Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([O:23][CH3:22])[CH:29]=4)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COc1cccc(B(O)O)c1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1
Product: COc1cccc(-c2ccc3oc(-c4cc([N+](=O)[O-])ccc4OC)nc3c2)c1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and 3-methoxyphenylboronic acid (261 mg, 1.71 mmol) the subtitle compound was obtained (280 mg, 51%). The product was used directly in the next step without purification.
Reaction SMILES: [C:1](OC)([O:5][CH3:6])([O:3]C)[CH3:2].[C:9]1([CH:15](O)[C:16]([CH3:18])=[CH2:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(=O)CC>CO>[CH3:17]/[C:16](=[CH:15]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[CH2:18][CH2:2][C:1]([O:5][CH3:6])=[O:3]
Reactant: COC(C)(OC)OC
Reactant: C=C(C)C(O)c1ccccc1
Solvent: CO
Solvent: CCC(=O)O
Product: COC(=O)CC/C(C)=C/c1ccccc1
Yield: 20.9 %

Procedure:
Trimethyl orthoacetate (186 g, 1.52 mol) and 1-phenyl-2-methyl-2-propen-1-ol (90% pure from Alfa Aesar, 25 g, 0.152 mol) were heated in the presence of propionic acid (0.2 ml) in an oil bath at 145° C. for 4 hours. The methanol formed during the reaction was distilled. The excess orthoacetate was then removed under vacuum and the residue was purified by column chromatography on silica gel (eluent: heptanes/ethyl acetate 25:1 to 8:1) followed by bulb-to-bulb distillation (67° C./0.001 mbar). 6.5 g (yield=21%) of the desired product were obtained.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH:8]([CH:20]1[CH2:25][C:24](=[O:26])[O:23][C:21]1=[O:22])=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CCCC.O>C1(C)C=CC=CC=1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[C:24](=[O:26])[CH2:25][CH:20]([CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:21]([OH:23])=[O:22]
Reactant: CCCCCCCCCCC=CC1CC(=O)OC1=O
Reactant: OCCNCCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCC=CC(CC(=O)N(CCO)CCO)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A 500 ml, two-neck flask was charged with 52.6 g (500 mmol) diethanolamine and 50 ml toluene. A temperature probe was placed into this solution through one of the necks of the flask and the flask was immersed into a water bath. A solution of 105.2 g (500 mmol) dodecenylsuccinic anhydride dissolved in 200 ml toluene was dripped into the magnetically stirred solution diethanolamine solution over a 40-minute period. Ice was added to the water bath as required to prevent temperature of the reaction mixture from getting above 25° C. The mixture was then stirred for another 2.5 hours at room temperature. The complete disappearance of the anhydride functional group was confirmed by infrared spectroscopy. The FTIR trace on this compound had significant absorptions at 2957, 2924, 2858, 1733, 1616, 1560, 1415, 1160, 1069, 969, and 728 wavenumbers. The solution was concentrated down to 50% solids in toluene and was then set aside for later use.
Reaction SMILES: NC1C(C(F)(F)F)=CC(/C=C(\CC([O-])=O)/C(OC)=[O:15])=CC=1Br.NC1C(C(F)(F)F)=CC(C[C@@H](CC(=O)N2CCC(N3CCC4C=CC=CC=4NC3=O)CC2)C(O)=O)=CC=1Br.[NH2:61][C:62]1[C:77]([C:78]([F:81])([F:80])[F:79])=[CH:76][C:65]([CH2:66][C@@H](CC([O-])=O)C(OC)=O)=[CH:64][C:63]=1[Cl:82].NC1C(C(F)(F)F)=CC(C[C@@H](CC(=O)N2CCC(N3CCC4C=CC=CC=4NC3=O)CC2)C(O)=O)=CC=1Cl>>[NH2:61][C:62]1[C:77]([C:78]([F:81])([F:80])[F:79])=[CH:76][C:65]([CH:66]=[O:15])=[CH:64][C:63]=1[Cl:82]
Reactant: COC(=O)/C(=C/c1cc(Br)c(N)c(C(F)(F)F)c1)CC(=O)[O-]
Reactant: COC(=O)[C@H](CC(=O)[O-])Cc1cc(Cl)c(N)c(C(F)(F)F)c1
Agent: Nc1c(Br)cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Agent: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Product: Nc1c(Cl)cc(C=O)cc1C(F)(F)F

