Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(C)(C)C.[OH:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:29]1([CH2:35][C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCCCC.O1CCCC1>[C:29]1([CH2:35][C:36]([O:6][CH:7]([C:20]2[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCCCCCCCCC(OC(=O)Cc1ccccc1)c1coc([Si](C)(C)C)c1
Reaction time: 0.08 h

Procedure:
tert-Butyl lithium (a 1.7 M solution in pentane; 0.29 ml, 0.49 mmol) was added dropwise to a solution of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (138.2 mg, 0.41 mmol) in tetrahydrofuran (7 ml) at -78 degrees under argon. After 5 minutes, a solution of phenylacetyl chloride (65 microliter, 0.49 mmol) in tetrahydrofuran (1/2ml) was added. Stirring was continued at room temperature for 16 hours and quenched with water. Extraction (ethyl ether) and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was purified by preparative TLC (20×20 cm, 500 micron silica plate; developed with 10% ethyl ether/hexane). The title ester was obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([OH:20])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[NH:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=2)=[O:23])=[CH:4][CH2:3]1.[C:32]([O:36]C)(=[O:35])[CH2:33]O.C(O)(C(F)(F)F)=O.[OH-].[K+]>C(Cl)Cl>[C:29]([C:26]1[NH:25][C:24]([C:22]([NH:21][C:9]2[CH:10]=[CH:11][C:12]([C:14]3([O:20][CH2:33][C:32]([OH:36])=[O:35])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:13][C:8]=2[C:5]2[CH2:6][CH2:7][C:2]([CH3:31])([CH3:1])[CH2:3][CH:4]=2)=[O:23])=[N:28][CH:27]=1)#[N:30]
Reactant: CC1(C)CC=C(c2cc(C3(O)CCOCC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Reactant: COC(=O)CO
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C3(OCC(=O)O)CCOCC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
To a suspension of 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(4-hydroxy-tetrahydro-pyran-4-yl)-phenyl]-amide (48.0 mg, 0.114 mmol)(prepared in Example 1, step (h)) in 1 mL of DCM was added methyl glycolate (0.215 mL, 2.78 mmol), TFA (0.036 mL, 0.464 mmol), and the mixture was stirred for 8 h at RT. The mixture was concentrated and the methyl ester of the title compound was eluted from a 10-g SPE column with 50% EtOAc/hexanes. The resulting ester was dissolved in 1 mL of MeOH, 2N KOH (0.30 mL, 0.60 mmol) was added and the mixture stirred for 8 h at RT. The title compound was purified by RP-HPLC on a C18 column eluting with a linear gradient of 30-60% CH3CN in 0.1% TFA/H2O over 12 min to give 13 mg (30%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.34 (d, J=8.6 Hz, 1H), 7.85 (s, 1H), 7.60 (s, 1H), 7.37 (dd, J=8.6, 2.2 Hz, 1H), 7.28 (d, J=2.2 Hz, 1H), 5.79 (m, 1H), 4.03-3.94 (m, 2H), 3.88-3.80 (m, 2H), 3.72 (s, 2H), 2.35-2.27 (m, 2H), 2.13-2.06 (m, 4H), 1.60 (t, J=6.3 Hz, 2H), 1.11 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H30N4O5, 477.2 (M−H). found 477.2.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH:14]=[C:13]2[C:3]=1[C:4](=[O:24])[CH2:5][C:6]1([NH:12]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.CI.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:27][O:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][C:19]([OH:21])=[O:20])[CH:14]=[C:13]2[C:3]=1[C:4](=[O:24])[CH2:5][C:6]1([NH:12]2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CCOC(=O)COc1cc(O)c2c(c1)NC1(CCCCC1)CC2=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(OCC(=O)O)cc2c1C(=O)CC1(CCCCC1)N2
Temperature: 40 °C
Reaction time: 9 h

