Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](OS(C)(=O)=O)[CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:5][CH:4]=1.[C:23]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1)(=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CO>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH:11]([S:33][C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:23](=[O:25])[CH3:24])=[CH:32][CH:31]=2)[CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)=[CH:7][CH:8]=1
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: CS(=O)(=O)OC(CCc1ccc(Cl)cc1)Cn1ccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(SC(CCc2ccc(Cl)cc2)Cn2ccnc2)cc1
Yield: 84 %

Procedure:
A mixture of 1-[4-(4-chlorophenyl)-2-methanesulfonyloxy-n-butyl]imidazole hydrochloride (2.0 g), 4-acetylaminothiophenol (1.2 g) and anhydrous potassium carbonate (2.0 g) in 30 ml of acetone and 10 ml of methanol was stirred and refluxed overnight under nitrogen. The solvent was evaporated and the residue treated with water (50 ml) and ether (20 ml) and the mixture stirred until crystallization was complete. Filtration of the product and recrystallization from ethyl acetate gave 1.84 g of 1-[4-(4-chlorophenyl)-2-(4-acetylaminophenylthio)-n-butyl]imidazole as a pale cream solid, m.p. 165.5°-166.5° C. B. Similarly, proceeding as above substituting the appropriate thiophenol for 4-acetylaminothiophenol the following compounds are prepared:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CSC.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16]([C@@H:24](O)[CH3:25])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.CCCCCC>ClCCl>[Br:1][C@@H:24]([C:16]1[CH:15]=[C:14]([C:13]([F:28])([F:27])[F:12])[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=1)[CH3:25]
Reactant: C[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CSC
Solvent: CCCCCC
Product: C[C@@H](Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 9 h
Yield: 57.5 %

Procedure:
Under an argon atmosphere, a suspension of N-bromosuccinimide (206 mg, 1.16 mmol) in anhydrous dichloromethane (3.8 mL) was added dropwise with dimethyl sulfide (105 μL, 1.40 mmol) under ice cooling over 3 minutes. The mixture was added dropwise with a solution of (S)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (200 mg, 0.78 mmol, >99.5% ee) in anhydrous dichloromethane (2 mL) at −20° C., and the mixture was stirred at room temperature for 9 hours. The reaction mixture was add with n-hexane, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent, n-hexane) to obtain 144 mg of (R)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane as colorless oil.
Reaction SMILES: B.CSC.[I:5][C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].B(OC)(OC)OC.CO>C1COCC1.O>[I:5][C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:7]=1[CH2:8][OH:9]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1I
Agent: B
Agent: COB(OC)OC
Solvent: O
Solvent: CO
Solvent: CSC
Product: O=[N+]([O-])c1cccc(CO)c1I

Procedure:
Borane-dimethylsulfide (34 mL, 0.34 mmol) was added to a solution of 2-iodo-3-nitrobenzoic acid (43) [P. J. Culhane, Org. Synth. Coll. Vol 1, 1967, 125-127] (82.3 g, 0.28 mol) and trimethyl borate (64 mL, 0.56 mol) in dry THF (400 mL) under nitrogen, and the mixture stirred at reflux for 90 min. The solution was cooled, MeOH then H2O were added, and the mixture was evaporated. Aq NaCl was added to the residue and the mixture was extracted with EtOAc (×3). The extracts were washed with aq NaCl, dried (Na2SO4), and evaporated to give crude 2-iodo-3-nitrobenzyl alcohol (44) as a yellow-orange solid suitable for use in the next step. A sample was filtered through a short column of silica eluting with CH2Cl2 and recrystallized from PhH as pale yellow needles, mp 91-91.5° C. 1H NMR (CDCl3) δ 7.72 (dd, J=7.7, 1.1 Hz, 1 H, H-4 or 6), 7.59 (dd, J=8.1, 1.5 Hz, 1 H, H-4 or 6), 7.50 (t, J=7.8 Hz, 1 H, H-5), 4.78 (s, 2 H, CH2), 2.14 (br s, 1 H, OH). Anal. Calculated for C7H6INO3 : C, 30.1; H, 2.2; N, 5.0. Found: C, 30.4; H, 2.1; N, 4.9%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](=[O:39])[NH:16][CH:17]([C:25]2[S:26][CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36](=[O:38])[NH2:37])=[CH:32][CH:31]=3)[CH:29]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Cl:48])C(=O)C1>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:40])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](=[O:39])[NH:16][CH:17]([C:25]2[S:26][C:27]([Cl:48])=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36](=[O:38])[NH2:37])=[CH:32][CH:31]=3)[CH:29]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(Cc2ccccc2)c2cc(-c3ccc(C(N)=O)cc3)cs2)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(Cc2ccccc2)c2cc(-c3ccc(C(N)=O)cc3)c(Cl)s2)CC1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1C (336 mg, 0.6 mmol) and NCS (104 mg, 0.78 mmol) in chloroform (20 mL) was stirred at 60° C. under N2. After 1.5 h, the mixture was cooled to rt and concentrated. Reverse-phase HPLC purification gave ID as a light yellow solid. LC/MS m/z 596.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[C:3]([F:6])([F:5])[F:4].[H-].[Na+].Br[CH2:18][C:19]([O:21]CC)=[O:20]>O1CCCC1>[F:1][C:2]([F:14])([C:3]([F:5])([F:4])[F:6])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:18][C:19]([OH:21])=[O:20]
Reactant: OCCCCCCC(F)(F)C(F)(F)F
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)COCCCCCCC(F)(F)C(F)(F)F
Temperature: 20 °C
Yield: 39.6 %