Procedure:
Analogously to the sequence described in 9f to 9i, 1-methyl (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-succinate and (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid were able to be obtained from 4-amino-3-chloro-5-trifluoromethyl-benzaldehyde (see Example 1b).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:26]1[C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]2[C:35]([O:37][C:38](=O)[C:28]=2[CH:27]=1)=[O:36]>>[CH3:9][O:8][C:5]1[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]([N:1]2[C:35](=[O:36])[C:29]3[C:28](=[CH:27][CH:26]=[C:31]([C:32]([OH:34])=[O:33])[CH:30]=3)[C:38]2=[O:37])=[CH:7][CH:6]=1
Reactant: COc1ccc(N)cc1-c1nc2cc(-c3ccc(C)cc3)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccc(C)cc3)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-methoxyphenyl)-5-(4-methylphenyl)benzoxazole (75 mg, 0.23 mmol) and 1,2,4-benzenetricarboxylic anhydride (44 mg, 0.23 mmol) the title compound was obtained (78 mg, 67%). 1H NMR (DMSO) δ 8.43(dd, 1H), 8.33(s, 1H), 8.21(d, 1H), 8.10(d, 1H), 8.04(d, 1H), 7.85(d, 1H), 7.71(m, 2H), 7.63(d, 2H), 7.46(d, 1H), 7.30(d, 2H), 4.03(s, 3H), 2.36(s, 3H). MS 505.1 m/z (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](=O)([O-])[O-:20].[Cs+].[Cs+]>CO.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:20][CH3:19])=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [Cs+]
Solvent: CO
Product: COc1cc2c(cc1Cl)CN(C(=O)OC(C)(C)C)C2
Temperature: 140 °C
Reaction time: 16 h

Procedure:
Lit. Org. Lett. 2002, 4(6), 973-976. To a stirred suspension of 1.84 mmol 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) in 7 ml methanol were added 0.18 mmol copper(I) iodide, 3.69 mmol cesium carbonate and 0.37 mmol 1,20-phenanthroline and the reaction mixture was stirred at 140° C. for 16 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a light red solid. MS (m/e): 230.2 ({37Cl}[M+H-Me2C═CH2]+, 42%), 228.2 ({35Cl}[M+H-Me2C═CH2]+, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][C:13]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>>[CH3:12][C:13]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Cc1cccc(N)c1C
Reactant: O=C(O)Cc1ccccc1Br
Product: Cc1cccc(Nc2ccccc2CC(=O)O)c1C

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,3-dimethylaniline to yield 2-[(2,3-dimethylphenyl)amino]phenylacetic acid.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH2:24][OH:25])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:28])[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:32]3[CH:33]=[C:34]([CH3:37])[CH:35]=[CH:36][C:31]=3[CH3:30])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:27])[F:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C)c(O)c1
Reactant: OCc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Cc1ccc(C)c(OCc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}methanol and 2,5-dimethylphenol according to the procedure of Example 69. MS (ESI) m/z 498.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23]>N1C=CC=CC=1>[C:22]([NH:26][C:27]([N:15]1[CH2:14][CH:13]=[C:12]([C:10]2[N:9]=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)[CH2:17][CH2:16]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: C1=C(c2cn(-c3ccccc3)nn2)CCNC1
Reactant: CC(C)(C)N=C=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)NC(=O)N1CC=C(c2cn(-c3ccccc3)nn2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-[1-Phenyl-1H-[1,2,3]triazol-4-yl]-1,2,3,6-tetra-hydropyridine (35 mg) prepared in Example 49 was dissolved in 1 ml of pyridine and 1 ml of chloroform and 26 μl of tert-butyl isocyanate was added thereto followed by stirring at room temperature for 6 hours. The reaction solution was concentrated in vacuo and the resulting residue was separated and purified by a preparative thin-layer chromatography (chloroform/methanol=10/1+0.3% aqueous ammonia) and then recrystallized from chloroform-hexane to give 42 mg of the title compound as a white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:22](=[O:25])[CH2:23][CH3:24])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cccnc2)C1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Product: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amine 17 (100 mg, 0.34 mmol) and piperidinomethyl polystyrene resin (100 mg) in 1 mL of dry CH2Cl2 was added propionyl chloride (30 μL, 1 eq.) at room temperature. After being shaken at room temperature overnight, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2. Removal of CH2Cl2 afforded N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) propionamide 18 (85 mg, 71%). LRMS 248 (M-100)+.
Reaction SMILES: [F:1][C:2]1([F:40])[CH2:7][CH2:6][CH:5]([C:8]([NH:10][CH2:11][C:12]([CH3:39])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:13][CH2:14][N:15]2[C@H:20]3[CH2:21][CH2:22][C@@H:16]2[CH2:17][CH:18]([N:23]2[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[C:24]2[CH3:32])[CH2:19]3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].I[CH3:44].O>CN(C=O)C>[F:40][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]([N:10]([CH3:44])[CH2:11][C:12]([CH3:39])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:13][CH2:14][N:15]2[C@H:20]3[CH2:21][CH2:22][C@@H:16]2[CH2:17][CH:18]([N:23]2[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[C:24]2[CH3:32])[CH2:19]3)=[O:9])[CH2:4][CH2:3]1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC(C)(CNC(=O)C1CCC(F)(F)CC1)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC(C)(CN(C)C(=O)C1CCC(F)(F)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.9 %

