Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([NH:8]C2OC(C3C=CC(C#N)=CC=3)=CN=2)[CH:7]=1.Cl[C:24]1[O:25][C:26]([C:30]2[CH:37]=[C:36]([CH3:38])[C:33]([C:34]#[N:35])=[C:32]([CH3:39])[CH:31]=2)=[C:27]([Cl:29])[N:28]=1.ClC1OC(C2C=CC(C#N)=CC=2)=CN=1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([NH:8][C:24]2[O:25][C:26]([C:30]3[CH:37]=[C:36]([CH3:38])[C:33]([C:34]#[N:35])=[C:32]([CH3:39])[CH:31]=3)=[C:27]([Cl:29])[N:28]=2)[CH:7]=1
Reactant: Cc1ccc(N)cc1Nc1ncc(-c2ccc(C#N)cc2)o1
Reactant: Cc1cc(-c2oc(Cl)nc2Cl)cc(C)c1C#N
Agent: N#Cc1ccc(-c2cnc(Cl)o2)cc1
Product: Cc1ccc(N)cc1Nc1nc(Cl)c(-c2cc(C)c(C#N)c(C)c2)o1
Yield: 74 %

Procedure:
The same procedure outlined above in the preparation of 4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile was used. However 4-(2,4-dichlorooxazol-5-yl)-2,6-dimethylbenzonitrile was used instead 4-(2-Chloro-oxazol-5-yl)-benzonitrile. Yield=74%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)Cc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccccc1NCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title B compound, (2-amino-phenyl) acetic acid methyl ester (4.2 g, 25.4 mmol) is dissolved in DMF (30 mL). Powdered potassium carbonate (8.78 g, 63.5 mmol) and t-butyl bromoacetate (4.12 mL, 27.9 mmol) are added and the reaction is stirred at room temperature for 18 h and then at 50° C. for 1 h. The reaction is diluted with water (300 mL) and extracted with EtOAc (2×200 mL). Combined EtOAc layers are washed with water (2×100 mL) then brine (100 mL), dried over anhydrous MgSO4, filtered and concentrated to give a viscous brown oil. This residue is chromatographed on a 110 g silica gel RediSep (Isco Inc.) column with a 30 mL/min gradient elution of 10:90 (EtOAc:hexane) to 25:75 over 30 min. Fractions containing product are combined and evaporated to yield [2-(t-butoxy-carbonylmethyl-amino)-phenyl]-acetic acid methyl ester as a clear amber oil: [M+1]+=280.
Reaction SMILES: [CH2:1]([CH:11]([CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:12]([OH:23])[CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](O)=[O:41].CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>ClCCl.CN(C1C=CC=CN=1)C>[Br:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:23][CH:12]([CH:11]([CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:41]
Reactant: CCCCC/C=C\CCCC(O)C(CCC/C=C\CCCCC)CCC/C=C\CCCCC
Reactant: O=C(O)CCCCCBr
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(CCC/C=C\CCCCC)OC(=O)CCCCCBr
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To a solution of (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-ol 8 (2.4 g, 5.2 mmol), 6-bromohexanoic acid (1.5 g, 7.8 mmol), EDCI hydrochloride (1.5 g, 7.8 mmol), diisopropylethylamine (2.0 g, 15.6 mmol) in anhydrous dichloromethane (25 mL) was added dimethylaminopyridine (15 mg). The solution was refluxed for 2 hours, cooled to room temperature and concentrated in vacuo to dryness. The reaction mixture was purified by column chromatography on silica gel 60 (2″ W×10″ L; eluted with 5% EtOAc/Hex) to afford (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-yl 6-bromohexanoate 10 as a colorless oil (3.1 g, 94%). Rf 0.5 (10% EtOAc-Hexanes).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[CH3:22].[F-].[Cs+].[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=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.COCCOC>[CH3:22][C:3]1[CH:4]=[C:5]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:7][C:2]=1[C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:32]=1
Reactant: COC(=O)CCc1cccc(OCc2ccc(Br)c(C)c2)c1
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: COC(=O)CCc1cccc(OCc2ccc(-c3cccc(OC)c3)c(C)c2)c1
Temperature: 85 °C
Yield: 82.8 %