Procedure:
A mixture of ethyl 2-{(5-hydroxy-4-oxospiro [1,2,3,4-tetrahydroquinoline-2,1'-cyclohexan]-7-yl)oxy}acetate (prepared in Example 51 (1)) (0.15 g, 0.45 mmol), methyl iodide (0.071 g, 0.50 mmol), anhydrous potassium carbonate (0.094 g, 0.68 mmol), and dry DMF (4 ml) is stirred at 40° C. for 9 hours. After the addition of methyl iodide (0.14 g, 1.0 mmol), the stirring is continued for additional 4 hours. The solvent is removed by distillation and the residue is dissolved in ethyl acetate. The solution is washed with saturated brine, dried, and the solvent is removed. The residue is placed on a silica gel column and eluted with a mixture of ethyl acetate and dichloromethane (1:10). The earlier fractions containing oily materials are discarded. From the succeeding fractions, the desired product is obtained as a crystalline solid (0.067 g, 43%, m.p=158°-159° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:33][C:34]1[CH:35]=[C:36]([N:41]=[C:42]=[O:43])[CH:37]=[CH:38][C:39]=1[Cl:40]>ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:42]([NH:41][C:36]3[CH:37]=[CH:38][C:39]([Cl:40])=[C:34]([Cl:33])[CH:35]=3)=[O:43])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NC(=O)Nc3ccc(Cl)c(Cl)c3)cc2)COC1(C)C
Reaction time: 18 h
Yield: 93.5 %

Procedure:
To a stirred suspension of (S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (180 mg) in dichloromethane (3 ml) were added sequentially N,N-diisopropylethylamine (0.19 ml) and 3,4-dichlorophenyl isocyanate (137 mg, CAS 102-36-3) and stirring was continued at room temperature for 18 h. The mixture was then concentrated in vacuo and the residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-(2-{4-[3-(3,4-dichloro-phenyl)-ureido]-phenyl}-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (267 mg, 93%) as a colourless amorphous solid. MS (ISP): 529.4 ([{37Cl}M+NH4]+), 527.4 ([{37Cl35Cl}M+NH4]+), 525.4 ([{35Cl}M+NH4]+), 512.2 ([{37Cl}M+H]+), 510.2 ([{37Cl35Cl}M+H]+), 508.2 ([{35Cl}M+H]+), 456.2 ([{37Cl}M+H—C4H8]+), 454.2 ([{37Cl35Cl}M+H—C4H8]+), 452.2 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH:13]([C:28]([O:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:23])[CH3:22])=[C:16]([O:24][C:25](=[O:27])[CH3:26])[CH:15]=2)/[C:8](O)=[O:9])[N:6]=1.[C:44]1([CH:50]([O:57][C:58]([C:60]2[N:61]3[C@H:64]([S:65][CH2:66][C:67]=2[CH2:68][S:69][C:70]2[N:75]4[N:76]=[C:77]([C:79]([O:81][CH:82]([C:89]5[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=5)[C:83]5[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=5)=[O:80])[N:78]=[C:74]4[N:73]=[C:72]([CH3:95])[CH:71]=2)[C@H:63]([NH2:96])[C:62]3=[O:97])=[O:59])[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:44]1([CH:50]([O:57][C:58]([C:60]2[N:61]3[C@H:64]([S:65][CH2:66][C:67]=2[CH2:68][S:69][C:70]2[N:75]4[N:76]=[C:77]([C:79]([O:81][CH:82]([C:89]5[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=5)[C:83]5[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=5)=[O:80])[N:78]=[C:74]4[N:73]=[C:72]([CH3:95])[CH:71]=2)[C@H:63]([NH:96][C:8](=[O:9])/[C:7](/[C:5]2[N:6]=[C:2]([NH2:1])[S:3][CH:4]=2)=[N:11]\[O:12][CH:13]([C:28]([O:30][CH:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:29])[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:23])[CH3:22])=[C:16]([O:24][C:25](=[O:27])[CH3:26])[CH:15]=2)[C:62]3=[O:97])=[O:59])[C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](N)[C@H]3SC2)n2nc(C(=O)OC(c3ccccc3)c3ccccc3)nc2n1
Reactant: CC(=O)Oc1ccc(C(O/N=C(\C(=O)O)c2csc(N)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CSc4cc(C)nc5nc(C(=O)OC(c6ccccc6)c6ccccc6)nn45)CS[C@H]23)c2csc(N)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To an ice-cooled solution containing the product obtained in Step 1 (3.0 g) and (6R,7R)-7-amino-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester (3.75 g) in dichloromethane (100 ml) was added dicyclohexylcarbodiimide (1.54 g), and the mixture was stirred at room temperature. After filtering off the insoluble matters, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, giving 4.8 g of the objective compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[H-].[Na+].[C:15](OC(=O)C)(=[O:17])[CH3:16].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:15]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[C:5](=[O:12])[C:6]1=[O:11])(=[O:17])[CH3:16]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)N1C(=O)C(=O)c2cc(C)ccc21
Temperature: 0 °C
Yield: 47.6 %