Procedure:
To a solution of the title compound from example 21 (100 mg, 0.18 mmol) in dry DMF (1.5 mL) was added sodium hydride (9 mg, 0.22 mmol) as a 60% suspension in mineral oil and the solution stirred under a nitrogen atmosphere at room temperature for 30 min. Iodomethane (0.06 mL, 0.9 mmol) was added and the reaction stirred at room temperature for 2 h. Water was added and the reaction partitioned between ethyl acetate and water. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-5% methanol/CH2Cl2 followed by purification by HPLC eluting with 5-70% water/acetonitrile/0.1% TFA to afford the title compound (9 mg, 7%) which was isolated as the trifluoroacetate salt.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:20](I)[CH3:21]>O>[NH2:1][C:2]1[C:3]([C:11]([O:13][CH2:20][CH3:21])=[O:12])=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: CCI
Reactant: CCCc1ccnc(C(=O)O)c1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CCCc1ccnc(C(=O)OCC)c1N
Reaction time: 0.25 h
Yield: 84 %

Procedure:
3-Amino-4-n-propylpyridine-2-carboxylic acid (Preparation 4; 0.36 g, 0.002 mol) was added to a stirred mixture of cesium carbonate (0.325 g, 0.001 mol) in water (20 ml), then this mixture was evaporated under vacuum and the residue azeotroped with dimethylformamide (2×20 ml). The resulting cesium salt was suspended in dimethylformamide (3 ml) and the stirred suspension then treated dropwise with ethyl iodide (0.17 ml, 0.0021 mol). After a further 0.25 hour, the solvent was evaporated under vacuum and the residue partitioned between water (20 ml) and ethyl acetate (20 ml). The organic phase was washed with water (10 ml), dried (MgSO4) and evaporated under vacuum, then the residue crystallized from acetone:hexane to give the title compound as an off-white solid (0.35 g, 84%), m.p. 93-96° C.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[CH3:13][O:14][C:15](Cl)=[O:16].Cl.O>O>[CH3:13][O:14][C:15]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)=[O:16]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Oc1ccc(C(=O)O)cc1
Reaction time: 3 h

Procedure:
A solution of sodium hydroxide (15 g) in water (400 ml) was chilled to 0° C. in ice. To this the 4-hydroxy benzoic acid (17.9 g, 0.130 mol) was added. Methylchloroformate (20 g, 0.212 mol) was added slowly to prevent the temperature from rising above 5° C. The reaction mixture was stirred at 0°-5° C. for 3 h during which time a white suspension gradually formed. The pH was adjusted to 4-5 with addition of HCl/water (1:1). The voluminous precipitate was filtered off, washed with water and recrystallised from ethanol (200 ml).
Reaction SMILES: [C:1]1([CH:9]=O)[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.C(OC(=O)C)(=O)C>C1(C)C(C)=CC=CC=1>[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[CH:11]=[CH:9][C:1]1[CH:2]=[CH:3][C:4]([CH:7]=[O:8])=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(C=O)cc1
Reactant: Cc1ccc2ccccc2n1
Solvent: Cc1ccccc1C
Solvent: CC(=O)OC(C)=O
Product: O=Cc1ccc(C=Cc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Yield: 35 %