Procedure:
To a stirred solution of 6-(pentafluoroethyl)hexan-1-ol (500 mg) in tetrahydrofuran (10 ml) was added sodium hydride (60% dispersion in mineral oil; 118 mg) and the reaction was stirred at 20° C. for 30 mlnutes. Ethyl bromoacetate (379 mg) was added and the reaction was stirred for a further 3 hours. The reaction was quenched by the addition of ethanol (3 ml) followed by stirring for 30 mlnutes, then 2M sodium hydroxide (3 ml) was added and the reaction was stirred for a further 2 hours. The reaction mixture was partitioned between dichloromethane (100 ml) and water (100 ml). The aqueous layer was acidified to pH 1 by the addition of 2M hydrochloric acid and then extracted with dichloromethane (3×100 ml). The combined organic layers were dried over magnesium sulphate and the solvent was removed in vacuo to give the title compound as a white solid (250 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[CH:12]=[C:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=2[CH2:17][CH2:16][C:15]2[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:14]1=2>>[F:24][C:23]1[C:18]2[CH2:17][CH2:16][C:15]3[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:14]=3[C:13](=[CH:12][C:4]3[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=3)[C:19]=2[CH:20]=[CH:21][CH:22]=1
Reactant: Fc1cccc2c1CCc1c(F)cccc1C2=CBr
Reactant: OB(O)c1cccc(O)c1
Product: Oc1cccc(C=C2c3cccc(F)c3CCc3c(F)cccc32)c1
Yield: 113.1 %

Procedure:
Following procedures essentially as described in Example 219, below, and using 3-hydroxyphenyl boronic acid (380 mg, 2.75 mmol) and 5-bromomethylene-1,9-difluoro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (803 mg, 2.75 mmol), provides to 1.04 g of the title compound as crude product. The crude product is purified using column chromatography eluting with 15% EtOAc/hexane to 30% EtOAc/hexane to give 500 mg (60%) product as a light yellow foam, mp 129.5° C. MS (ES) 333 (M−1). HPLC (ISO90-10M) shows 98% at t=2.90 min.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8](=[O:13])[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:6]2[OH:20].Br.C(OC(=O)C)(=O)C.O1CCOCC1.C(OC(C)C)(C)C>C(O)(=O)C>[OH:20][C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([OH:2])[CH:4]=2)[O:9][C:8](=[O:13])[C:7]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc2oc(=O)c(-c3ccccc3)c(O)c2c1
Agent: Br
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=c1oc2ccc(O)cc2c(O)c1-c1ccccc1
Yield: 33.7 %

Procedure:
Prepared in the manner described in Example 25, Stage A, from 37.6 g. (0.14 mol) of 6-methoxy-4-hydroxy-3-phenyl-coumarin, 375 ml. of glacial acetic acid, 750 ml. of 62% hydrobromic acid and 375 ml. of acetic anhydride. Weight 12.2 g.; yield 33.7% (theoretical yield 35.6 g.); M.P. 261°-263° C. (dioxane-diisopropyl ether: 50-50).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([OH:11])[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:7][C:6]=1[OH:29])(=O)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:13]([O:12][C:8]1[C:9]([OH:11])=[CH:10][C:5]2[N:4]=[C:1]([CH3:2])[O:29][C:6]=2[CH:7]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCOc1cc(O)c(NC(C)=O)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCOc1cc2oc(C)nc2cc1O

