]1[N:38]=[C:39]2[C:44]([F:1])=[CH:43][N:42]([C:45]3[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=3)[C:41](=[O:52])[N:40]2[CH:53]=1
Reactant: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Reactant: Nc1nc(=O)[nH]cc1F
Agent: Nc1ccn(-c2ccc(F)cc2)c(=O)n1
Agent: OB(O)c1ccc(F)cc1
Product: O=c1n(-c2ccc(F)cc2)cc(F)c2nc(CCl)cn12

Procedure:
2-Chloromethyl-8-fluoro-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one was prepared from 5-fluorocytosine and 4-fluorophenylboronic acid using the methods as described above for the preparation of 4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one and 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[O:7]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>CCO>[O:7]([C:14]1[CH:15]=[C:16]([NH:17][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: Brc1nccs1
Agent: Cl
Solvent: CCO
Product: c1ccc(Oc2cccc(Nc3nccs3)c2)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(thiazol-2-ylamino)phenol, 2-bromothiazole (0.09 mL, 1.02 mmol), 3-phenoxyaniline (94 mg, 0.51 mmol) and 37% HCl solution (0.09 mL, 1.02 mmol) in 10% aqueous EtOH solution (1 mL) was stirred at 90° C. for 24 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 9/1) in 75% yield (102 mg).
Reaction SMILES: [N:1]([C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:9])[C:5]([O:7]C)=O)=[C:2]=[S:3].[NH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17].O.C(O)(=O)C>O1CCCC1>[CH3:9][C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:1][C:2](=[S:3])[N:17]([NH:16][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:5]1=[O:7]
Reactant: COC(=O)C(C)(N=C=S)c1ccccc1
Reactant: NNc1ccccn1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(c2ccccc2)NC(=S)N(Nc2ccccn2)C1=O
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
2 g (9 mmol) of methyl 2-isothiocyanato-2-phenylpropionate are dissolved in 30 ml of tetrahydrofuran. A solution containing 0.99 g of 2-hydrazinopyridine and 10 ml of tetrahydrofuran is added: the temperature of the mixture rises from 20° to 30° C. and a solid precipitates. The mixture is allowed to met for 0.5 hour at 30° C. and then is cooled to 5° C. A solution containing 1 g of potassium tert-butoxide and 10 ml of tetrahydrofuran is then added: the mixture becomes violet in color. The mixture is left to return to room temperature and is left to react for 2 hours. The mixture is poured into 150 ml of water. The mixture is neutralized with acetic acid. The product is extracted with 150 ml of ethyl acetate. The solution is washed with water, dried over magnesium sulfate and then treated with active charcoal. The solution is concentrated and the product is crystallized from 20 ml of diethyl ether. The above-mentioned product is filtered and is dried under vacuum. 1.6 g (yield: 60%) of 5-methyl-5-phenyl-3-(2-pyridylamino)-2-thiohydantoin is obtained as a pale-yellow solid melting at 80° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:41]=[C:42]([O:46][CH3:47])[C:43]=1[O:44][CH3:45])[CH2:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:47][O:46][C:42]1[CH:41]=[C:33]([CH:32]=[C:31]([O:30][CH3:29])[C:43]=1[O:44][CH3:45])[CH2:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:37][CH2:36]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CN2CCN(Cc3ccc(NC(=O)C4=Cc5cc(-c6ccc(C)cc6)ccc5CC4)cc3)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.9 %

Procedure:
In DMF (3 ml) was dissolved N-[4—(chloromethyl)-phenyl]-7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the solution were added 1—(3,4,5-trimethoxybenzyl)piperazine (138 mg) and potassium carbonate (268 mg). The mixture was stirred at room temperature for 48 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give N-[4-[1—(3,4,5-trimethoxybenzyl)-4-piperazinylmethyl]-phenyl]-7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 45) (155 mg) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)=[O:3].[CH3:15][O:16][CH2:17][CH2:18][NH:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:15][O:16][CH2:17][CH2:18][N:19]([CH3:20])[C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[C:11]([F:14])([F:13])[F:12]
Reactant: CNCCOC
Reactant: CC(=O)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COCCN(C)c1ccc(C(C)=O)cc1C(F)(F)F
Yield: 81.8 %

Procedure:
A solution of 4-fluoro-3-(trifluoromethyl)acetophenone (500 mg, 2.43 mmol), N-(2-methoxyethyl)methylamine (649 mg, 7.28 mmol) and potassium carbonate (335 mg, 2.43 mmol) in DMSO (6 mL) was stirred for 30 min at 150° C. in the microwave. The cooled reaction mixture was diluted with water, extracted with ethyl acetate, dried over sodium sulphate, filtered and the solvent was removed under reduced pressure. Finally 547 mg (yield: 82%) of the title compound was obtained.