Procedure:
To a 2 dram vial charged with methyl ester 1.3 (0.0700 g, 0.193 mmol), tetrakis(triphenylphosphine)palladium (0) (0.0445 g, 0.0385 mmol), cesium fluoride (0.0356 mL, 0.964 mmol), and 3-methoxyphenylboronic acid (available from Aldrich) (0.0878 g, 0.578 mmol), was added DME (1 mL). The resulting mixture was then heated at 85° C. overnight. The reaction was allowed to cool and then filtered and concentrated. The crude product was purified by combiflash (0 to 20% EtOAc/hexanes) yielding 1.4 (0.0624 g, 82.9% yield). MS ESI (pos.) m/e: 391.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:36][CH2:37][CH:38]1[O:42][NH:41][C:40](=[O:43])[CH2:39]1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:36][CH2:37][CH:38]2[O:42][NH:41][C:40](=[O:43])[CH2:39]2)=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NCC1CC(=O)NO1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCC2CC(=O)NO2)cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 5 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) in DMF (2 mL) was added 1,1′-carbonyl-diimidazole (115 mg, 0.71 mmol) and the reaction mixture was stirred for 0.5 h at 80° C. After cooling to ambient temperature 5-aminomethyl-isoxazolidin-3-one (82 mg, 0.71 mmol) was added and stirring was continued for 1 h at this temperature and for 2 h at 80° C. It was diluted with ethyl acetate (10 mL) and washed with water (10 mL) and aqueous sodium chloride (saturated, 10 mL). The organic layer was dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate:methanol=40:60:0 to 0:90:10) afforded the title compound (13 mg, 5%) as a white solid. MS: m/e=409.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[C:21]2[C:22](=[O:30])[C:23]3[S:29][CH:28]=[CH:27][C:24]=3[CH2:25][S:26][C:20]=2[CH:19]=[CH:18][CH:17]=1>CC(N(C)C)=O>[F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4]([NH:15][C:16]1[C:21]2[C:22](=[O:30])[C:23]3[S:29][CH:28]=[CH:27][C:24]=3[CH2:25][S:26][C:20]=2[CH:19]=[CH:18][CH:17]=1)=[O:5]
Reactant: Nc1cccc2c1C(=O)c1sccc1CS2
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1cccc2c1C(=O)c1sccc1CS2)C(F)(F)F
Temperature: -10 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
In dimethylacetamide (10 ml) was dissolved 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.79 g, 5.0 mmol), and thionyl chloride (0.36 ml, 5.0 mmol) was added thereto at −15  C., followed by stirring at −15 to −5° C. for one hour. To the resulting mixture was added 9-amino-4,10-dihydrothieno[3,2-c][1]benzothiepin-10-one obtained in Reference Example 5 (0.62 g, 2.5 mmol), and the mixture was stirred overnight at room temperature. After the reaction mixture was concentrated under reduced pressure, the obtained oily residue was dissolved in ethyl acetate (50 ml). The organic layer was washed successively with a 5% aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained oily residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1), followed by trituration with hexane to give 9-(3,3,3-trifluoro-2-hydroxy-2-methylpropanoylamino)-4,10-dihydrothieno[3,2-c][1]benzothiepin-10-one (0.60 g, 63%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH2:19].O>CS(C)=O>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH:19][C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(O)c2n1
Yield: 40.7 %

Procedure:
4-Chloro-8-hydroxy-2-methylquinoline (500 mg, 2.58 mmole) and 3,4-dichlorobenzylamine (910 mg, 5.16 mmole) in dimethylsulfoxide (5 mL) were stirred at 140° C. for 90 min in a microwave oven. Water was added and the mixture was decanted to obtain an oily residue. The residue was washed with ethyl acetate to give a brownish solid (350 mg, 41%). ESI-MS [M+H]+=333.1/337.0 calculated for C17H14Cl2N2O=333 g/mole
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:12]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:12]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:25][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1cccc(Cl)c1)C1(O)CCCCC1
Reactant: NC1CCCCC1
Product: O=C(NC1CCCCC1)C(c1cccc(Cl)c1)C1(O)CCCCC1