Procedure:
A mixture composed of 93.0 g of (1-c), 22.3 g of p-toluenesulfonic acid monohydrate and 1 l of toluene was refluxed with heating for 3 hours to distill away the water formed. After being allowed to cool, the crystals formed were washed with acetone and dried. Yield: 73 g.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH:18]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=2)[NH:20][C:19]1=[O:28])[CH2:4][C:5]([CH3:17])([CH3:16])[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[Cl:29][C:30]1[C:31]([F:38])=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:12]([Si:9]([CH3:11])([CH3:10])[O:8][CH2:7][CH2:6][C:5]([CH3:17])([CH3:16])[CH2:4][CH:3]1[CH2:2][NH:1][CH:33]([C:32]2[CH:35]=[CH:36][CH:37]=[C:30]([Cl:29])[C:31]=2[F:38])[C:18]21[C:26]1[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=1)[NH:20][C:19]2=[O:28])([CH3:13])([CH3:14])[CH3:15]
Reactant: O=Cc1cccc(Cl)c1F
Reactant: CC(C)(CCO[Si](C)(C)C(C)(C)C)CC(CN)C1C(=O)Nc2cc(Cl)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(CCO[Si](C)(C)C(C)(C)C)CC1CNC(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 130 °C
Yield: 6.1 %

Procedure:
To a solution of racemic 3-[1-aminomethyl-5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentyl]-6-chloro-1,3-dihydro-indol-2-one (1.5 g, 3.5 mmol) in toluene (30 mL) was added 3-chloro-2-fluoro-benzaldehyde (Oakwood) (0.56 g, 3.5 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate (67 mg, 0.35 mmol). The reaction mixture was heated at 130° C. for 2 h. The mixture was cooled to room temperature, then partitioned between ethyl acetate and aqueous NaHCO3 solution. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by chromatography (50-100% EtOAc in hexanes) to give rac-(2′S,3′S,4′S)-4′-[4-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-butyl]-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one as a white solid (0.12 g, 6%)
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl[C:19]1[CH:20]=[CH:21][C:22]([N+:34]([O-:36])=[O:35])=[C:23]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:24]=1.[H-].[Na+]>CN(C)C=O>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:19]4[CH:20]=[CH:21][C:22]([N+:34]([O-:36])=[O:35])=[C:23]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[CH:24]=4)=[CH:15][CH:16]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)ccc1[N+](=O)[O-]
Yield: 90 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-(1-adamantyl)phenol (2.28 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.87 g), sodium hydride (55 wt. %, 0.44 g) and anhydrous N,N-dimethylformamide (40 ml) and the reaction mixture was purified to give the title compound (4.30 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C([Li])CCC.[I:21]CCI>CCCCCC.C(OCC)C>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]([I:21])=[CH:12][N:13]=2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(-c2nccs2)cc1
Reactant: ICCI
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: FC(F)(F)c1ccc(-c2ncc(I)s2)cc1
Yield: 46.5 %

Procedure:
In a manner similar to Step C of Example 1, the reaction of 5.45 grams (0.0238 mole) of 2-(4-trifluoromethylphenyl)thiazole, 9.5 ml of a 2.5 M solution of n-butyllithium in hexane, and 6.71 grams (0.0238 mole) of 1,2-diiodoethane in 40 ml of diethyl ether produced 3.93 grams of 2-(4-trifluoromethylphenyl)-5-iodothiazole as a solid.
Reaction SMILES: ClCC(C1C=CC=CC=1)=O.CC1(C2C=CC=CC=2Cl)C=CC=C(C=CC#N)C1.[2H][2H].[CH3:31][CH:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:42])[CH2:33][CH2:34][NH2:35].[CH3:43][O:44][C:45]1[CH:46]=[C:47]([C:51](=O)[CH3:52])[CH:48]=[CH:49][CH:50]=1.C([BH3-])#N.[Na+]>[OH-].[Pd+2].[OH-].CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)(=O)C>[CH3:31][CH:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:42])[CH2:33][CH2:34][NH:35][CH:51]([C:47]1[CH:48]=[CH:49][CH:50]=[C:45]([O:44][CH3:43])[CH:46]=1)[CH3:52]
Reactant: CC(CCN)c1ccccc1Cl
Reactant: COc1cccc(C(C)=O)c1
Agent: [Pd+2]
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC(=O)O
Product: COc1cccc(C(C)NCCC(C)c2ccccc2Cl)c1

