Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.C(O[C:6](=[NH:47])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][N:14]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:15]CCCCCCCCCCCCCCC)[CH:8]=1)C.[NH3:48]>C(O)C>[CH2:31]([N:14]([CH2:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([NH2:47])=[NH:48])[CH2:15][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: N
Reactant: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)OCC)c1
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)N)c1
Reaction time: 3 h
Yield: 74 %

Procedure:
Ethyl-m-[N,N-di(n-hexadecyl)aminomethyl]-benzimidate dihydrochloride (35.0 g., 0.05 mole) was dissolved in ethanol (150 ml.) and the mixture saturated with ammonia gas at 20° C. The mixture was held for three hours at 20° C., resaturated with ammonia gas at 20° C., and then stoppered and held overnight at room temperature. The mixture was evaporated in vacuo to a solid which was triturated with acetone (200 ml.), filtered, washed with water (4 × 100 ml.), triturated again with acetone (2 × 100 ml.), filtered and dried in vacuo overnight [22.0 g., 74% yield, Rf 0.42 (4:1, benzene:ethanol on silicic acid)]. The crude product was recrystallized from hot acetone (20.9 g., 70% yield, m.p.-forms a gel at 84° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[N+:10]([CH:13]([CH:16]=O)[CH:14]=[O:15])([O-:12])=[O:11]>Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][CH:16]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: COc1cccc(N)c1
Agent: Cl
Solvent: O
Product: COc1cccc(NC=C(C=O)[N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To the HCl salt of 3-methoxy-phenylamine (4.6 g, 28.9 mmol) in 1N HCl (300 mL) was added a solution of 2-nitro-malonaldehyde (2.7 g, 19.3 mmol) in 150 mL water. After 30 min, the precipitate was filtered and rinsed with 0.1 N HCl. Air-drying in a Büchner funnel for 18 h gave 3.36 g (78%) of a light yellow/green powder. LC/MS (m/z): 245.1 (MH++Na), Rt 2.21 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@@H:4]([NH:15][CH2:16][CH2:17][N:18]([CH2:27][CH2:28][C:29]([OH:31])=O)[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.C(N(CC)CC)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:32])[C@@H:4]([N:15]1[C:29](=[O:31])[CH2:28][CH2:27][N:18]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:17][CH2:16]1)[CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)[C@H](CCOCc1ccccc1)NCCN(CCC(=O)O)c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCOCc1ccccc1)N1CCN(c2ccc(Cl)c(Cl)c2)CCC1=O
Reaction time: 15 h
Yield: 76.9 %

Procedure:
A solution of 8.20 g (15.77 mmol) of (S)-4-benzyloxy-2-{2-[(2-carboxy-ethyl)-(3,4-dichloro-phenyl)-amino]-ethylamino}-butyric acid methyl ester; HCl in 130 ml CH2Cl2 was treated with 2.20 (15.77 mmol) of triethylamine and at 0° C. with 3.70 g (18.93 mmol) of EDCI. The cooling bath was allowed to come to RT and after 15 h the reaction was extracted with aq. 10% KHSO4/Et2O (3×). The organic phases were washed with aq 10% KHSO4. solution, 10% NaCl and dried over Na2SO4 and purified by flash silica gel column (n-heptane:EtOAc 75:25 to 1:1) to yield 5.64 g (77%) of the title compound as a light yellow oil. MS: 465.1 (MH+, 2Cl).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:7][CH:6]=1)=O.[NH2:20][C:21]([NH2:23])=[S:22]>C(O)(C)C>[NH2:23][C:21]1[S:22][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:7][CH:6]=2)[N:20]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)c1ccc(CCNC(=O)C(F)(F)F)cc1
Solvent: CC(C)O
Product: Nc1nc(-c2ccc(CCNC(=O)C(F)(F)F)cc2)cs1

Procedure:
The title compound: A solution of N-{2-{4-(2-bromoacetyl)phenyl}ethyl}-2,2,2,-trifluoroacetamide (1.00 g, 2.96 mmol), prepared in the preceding section (c), and thiourea (225 mg, 2.96 mmol) in isopropanol (30 mL) was heated at reflux for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in a mixture of EtOAc and aqueous 10% HCl and the phases were separated. The aqueous layer was washed with EtOAc then rendered basic with solid K2CO3. The resulting mixture was extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, EtOAc:Hexane, 1:1) to give N-{2-{4-(2-amino-4-thiazolyl)phenyl}ethyl}-2,2,2-trifluoroacetamide (240 mg, 26% yield): M.p. 180-182°; 1H NMR (DMSO-d6) δ 9.48 (broad t, J=5.4 Hz, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 7.00 (broad s, 2H), 6.95 (s, 1H), 3.43 (broad q, J=6.8 Hz, 2H), 2.80 (t, J=7.2 Hz, 2H); MS (FAB) m/z 316 (MH)+ ; Anal. Calcd for C13H12F3N3OS: C, 49.52; H, 3.84; N, 13.33; S, 10.17. Found: C, 49.69; H, 3.82; N, 13.36; S, 10.00.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[O:28])=[CH:22][C:21]=1[O:35]CC1C=CC=CC=1)(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:43])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[O:28])=[CH:22][C:21]=1[OH:35])(=[O:18])=[O:19])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(=O)NCCN(C)C)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(=O)NCCN(C)C)cc1O
Yield: 99.7 %