Procedure:
1,4-Benzenedialdehyde (30 g, 0.22 mol), 2-methylquinoline (21 g, 0.15 mol) and acetic anhydride (41.5 ml, 0.40 mol) were dissolved in 160 ml of xylene, followed by heating under reflux for 7 hours. After the reaction mixture was allowed to cool down to room temperature, 200 ml of petroleum ether were added and the resulting precipitate was collected by filtration. Further, the mother liquor was concentrated under reduced pressure and the residue was recrystallized from diethyl ether, whereby 13.6 g of the title compound were obtained (yield: 35%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[CH2:9](O)[CH2:10][OH:11].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1
Reactant: O=Cc1sccc1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Brc1ccsc1C1OCCO1
Reaction time: 16 h

Procedure:
3-bromo-2-formylthiophene (3.89 parts, 0.02M) was heated at reflux with dry ethyleneglycol (1.6 parts) toluene (25 parts) and p-toluene sulphonic acid (0.1 parts) in a vessel equipped with a Dean and Stark separator for 16 hours. The reactants were then cooled and evaporated into silica. The silica was formed into a column which was then developed by elution with hexane containing increasing amounts of dichloromethane. The product was obtained from fractions containing 10-60% dichloromethane as a pale straw-coloured oil (4.42 parts).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH3:20].C([Li])CCC.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][C:28]=1[C:35]([CH3:37])=[CH2:36]>C1COCC1.CCOC(C)=O>[CH3:20][C:3]1[CH:4]=[C:5]([O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])[CH:6]=[C:7]([CH3:8])[C:2]=1[CH:31]([C:30]1[CH:33]=[CH:34][C:27]([F:26])=[C:28]([C:35]([CH3:37])=[CH2:36])[CH:29]=1)[OH:32]
Reactant: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C)c1Br
Reactant: C=C(C)c1cc(C=O)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)c1cc(C(O)c2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)ccc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-3,5-dimethyl-triisopropylsilanoxybenzene (1.29 g, 3.6 mmol, Chiellini et al., Bioorg. Med. Chem. Lett. 10:2607 (2000)) in THF at −78° C. was added n-butyllithium (1.58 mL, 3.96 mmol, 2.5 M in THF). After 30 min, a solution of 4-fluoro-3-isopropenylbenzaldehyde (500 mg, 3.0 mmol) in THF was added. The reaction mixture was stirred at −78° C. for 1 h, allowed to warm to room temperature, diluted with EtOAc and quenched with water. The organic layer was dried over MgSO4, filtered and concentrated to afford crude 1-(2,6-dimethyl-4-triisopropylsilanyloxyphenyl)-1-(4′-fluoro-3′-isopropenylphenyl)methanol as an oil: 1H NMR (200 MHz, CDCl3): δ 7.18 (m, 1H), 7.02 (m, 1H), 6.94 (m, 1H), 6.56 (s, 2H), 6.22 (s, 1H), 5.18 (m, 2H), 2.20 (s, 6H), 2.08 (s, 3H), 1.25 (m, 3H), 1.11 (m, 18).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]2[CH3:18])=[CH:4][C:3]=1[C:19]#N.C([Al]CC(C)C)C(C)C.C[OH:31]>O1CCCC1.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]2[CH3:18])=[CH:4][C:3]=1[CH:19]=[O:31]
Reactant: CO
Reactant: Cc1cn(-c2cc(C#N)c(N)c(C(F)(F)F)c2)c(C)n1
Agent: CC(C)C[Al]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cn(-c2cc(C=O)c(N)c(C(F)(F)F)c2)c(C)n1
Temperature: 0 °C