Procedure:
In an analogous manner to Example 1, step 1 2-(3-chlorophenyl-N-cyclohexyl-2-(1-hydroxycyclohexyl)acetamide was prepared from (3-chlorophenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-a) and cyclohexylamine. MS (ESI) m/z 350/352 ([M+H]+).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([N:29]2[CH2:34][C:33](=[O:35])[O:32][C:31](=[O:36])[CH2:30]2)[CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:37][OH:38]>>[CH3:37][O:38][C:33](=[O:35])[CH2:34][N:29]([C:14]1[CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:13]=1)[CH2:30][C:31]([OH:36])=[O:32]
Reactant: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N2CC(=O)OC(=O)C2)c1
Reactant: CO
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N(CC(=O)O)CC(=O)OC)c1
Reaction time: 17 h

Procedure:
A solution of 0.469 g of 4-[3,5-bis(decyloxy)phenyl]2,6-morpholinedione in 50 ml of methanol was warmed to 50° and then was left at room temperature for 17 hours. The solvent was removed at reduced pressure to give 0.44 g, mp 61°-62° of pure N-(2-methoxy-2-oxoethyl)-N-[3,5-bis(decyloxy)phenyl]glycine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH:7]=[CH:8][O:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:32]1([CH2:37][CH2:38]O)[CH:36]=[CH:35][N:34]=[CH:33]1.N(C(OCC)=O)=NC(OCC)=O>CCOC(C)=O.C1COCC1>[N:32]1([CH2:37][CH2:38][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:12])[CH:7]=[CH:8][O:9]3)=[CH:4][CH:3]=2)[CH:36]=[CH:35][N:34]=[CH:33]1
Reactant: OCCn1ccnc1
Reactant: O=c1ccoc2cc(O)ccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1ccoc2cc(OCCn3ccnc3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
Under N2, a solution of 0.75 g (4.6 mmol) of 7-hydroxy-4H-4-chromenone (J. Med. Chem., 1991;34:248) in 20 ml, of THF was treated with 1.21 g (4.6 mmol) of triphenylphosphine and 0.5 g (5.1 mmol) of 2-(1H-1-imidazolyl)-1-ethanol and the solution cooled in ice. This was then treated over 10 minutes with 0.72 mL (4.6 mmol) of diethyl azodicarboxylate, and the solution stirred at room temperature overnight. The solution was diluted with EtOAc, washed twice with H2O, twice with saturated NaHCO3, and then with saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure gave the crude product. Chromatography on silica gel, eluting with a gradient of CH2Cl2 to CH2Cl2/MeOH (96/4) gave 0.12 g (10% yield) of the product as a pink solid, mp 131-133° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 257 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[CH2:24]([N:26]1[CH:30]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:28]([OH:36])=[N:27]1)[CH3:25].CN(C)C=O.[H-].[Na+]>O>[CH2:24]([N:26]1[CH:30]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:28]([O:36][CH2:2][C:3]2[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[O:16][CH:17]=[CH:18][CH:19]=4)[O:12][C:13]=3[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=2)=[N:27]1)[CH3:25]
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(=O)c1cn(CC)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(CC)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (3.50 g), ethyl 1-ethyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.50 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.36 g) at room temperature, and the mixture was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 1-ethyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (2.94 g, yield 75%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 114-115° C.
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(Cl)(Cl)Cl.[C:26]12([C:36](Cl)=[O:37])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2>C(N(CC)CC)C>[C:26]12([C:36]([N:4]3[CH2:5][CH2:6][N:1]([C:7]4[N:16]=[C:15]([NH2:17])[C:14]5[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=5)[N:8]=4)[CH2:2][CH2:3]3)=[O:37])[CH2:33][CH:32]3[CH2:31][CH:30]([CH2:29][CH:28]([CH2:34]3)[CH2:27]1)[CH2:35]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nc(N3CCN(C(=O)C45CC6CC(CC(C6)C4)C5)CC3)nc(N)c2cc1OC