Procedure:
In a similar fashion, 2-chloroacetophenone was used to prepare 3-methyl-3-(2-chlorophenyl)cinnamonitrile. The nitrile was catalytically reduced (palladium hydroxide, acetic acid, 60 p.s.i. hydrogen 2 hr) to generate 3-methyl-3-(2-chlorophenyl)propylamine. An equal molar amount of the amine, 3′-methoxyacetophenone and 1.25 molar equivalents titanium(IV) isopropoxide were mixed 4 hr at rt and the intermediate imine treated with an ethanolic sodium cyanoborohydride (5 ml of 1 M, 5 mmol). Work-up and chromatography afforded N-[3-methyl-3-(2-chlorophenyl)propyl]-1-(3-methoxyphenyl)ethylamine, 4Y, as an oil; m/z (rel. int.) 283 (M+, 17), 268 (71), 164 (13), 135 (100), 121 (21), 105 (27), 91 (26), 77 (14).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1.Cl[CH:21]([CH3:29])[CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH:21]([CH3:29])[CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCNC3
Reactant: CC(Cl)CN1CCOCC1
Product: COc1cc2oc(=O)c3c(c2cc1OC)CCN(C(C)CN1CCOCC1)C3

Procedure:
In the same way described in Example 5, 0.02 m of 1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one was alkylated with N-(2-chloropropyl)-morpholine to give, after recrystallization from 95% EtOH 1.3 g of product; mp 228°-230° C.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:15][CH2:16][C:17]1[C:18]([F:34])=[C:19]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:28]#[N:29])[C:20]([Br:23])=[CH:21][CH:22]=1.[Cl:35][C:36]1[N:37]=[CH:38][N:39](COCC[Si](C)(C)C)[C:40]=1[C:41](O)=[O:42].FC(F)(F)C(O)=O>CN(C=O)C.ClCCl>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH:15][C:41]([C:40]2[NH:39][CH:38]=[N:37][C:36]=2[Cl:35])=[O:42])=[C:18]([F:34])[C:19]=1[O:24][C:25]1[CH:26]=[C:27]([C:28]#[N:29])[CH:30]=[C:31]([Cl:33])[CH:32]=1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN)c2F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.8 %

Procedure:
EDC (0.028 g, 0.148 mmol) and HOBT (0.020 g, 0.148 mmol) were added to a solution of 3-{[3-(aminomethyl)-6-bromo-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.053 g, 0.148 mmol) and 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.041 g, 0.148 mmol) in DMF (2 mL). The mixture was stirred at RT overnight. The reaction mixture was extracted with ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated to give a yellow oil which was dissolved in dichloromethane (1.5 mL). Trifluoroacetic acid (0.5 ml, 6.49 mmol) was added and the mixture was stirred at RT overnight. Purification by reverse phase HPLC (acetonitrile:water with 0.1% formic acid) gave the title compound 0.002 g, 2.5%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ ppm 7.69 (s, 1H), 7.48-7.55 (m, 2H), 7.29 (t, 1H), 7.22 (d, 1H), 7.19 (s, 1H), 4.61 (s, 2H). ES MS m/z 483 (M+1).
Reaction SMILES: [C:1]([C:4]1[NH:9][C:8](=O)[CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CS(Cl)(=O)=O.N1CCCCC1>ClCCl>[N:11]1([C:8]2[CH:7]=[CH:6][N:5]=[C:4]([C:1](=[O:3])[CH3:2])[N:9]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: c1ccncc1
Reactant: CC(=O)c1nccc(=O)[nH]1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(=O)c1nccc(N2CCCCC2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 26.9 %