Procedure:
To (S)-3-{2-benzyloxy-4-[3-(2-dimethylamino-ethyl)-ureido]-benzenesulfonylamino}-4,4-diethoxy-butyric acid tert-butyl ester (1.80 g, 2.9 mmol) in ethanol (100 mL) was added 20% Pd on carbon (250 mg) and stirred under 1 atmosphere of hydrogen for 24 h. The reaction was judged complete by thin layer analysis and filtered. The filtrate was evaporated to give (S)-3-{4-[3-(2-dimethylamino-ethyl)-ureido]-2-hydroxy-benzenesulfonylamino}-4,4-diethoxy-butyric acid tert-butyl ester as a colorless foam 1.54 g (100%). MS (APCI) m/z 533.4 (M+1).
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:3]1.[SH:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>>[OH:26][CH:23]([CH2:24][OH:25])[CH2:22][S:21][CH:9]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:8][C:4]1[O:3][C:2]([CH3:1])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=1
Reactant: CC1(c2ccccc2)OC(/C=C/c2ccsc2)=CC1=O
Reactant: OCC(O)CS
Product: CC1(c2ccccc2)OC(CC(SCC(O)CO)c2ccsc2)=CC1=O

Procedure:
According to the procedure of Method A, Example 1, (E)-2-methyl-2-phenyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with 3-mercapto-1,2-propanediol to provide 5-[2-[(2,3-dihydroxypropyl)thio]-2-(3-thienyl)ethyl]-2-methyl-2-phenylfuran-3(2H)-one; 1H NMR (CDCl3) δ1.66 and 1.68 (singlets, 3H), 1.83 (br s, 1H), 2.44 (br s with fine structure, 1H) and overlapping 2.45-2.58 (m, 2H), 3.10-3.28 (m, 2H), 3.47 (br s with fine structure, 1H), 3.55-3.78 (m, 2H), 4.50 (m, 1H), 5.39 and 5.40 (overlapping singlets, 1H), 7.05-7.20 (m, 2H), 7.27-7.43 (m, 6H); MS (HR-EI) m/z 390.0948 (M+ calcd. for C20H22O4S2 390.0959).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.Br.Br.[C:27]12[CH2:34][NH:33][CH2:32][C:31]=1[CH2:30][NH:29][CH2:28]2.N12CCCN=C1CCCCC2>C(#N)C>[C:27]12[CH2:34][NH:33][CH2:32][C:31]=1[CH2:30][N:29]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:13][C:14]=1[F:20])[CH2:28]2
Reactant: C1NCC2=C1CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 67 %

Procedure:
1-(4-Fluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.33 g), 3,7-diazabicyclo[3.3.0] oct-1(5)-ene dihydrobromide (0.27 g) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU, 1 ml) were dissolved in acetonitrile (10 ml) and refluxed for 4 hours. The reaction mixture was kept overnight at room temperature and the produced precipitate was filtered, washed with acetonitrile, methanol to give the title compound (0.28 g, yield 66%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([CH2:16][C:17](=O)[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[C:6]([NH:8]C(=O)OC(C)(C)C)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([CH:16]=[C:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:8]2)=[CH:4][C:3]=1[O:25][CH3:26]
Reactant: COc1cc(CC(=O)c2cccnc2)c(NC(=O)OC(C)(C)C)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2cc(-c3cccnc3)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
To a solution of tert-butyl [5-chloro-4-methoxy-2-(2-oxo-2-pyridin-3-ylethyl)phenyl]carbamate (1.28 g) in dichloromethane (17 mL) was added trifluoroacetic acid (3.4 mL) under ice-cooling, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine successively. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (812 mg). 1H-NMR (CDCl3) δ ppm: 3.95 (3H, s), 6.77-6.85 (1H, m), 7.14 (1H, s), 7.38 (1H, dd, J=4.8, 8.0 Hz), 7.45 (1H, s), 7.86-7.96 (1H, m), 8.36 (1H, br s), 8.53-8.60 (1H, m), 8.90-8.97 (1H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH:5]=O.[N:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N+:12]=[N-:13].[O-]CC.[Na+].O>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:14]([N:11]=[N+:12]=[N-:13])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[C:8]([CH3:10])[CH:9]=1
Reactant: Cc1cc(C)cc(C=O)c1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=Cc1cc(C)cc(C)c1)N=[N+]=[N-]
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A mixture of 5 g of 3,5-dimethylbenzaldehyde and 19.3 g of ethyl azidoacetate is added, at −10° C. under dry nitrogen, to a mixture of 25 ml of ethanol and 50 ml of a 21% solution of sodium ethoxide in ethanol. The mixture is left stirring for 1 hour at −10° C. and for fourteen and a half hours at +5° C. It is poured into 100 ml of water and the precipitate formed is filtered off and washed with water. The precipitate is dissolved in ether and this solution is dried over MgSO4 and then evaporated to give the product, which is used without further purification in the subsequent step.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[Br:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[Br:25][CH2:26][C:27]([N:5]([CH2:4][C:3]1[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:2]=1[F:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:28]
Reactant: CCCCCCCNCc1ccc(F)cc1F
Reactant: O=C(Cl)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)CBr
Reaction time: 2 h
Yield: 80.2 %