Procedure:
To an ice-cooled stirred solution of 1-(4-amino-3-cyano-5-trifluoromethylphenyl)-2,4-dimethylimidazole (0.7 g) in tetrahydrofuran (10 cm3) was added 3.5 cm3 of a 1.5M solution of diisobutyl aluminium in toluene. The mixture was heated at 40° for 2 hours, cooled in ice, treated with methanol (2 cm3), and evaporated in vacuo. The residue was treated with water (25 cm3) and 2M hydrochloric acid (5 cm3), and heated on a steam bath for five minutes. The solution was then cooled, basified to pH 8 with aqueous sodium carbonate solution, and extracted with chloroform:methanol, 20:1 (3×30 cm3). The combined organic extracts were dried (MgSO4), evaporated in vacuo, and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl acetate:methanol, 50:1, to afford 1-(4-amino-3-formyl-5-trifluoromethylphenyl)-2,4-dimethylimidazole, m.p. 200°-202°, (0.391 g).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]([CH3:14])([CH3:13])[C:8](OCC)=[O:9])=[CH:4][CH:3]=1.O.[NH2:18][NH2:19].C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]([CH3:14])([CH3:13])[C:8]([NH:18][NH2:19])=[O:9])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)C(C)(C)Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(Oc1ccc(F)cc1)C(=O)NN
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Ethyl 2-(4-fluorophenoxy)-2-methylpropanoate (5.13 g) was dissolved in methanol (50 ml), hydrazine monohydrate (11 ml) and potassium carbonate (3.14 g) were added thereto, followed by stirring at 70° C. for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Water and saturated aqueous sodium bicarbonate were added to the residue, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=99:1) to obtain 2-(4-fluorophenoxy)-2-methylpropanohydrazide (1.98 g) as a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[C:5]([C:34]([O:36]CC1C=CC(OC)=CC=1)=[O:35])=[N:6][N:7]2[CH2:32][CH3:33].[OH-].[K+]>CO.O>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[C:5]([C:34]([OH:36])=[O:35])=[N:6][N:7]2[CH2:32][CH3:33]
Reactant: CCn1nc(C(=O)OCc2ccc(OC)cc2)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCn1nc(C(=O)O)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Yield: 64.5 %

Procedure:
To the solution of 4-methoxybenzyl 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (24 g, 37.2 mmol) in methanol (400 mL) and water (133 mL) was added potassium hydroxide (8.35 g, 149 mmol). The reaction mixture was heated to reflux for 3 h. Solvent was removed under vacuum. The residue was suspended in water and the resulting mixture was acidified to pH4 with 2N hydrochloric acid. The precipitated solid was filtered and dried to afford 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carboxylic acid (12.6 g, 24.00 mmol, 64.5% yield). LCMS: (M+H)+: 525.2
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31](=[O:32])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=3)=[CH:29][CH:30]=2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CC(C)(C)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cc2)CC1
Yield: 35.2 %

Procedure:
A mixture of 3-tert-butyl aniline (117 mg, 0.78 mmol), 4-(4-carboxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (prepared as described in Biog. Med. Chem. 2006, 14, 2089) (200 mg, 0.65 mmol), EDCl (375 mg, 0.95 mmol) and a catalytic amount of DMAP in CH2Cl2 was stirred at room temperature overnight. The next day the mixture was partitioned between EtOAc and water. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The residue was chromatographed with silica gel column amd 0-30% EtOAc in hexanes gradient to afford the product (100 mg, Yield: 35%). HRMS m/z calcd for C26H35N3O3 [M+H]+: 438.2751. Found: 438.2753.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9](Cl)[CH:8]=[CH:7][N:6]=1>C1COCC1.C(OCC)(=O)C>[Cl:4][C:5]1[N:10]=[C:9]([S:2][CH3:1])[CH:8]=[CH:7][N:6]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ccnc(Cl)n1
Reaction time: 8 h
Yield: 70.5 %

Procedure:
Sodium thiomethoxide (5.18 g, 73.8 mmol) was added slowly portion-wise via powder addition funnel to a stirring solution of 2,4-dichloropyrimidine (10 g, 67.1 mmol) in THF (150 mL) at room temperature. After stirring overnight, the reaction was taken up in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate and hexanes to give 2-chloro-4-(methylsulfanyl)pyrimidine (10.127 g, 47.3 mmol, 70.4%) as a white solid.