Procedure:
With stirring at 0° C., 8.06 g (50.0 mmols) of 5-methylisatin was added by small portions to a solution of 2.00 g (50.0 mmols) of sodium hydride in toluene. While stirring under ice cooling, 4.7 ml (50.0 mmols) of acetic anhydride was dropwise added to the mixture followed by heating at 80° C. for further an hour with stirring. After completion of the reaction, an aqueous saturated sodium bicarbonate solution was added to the reaction mixture. The crystals were filtered, washed with water and dried to give 4.84 g (yield, 47%) of 1-acetyl-5-methylisatin.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([F:26])([F:25])[F:24])[C:17]=1[OH:27]>CN(C=O)C>[CH2:7]([O:27][C:17]1[C:18]([CH2:22][C:23]([F:24])([F:25])[F:26])=[CH:19][CH:20]=[CH:21][C:16]=1[CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cccc(CC(F)(F)F)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(CC(F)(F)F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 108.7 %

Procedure:
Potassium carbonate (953 mg, 6.89 mmol) followed by benzyl bromide (0.8 mL, 6.89 mmol) were added to a solution of 2-methyl-6-(2,2,2-trifluoro-ethyl)-phenol (1.78 g, 6.89 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 15 hours and then partitioned between H2O and EtOAc. The organic layer was washed with 1N HCl, brine, dried over Na2SO4 and concentrated to a brown oil. Purification by flash column chromatography (0% to 20% EtOAc in hexanes) gave the product as a clear oil (2.1 g). LCMS: APCI−VE=279
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)=[CH:17][CH:16]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2ccc3c(c2)CCCC3=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Hydroxy-1-tetralone (52.1)(3.24 g, 20 mmol) and 4-methoxybenzyl chloride (52.2) (3.13 g, 20 mmol) were dissolved in DMF (20 mL). Cs2CO3 (7.17 g, 22 mmol) was added to the mixture, and the resulting mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with saturated brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was used without further purification for the next step. MS ESI (pos.) m/e: 283 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccccn2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCc2ccccc2)nc(N)nc1-c1ccccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile and benzylamine in DME. ES-MS m/e (%): 303 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]=[C:9]2[CH2:18][NH:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31]I.Cl>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]2[CH2:18][N:19]([CH3:31])[C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCOC(=O)c1cnc(CNc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(Cc1ncc(C(=O)O)n1-c1ccc(F)cc1)c1c(F)ccc(F)c1F
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)-2-(((2,3,6-trifluorophenyl)amino)methyl)-1H-imidazole-5-carboxylate (23) (56 mg, 0.14 mmol) in DMF (2 mL) was added sodium hydride (60% in mineral oil, 7 mg, 0.28 mmol) and stirred for 30 minutes. To the solution was added methyl iodide (18 μL, 0.28 mmol) and again stirred overnight at room temperature. Ethyl acetate was added and the reaction was acidified with 2N HCl. The ethyl acetate was separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 1-(4-fluorophenyl)-2-((methyl(2,3,6-trifluorophenyl)amino)methyl)-1H-imidazole-5-carboxylic acid (24).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[N+:12]([C:15]1[CH:34]=[CH:33][C:18]([CH:19]=[N:20][NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]>C(Cl)Cl>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([Cl:1])=[N:20][NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:24][CH:23]=2)=[CH:33][CH:34]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(C=NNc2ccc(OC(F)(F)F)cc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CSC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C(Cl)=NNc2ccc(OC(F)(F)F)cc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a magnetically stirred solution of N-chlorosuccinimide (1.23 g, 9.22 mmoL) in CH2Cl2 (16 mL) at 0° C. was added dimethyl sulfide (1.36 mL, 18.45 mmoL) and the reaction mixture was stirred for 15 min and then cooled to −78° C. To this solution was added 1-(4-nitrobenzylidene)-2-(4-(trifluoromethoxy)-phenyl)hydrazine (2 g, 6.15 mmoL) dissolved in CH2Cl2 (16 mL) and the reaction mixture was stirred at this temperature for 1 h, warmed to room temperature and stirred for 2 h. The solution was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (15 mL) and added to a SiO2 loading cartridge and purified via flash column chromatography (Gradient EtOAc/hexanes). The title compound was isolated as a yellow solid: mp 172-175° C.; 1H NMR (400 MHz, CDCl3) δ 8.29-8.26 (m, 3H), 8.09-8.05 (m, 3H), 7.22 (s, 4H); 19F NMR (376 MHz, CDCl3) δ −58.30; ESIMS m/z 359 ([M+H])+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:28])[CH2:9][NH:10][C:11]([C@@:13]2([CH3:27])[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[N:14]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:12])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[F:33][C:34]([F:48])([F:47])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]O)=[CH:37][CH:36]=1>C(#N)C.O>[CH3:18][C:15]1([CH3:19])[N:14]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[C@@:13]([CH3:27])([C:11](=[O:12])[NH:10][CH2:9][C:8](=[O:28])[C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][C:38]3[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:47])[F:48])=[CH:40][CH:39]=3)=[C:3]([C:29]([F:31])([F:32])[F:30])[CH:4]=2)[CH2:17][O:16]1
Reactant: OCCCCCc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)NCC(=O)c1ccc(O)c(C(F)(F)F)c1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)NCC(=O)c1ccc(OCCCCCc2ccc(C(F)(F)F)cc2)c(C(F)(F)F)c1
Yield: 31 %