Procedure:
To a mixture of 2-piperazino-4-amino-6,7-dimethoxyquinazoline (1 g), chloroform (50 ml) and triethylamine (0.42 g), was gradually added 1-adamantanecarbonyl chloride (0.83 g). The almost dissolved mixture was heated at 45°-50° C. for 2 hours. After cooling, the mixture was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 2-{4-(1-adamantanecarbonyl)-1-piperazinyl}-4-amino-6,7-dimethoxyquinazoline, m.p. 240°-242° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13]/[N:14]=[C:15](/[C:23](=[O:25])[CH3:24])\[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].O[C@@H:27]1[CH2:32][CH2:31][C@H:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:19]([O:18][C:16](=[O:17])/[C:15](=[N:14]\[O:13][C@H:27]1[CH2:32][CH2:31][C@H:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]1)/[C:23](=[O:25])[CH3:24])([CH3:21])([CH3:20])[CH3:22]
Reactant: COC(=O)[C@H]1CC[C@@H](O)CC1
Reactant: CC(=O)/C(=N/O)C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](O/N=C(/C(C)=O)C(=O)OC(C)(C)C)CC1

Procedure:
A solution of diethyl azodicarboxylate (1.62 ml) in tetrahydrofuran (5 ml) was added dropwise to a solution of tert-butyl (Z)-2-hydroxyimino-3-oxobutyrate (1.6 g), methyl cis-4-hydroxycyclohexanecarboxylate (1.9 g) and triphenylphosphine (2.7 g) in tetrahydrofuran (20 ml) over 15 min at room temperature. The mixture was stirred for 18h, then the solvent removed under reduced pressure. The residue was chromatographed on silica to give the title compound (0.93 g, 33%) as a colourless liquid. νmax (film) 2950, 1730, and 1690 cm-1. δH (CDCl3) 1.47-1.64 (3H, m), 1.53 (9H, s), 1.56 (3H, d, J 5.3 Hz), 2.05 (2H, m), 2.17 (2H, m), 2.35 (1H, m), 2.37 (3H, s), 3.69 (3H, s), and 4.24 (1H, tt, J 4.1, 10.0 Hz), δC (CDCl3) 25.2, 26.3 (2C), 28.1 (3C), 29.9 (2C), 41.6, 51.7, 82.9, 84.0, 160.6, 175.5, and 193.0. [Mass spectrum +ve ion (ammonia) MH+ (328), MNH4+ (345)].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:20]1[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=1)[CH:9]=2)=[O:4]
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Product: COC(=O)c1c(O)c2ccc(-c3cccnc3)cc2sc1=O

Procedure:
4-Hydroxy-2-oxo-7-pyridin-3-yl-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) and 3-pyridyl-boronic acid under conditions analogous to Example 14(a). MS ESI(+) m/e: 314.12 (M+1).
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([O:28][CH3:29])=[CH:20][C:3]=1[CH2:4][N:5]1[C@H:9]([C:10]([CH3:18])([CH3:17])[O:11][SiH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][CH2:7][C:6]1=[O:19].[CH2:30]([O:37][C:38]1[C:43](B(O)O)=[CH:42][CH:41]=[CH:40][N:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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>[CH2:30]([O:37][C:38]1[C:43]([C:2]2[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([O:28][CH3:29])=[CH:20][C:3]=2[CH2:4][N:5]2[C@H:9]([C:10]([CH3:18])([CH3:17])[O:11][SiH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][CH2:7][C:6]2=[O:19])=[CH:42][CH:41]=[CH:40][N:39]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: OB(O)c1cccnc1OCc1ccccc1
Reactant: COc1cc(CN2C(=O)CC[C@H]2C(C)(C)O[SiH2]C(C)(C)C)c(Br)cc1C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(CN2C(=O)CC[C@H]2C(C)(C)O[SiH2]C(C)(C)C)c(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Yield: 75 %