Procedure:
To a stirred solution of 2-acetylpyrimidin-4(3H)-one (Intermediate 51, 500 mg, 3.62 mmol) in dichloromethane (10 mL) cooled to 0° C., pyridine (860 mg, 10.87 mmol) was added and stirred for 10 min at 0° C., followed by the addition of methane sulfonyl chloride (830 mg, 7.23 mmol) at 0° C. The above reaction mixture was stirred at room temperature for overnight. The reaction mixture was washed with water (50 mL), the aqueous layer was extracted with dichloromethane (50 mL). The combined organic layer was washed with brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude residue was dissolved in acetonitrile; piperidine (616 mg, 7.24 mmol) was added and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated under reduced pressure; water (50 mL) was added and extracted with ethyl acetate (2×30 mL). The combined organic layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure to yield the crude product, which was purified by column chromatography over silica gel (10-50% ethyl acetate/pet ether) to obtain 1-[4-(piperidin-1-yl)pyrimidin-2-yl]ethanone 200 mg (46.8%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.Cl[C:17]1[CH:22]=[C:21]([CH:23]([F:25])[F:24])[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C(OCC)(=O)C>[F:24][CH:23]([F:25])[C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)[CH:22]=1
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Reactant: FC(F)c1cc(Cl)ncn1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)c1cc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.8 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 100 mg, 0.465 mmol), 4-chloro-6-(difluoromethyl)pyrimidine (Intermediate 22, 117 mg, 0.711 mmol) and DIPEA (0.162 mL, 0.929 mmol) were added together in N-methyl-2-pyrrolidone (3 mL) and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by MDAP. Product containing fractions were combined and evaporated under reduced pressure. The resulting solid was dried under high vacuum at 45° C. for 18 hours to give the title compound as a white solid (30 mg);
Reaction SMILES: [OH2:1].[Se](=O)=O.[CH3:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][CH:7]=1>O1CCOCC1>[C:16]1([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][CH:7]=[C:6]3[CH:5]=[O:1])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O
Reactant: Cc1ccnc2ccc(-c3ccccc3)cc12
Agent: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1ccnc2ccc(-c3ccccc3)cc12
Reaction time: 1 h

Procedure:
1.4 ml of water and 17 g of selenium dioxide are added to 8.5 g (38.8 mmol) of 4-methyl-6-phenyl-quinoline in 85 ml of dioxane and the mixture is boiled for 1 hour. The selenium is filtered off with suction and washed with methanol and the filtrate is concentrated. The resulting mixture is separated by flash chromatography, the clean fractions are concentrated and the residue is stirred with ether, filtered off with suction and washed with ether. 3.2 g of colourless crystals of melting point 115° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH:24]=[CH2:25].Cl>CN(C=O)C>[CH2:22]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=[C:2]([O:1][CH2:9][CH2:10][CH:2]=[CH2:3])[CH:3]=1)[CH2:23][CH:24]=[CH2:25]
Reactant: C=CCCBr
Reactant: O=C(O)c1cc(O)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCCOC(=O)c1cc(OCCC=C)cc(C(F)(F)F)c1
Yield: 158.5 %

Procedure:
3-Hydroxy-5-trifluoromethyl-benzoic acid (2.17 g, 10.6 mmol), potassium carbonate (8.73 g, 63.2 mmol) and 4-bromo-1-butene (4.34 ml, 43.7 mmol) were dissolved in DMF (21 ml), and this mixture was irradiated in a microwave apparatus (100° C., 60 min). The reaction solution was poured into a cooled aqueous dilute hydrochloric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to give 3-but-3-enyloxy-5-trifluoromethyl-benzoic acid but-3-enyl ester (2.64 g, 80%).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=[O:10])[CH2:8]Br)=[CH:5][CH:4]=1)#[N:2].[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(O)C>CCOCC>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][CH2:8][C:7]([C:6]2[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:10])=[CH:16][CH:15]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: Nc1ccc(Br)cc1
Solvent: CCOCC
Solvent: CCO
Product: N#Cc1ccc(C(=O)CNc2ccc(Br)cc2)cc1
Reaction time: 16 h

Procedure:
p-Cyanophenacyl bromide (29.8 g, 0.138 mole) and p-bromoaniline (47.13 g, 0.266 mole) were combined with 53.2 g of absolute ethanol and stirred 16 hours. The solution was then diluted with ether and the resulting slurry filtered. The filter cake was repulped in 500 ml ether, filtered, repulped in 400 ml acetone and again filtered to yield title product: 17.14 g (40.9%); m.p. 154°-157°.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:33])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: COc1cccc(-c2ocnc2C(=O)O)c1
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Product: COc1cccc(-c2ocnc2C(=O)Nc2ccn(Cc3nc(C(C)=O)cs3)n2)c1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-methoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.83 min; [M+H]+=424.07.