Procedure:
N-(2,4-difluorobenzyl)-N-heptylamine (2.004 g, 8.304 mmol) was dissolved in DCM (30 ml). It was then cooled in an ice-bath. Triethylamine (1.092 g, 10.796 mmol) was added and then bromacetyl chloride (1.438 g, 9.135 mmol) was dropped in. The mixture was stirred for 2 hours (ice-bath). It was then washed with water (with additional of 1% hydrochloric acid, pH-3), water and brine, and dried (magnesium sulphate) and evaporated. The crude oil product was dissolved in DCM, then loaded onto a column (ISOLUTE®SI 5 g/25 ml) and eluted with more DCM. Oil product 2.412 g was obtained, yield 80%
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[C:4]([NH:6][C:7]1[NH:11][C:10]2[C:12]3[CH2:13][C:14]([CH3:24])([CH3:23])[O:15][C:16]=3[C:17]([C:19](OC)=[O:20])=[CH:18][C:9]=2[N:8]=1)=[O:5].[F:30][C:31]([F:40])([F:39])[C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[C:4]([NH:6][C:7]1[NH:11][C:10]2[C:12]3[CH2:13][C:14]([CH3:24])([CH3:23])[O:15][C:16]=3[C:17]([C:19]([NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[C:32]([C:31]([F:30])([F:39])[F:40])[CH:33]=3)=[O:20])=[CH:18][C:9]=2[N:8]=1)=[O:5]
Reactant: COC(=O)c1cc2nc(NC(=O)c3c(F)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3cccc(C(F)(F)F)c3)cc3nc(NC(=O)c4c(F)cccc4Cl)[nH]c23)O1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 4.2 %

Procedure:
The title compound was prepared by following the procedure as described for Example-137 using methyl 2-(2-chloro-6-fluorobenzamido)-7,7-dimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Intermediate-51, 0.200 g, 0.477 mmol), 3-trifloromethyl aniline (0.230 g, 1.43 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL). The reaction mass was stirred at RT for 4-5 h. The obtained crude was purified on preparative TLC using 4% DCM:MeOH as solvent system to afford 0.011 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 3.14 (s, 2H), 6.30 (s, 1H), 7.43 (d, J=7.8 Hz, 2H), 7.56-7.70 (m, 4H), 7.86 (q, J=6.3 Hz, 1H), 8.15 (bs, 2H), 9.71 (s, 1H); MS [M+H]+: 547.06.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH:29](=O)/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CN(P(N(C)C)(N(C)C)=O)C.C1COCC1>[C:2]([OH:4])(=[O:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:29][CH:30]=[CH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC/C=C/C=O
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCC=CC=CCCCCC(=O)O
Yield: 42.6 %

Procedure:
This compound was synthesized from 5-carboxypentyltriphenylphosphonium bromide (9.50 g, 20 mmol) and 2-trans-octenal (2.52 g, 20 mmol) in 10% HMPA-THF (100 mL) by Wittig reaction. Kugelrohr distillation yielded the product (1.91 g, 43%) as a pale yellow oil (bp 122-125° C./0.01 torr). IR: 3500-2500, 1730 cm-1 ; 1H-NMR: 0.95 (t, 3H), 1.40 (m, 10H), 2.30 (m, 6H), 6.00 (m, 4H), 11.30 (bs, 1H). Anal. Calcd. for C14H24O2 : C, 74.95, H, 10.78%; Found: C, 75.04, H, 10.80%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:16](Cl)(=[O:18])[CH3:17].FC(F)(F)C(O)=O>O>[C:16]([O:9][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:18])[CH3:17]
Reactant: OC(c1ccccc1)c1cccnc1Cl
Reactant: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)OC(c1ccccc1)c1cccnc1Cl
Reaction time: 1 h