Procedure:
The title compound was prepared from (R)-tert-butyl 4-(2-(4-hydroxy-3-(trifluoromethyl)phenyl)-2-oxoethylcarbamoyl)-2,2,4-trimethyloxazolidine-3-carboxylate (0.25 mmol, 1.0 equiv) and 5-(4-(trifluoromethyl)phenyl)pentan-1-ol (0.25 mmol, 1.0 equiv) according to the general procedure in 31% yield. HPLC retention time on a C18 column (30×4.6 mm, 3.5 V) was 3.26 min with gradient 50-95% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase. MS (ESI, M+H+)=675.6.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)=[C:6]([CH:12]([OH:14])[CH3:13])[O:7]2.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:30][S:31]([O:14][C@@H:12]([C:6]1[O:7][C:8]2[C:3]([C:4](=[O:22])[C:5]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)=[C:2]([F:1])[CH:11]=[CH:10][CH:9]=2)[CH3:13])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1oc2cccc(F)c2c(=O)c1-c1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](OS(C)(=O)=O)c1oc2cccc(F)c2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of (+)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one (0.800 g, 2.63 mmol) in dichloromethane (16 ml) and triethylamine (1.10 ml, 7.91 mmol), methanesulphonyl chloride (0.400 ml, 5.27 mmol) is added stirred at room temperature for 2 h. The reaction mass is quenched with water, extracted with dichloromethane, dried over sodium sulphate and concentrated to afford the title compound as brown solid which is used as such in next step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[N:6]=[CH:5]2.[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C=O)C>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[N:6]=[CH:5]2)[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3cc(O)ccc32)CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(cnn2C2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of tert-butyl 4-(5-hydroxy-1H-indazol-1-yl)piperidine-1-carboxylate (150 mg, 0.458 mmol) in DMF (10 mL) at 0° C. was added NaH (60% in mineral oil) (16.8 mg, 0.706 mmol) and ethyl 2-bromoacetate (119 mg, 0.706 mmol). The mixture was stirred at 25° C. for 3 h, poured into water, and the product extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4, concentrated under reduced pressure and purified by TLC (Pet.Ether:EtOAc=1:1) to give tert-butyl 4-(5-(2-ethoxy-2-oxoethoxy)-1H-indazol-1-yl)piperidine-1-carboxylate (120 mg, yield 65%) as a colorless oil. LCMS (m/z): 404.2 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:7]([CH2:21][CH2:22][N:23]=3)[C:8]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)=[N:9][C:10]=2[CH:11]=1.Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:25][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:7]([CH2:21][CH2:22][N:23]=4)[C:8]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)=[N:9][C:10]=3[CH:11]=2)=[CH:27][CH:28]=1)(=[O:33])=[O:34]
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: O=C(NC1=Nc2cc(O)ccc2C2=NCCN12)c1cccnc1
Product: CS(=O)(=O)c1ccc(COc2ccc3c(c2)N=C(NC(=O)c2cccnc2)N2CCN=C32)cc1