Procedure:
step 2—A sealed tube containing 104 (141 mg, 0.29 mmol), 2-benzyloxy-pyridin-3-yl boronic acid (100 mg, 0.44 mmol), Na2CO3 (92 mg, 0.87 mmol) and Pd(PPh3)4 (33 mg, 0.029 mmol) in a mixture of MeOH (1.5 mL) and DCM (0.5 mL) was irradiated in a microwave synthesizer at 100° C. for 30 min. The reaction mixture was diluted with DCM, filtered through a pad of CELITE and the filtrate was concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 40% EtOAc/hexanes to afford 128 mg (75%) of (S)-1-[2-(2-benzyloxy-pyridin-3-yl)-4-tert-butyl-5-methoxy-benzyl]-5-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-2-one (106).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:20])[C:8]=2[CH:7]=1.[CH3:21][NH2:22].[I-].[Na+]>C(#N)C.O>[CH3:21][NH:22][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:20])[C:8]=2[CH:7]=1
Reactant: O=c1c2ccccc2sc2ccc(OCCCCl)cc12
Reactant: CN
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CNCCCOc1ccc2sc3ccccc3c(=O)c2c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
26 g (85 mmol) 2-(3-chloropropoxy)-9H-thioxanthen-9-one is suspended in 140 mL acetonitrile. 66 g (73.2 mL, 0.85 mol) of a 40% solution of methyl amine in water was added and the mixture was heated to 60° C. After four hours, 1.3 g (8.5 mmol) sodium iodide and 20 mL of a 40% solution of methyl amine in water were added and the reaction was allowed to continue for 16 hours at 60° C. The precipitated compounds were isolated by filtration and washed three times with 100 mL acetonitrile. The pooled acetonitrile fractions were evaporated under reduced pressure. The crude 2-(3-methylaminopropoxy)thioxanthen-9-one was crystallized from 200 mL hexane, isolated by filtration and dried. 19 g of 2-(3-methylaminopropoxy)thioxanthen-9-one was isolated. 2-(3-methylaminopropoxy)thioxanthen-9-one was further purified by preparative column chromatography on a Prochrom LC80 column, using Kromasil C18 100A 10 mm as silica and methanol/1M ammonium acetate 68/32 as eluent at a flow rate of 150 mL per minute.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38]>CS(C)=O.O>[C:11]1([C:8]2[N:6]3[N:7]=[C:2]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ccc2ncc(-c3cccc4ccccc34)n2n1
Reactant: NCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CS(C)=O
Product: OCCCCNc1ccc2ncc(-c3cccc4ccccc34)n2n1
Temperature: 100 °C
Yield: 50.4 %

Procedure:
To a solution of 6-chloro-3-(naphthalen-1-yl)imidazo[1,2-b]pyridazine (50 mg, 0.179 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonic acid monohydrate (35 mg, 0.184 mmol, 1.0 equiv) and 4-aminobutan-1-ol (200 mg, 2.24 mmol, 12.5 equiv) and heated to 100° C. for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate. Purification by column chromatography using 5% methanol in dichloromethane elution gave 30 mg of a white solid, 50%.
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(O)(=[O:3])=[O:2].[K].[Cl:15]S(O)(=O)=O>>[Cl:15][S:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])=[O:2]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccc(S(=O)(=O)O)cc1
Agent: [K]
Product: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
4-Chlorosulfonylbenzoic acid is prepared by procedures described in (J. Chem. Soc., Vol. 121, 2022-26, 1922). A 250 mL flask equipped with condenser, CaCl2 drying tube and magnetic stirrer is charged with 35.1 g (0.146 mol) of potassium 4-sulfobenzoic acid and 50 mL of chlorosulfonic acid. The flask is placed in an oil bath and warmed to 100° C. After 1 hour at temperature, the reaction mixture is homogeneous. The reaction mixture is cooled and poured onto 300 g of crushed ice. The white precipitate is collected by filtration and washed 3 times with 100 mL portions of cold water. After air drying the solid is placed in a vacuum oven at 65° C. to yield 26.7 g of 4-chlorosulfonyl benzoic acid.