Procedure:
The procedure used for the preparation of Example 24 was used to prepare the title compound from N-(8-hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (Example 2-5 in WO2004029055) and 1-(chloromethyl)-4-(methylsulfonyl)benzene (20 mg, 4%). TLC: Rf=0.91 in 10% MeOH/CH2Cl2, HPLC MS RT=1.91 min, MH+=476.2; 1H NMR (DMSO-d6) δ: 3.22 (3H, s), 4.00-4.15 (4H, m), 5.33 (2H, s), 6.93 (1H, d), 7.39 (1H, s), 7.51 (1H, dd), 7.71 (2H, d), 7.78 (1H, d), 7.95 (2H, d), 8.42 (1H, d), 8.70 (1H, m), 9.29 (1H, s), 12.31 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]=[CH:21]1.O>CN(C=O)C>[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([O:12][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH:21]=1
Reactant: BrC1C=CCCC1
Reactant: COC(=O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1OC1C=CCCC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 18.6 g of methyl 5-chlorosalicylate, 28 g of K2CO3 and 20 g of 3-bromocyclohexene in 200 ml of DMF is stirred at 90° C. overnight. The mixture is then Poured into water, extracted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated to dryness to obtain crude product. This is purified by flash chromatography using hexane as the eluent to give pure methyl 2-(cyclohexen-3-yloxy)-5-chlorobenzoate as the first fraction which is used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:15]([CH:16]([CH3:18])[CH3:17])=[CH:14][C:13]([OH:19])=[C:12]([I:20])[CH:11]=2)=[CH:4][N:3]=1.[CH2:21](Br)[CH3:22]>CN(C=O)C>[CH2:21]([O:19][C:13]1[C:12]([I:20])=[CH:11][C:10]([O:9][C:5]2[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[C:15]([CH:16]([CH3:18])[CH3:17])[CH:14]=1)[CH3:22]
Reactant: CCBr
Reactant: CC(C)c1cc(O)c(I)cc1Oc1cnc(N)nc1N
Solvent: CN(C)C=O
Product: CCOc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Yield: 78.9 %

Procedure:
To a solution of 4-(2,4-Diamino-pyrimidin-5-yloxy)-2-iodo-5-isopropyl-phenol (0.2 g, 0.52 mmol) in anhydrous DMF (2 ml) was added EtBr (57 mg, 0.52 mmol) in portions. The reaction mixture was partitioned between EtOAc and H2O. The organic extract was dried over Na2SO4, filtered and concentrated. Flash chromatography on silica (3% MeOH in methylene chloride with 1% NH4OH) gave 5-(4-Ethoxy-5-iodo-2-isopropyl-phenoxy)-pyrimidine-2,4-diamine (0.17 g, 28%) as a yellow solid. (M+H)=415.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[N:23][CH:22]=[N:21]3)=[CH:16][CH:15]=2)=[CH2:13])[CH2:11][O:10]1.[NH:25]1[CH:29]=[N:28][CH:27]=[N:26]1.[Na]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([C:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)=[CH:16][CH:15]=1)=[CH2:13])[CH2:11][N:25]1[CH:29]=[N:28][CH:27]=[N:26]1
Reactant: C=C(c1ccc(-n2cncn2)cc1)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CN(C)C=O
Product: C=C(c1ccc(-n2cncn2)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 89 %

Procedure:
By the method of Preparation 20(v), 2-(2,4-difluorophenyl)-2-[1-{4-(1,2,4-triazol-1-yl)phenyl}ethenyl]oxirane (570 mg, 1.75 mmol) was treated with sodium 1,2,4-triazole in DMF (10 ml) at 70° C. for 8 hours, to give 2-(2,4-difluorophenyl)-1-(1,2,4-triazol-1-yl)-3-[4-(1,2,4-triazol-1-yl)phenyl]-3-buten-2-ol (620 mg, 89%), as a solid, which was characterised by 1H-N.M.R. spectroscopy.