Procedure:
A mixture of 4.39 g 2-chloro-α-phenyl-3-pyridinemetanol (see Ex. 20), 3.14 g acetyl chloride and 8 ml trifluoroacetic acid is stirred for 1 hr. at room temperature. The reaction liquid is added dropwise to water, and the solid formed is filtered, washed, dried and crystallised from cyclohexane. Yield: 4.46 g title product, m.p. 100°-2° C.; Cl 13.82 (13.55).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].[CH3:16][O:17][CH2:18][CH2:19]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:16][O:17][CH2:18][CH2:19][O:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COCCCl
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1c([N+](=O)[O-])ccc(C(=O)OC)c1C
Temperature: 90 °C
Reaction time: 20 h
Yield: 106.3 %

Procedure:
Methyl 3-hydroxy-2-methyl-4-nitrobenzoate (1.55 g) and 2-chloroethyl methyl ether (1.8 g) were dissolved in anhydrous DMF (20 mL), and potassium carbonate (1.25 g) and potassium iodide (300 mg) were added, followed by stirring at 90° C. for 20 hours. To the reaction mixture, ethyl acetate (200 mL) was added, followed by washing twice with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain methyl 3-(2-methoxyethoxy)-2-methyl-4-nitrobenzoate (2.1 g) as pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12]Br.[Cl:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[CH3:29].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][NH:21][C:19]1[CH:18]=[CH:17][C:16]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[CH3:29])=[C:15]([Cl:14])[CH:20]=1
Reactant: Cc1cc(Cl)ccc1-c1ccc(N)cc1Cl
Reactant: FC(F)(F)c1ccc(CBr)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ccc1-c1ccc(NCc2ccc(C(F)(F)F)cc2Br)cc1Cl
Temperature: 80 °C

Procedure:
2-Bromo-1-(bromomethyl)-4-(trifluoromethyl)benzene (2.0 g, 6.3 mmol), 2,4′-dichloro-2′-methyl-[1,1′-biphenyl]-4-amine (1.7 g, 6.9 mmol), and K2CO3 (1.3 g, 9.4 mmol) were diluted with DMF (20 mL) and heated to 80° C. After 3 h the resulting mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[N:4]([CH3:35])[C:5](=[O:34])[N:6]2[C@H:21]1[CH2:26][CH2:25][C@H:24]([O:27]C2CCCCO2)[CH2:23][CH2:22]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(O)C.O>[Cl:1][C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[N:4]([CH3:35])[C:5](=[O:34])[N:6]2[C@H:21]1[CH2:22][CH2:23][C@H:24]([OH:27])[CH2:25][CH2:26]1
Reactant: Cn1c(=O)n([C@H]2CC[C@H](OC3CCCCO3)CC2)c2nc(-n3cnc4ccc(F)cc43)nc(Cl)c21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCO
Product: Cn1c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(-n3cnc4ccc(F)cc43)nc(Cl)c21

Procedure:
A solution of 6-chloro-2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-7-methyl-9-(trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl)-7H-purin-8(9H)-one (0.06 mmol) and PPTS (5 mg) in ethanol/water (4.5 mL/0.5 mL) was stirred at reflux for 1 h. The solvent was evaporated in vacuo and the residue could be purified by chromatography or used in the next step without purification. MS (EI) m/z 417.0 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[NH:10][C:9]([CH2:11][N:12]3[CH:17]=[CH:16][C:15]4[C:18]([C:21](=[O:31])[C:22]5[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=5[F:30])=[CH:19][NH:20][C:14]=4[C:13]3=[O:32])=[N:8][C:5]2=[N:6][CH:7]=1.C(OC([N:40]1[CH:44]=[CH:43][CH:42]=[C:41]1B(O)O)=O)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C.O>[NH:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[C:2]1[CH:3]=[C:4]2[NH:10][C:9]([CH2:11][N:12]3[CH:17]=[CH:16][C:15]4[C:18]([C:21](=[O:31])[C:22]5[C:23]([F:30])=[CH:24][C:25]([F:29])=[CH:26][C:27]=5[F:28])=[CH:19][NH:20][C:14]=4[C:13]3=[O:32])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: O=C(c1c(F)cc(F)cc1F)c1c[nH]c2c(=O)n(Cc3nc4ncc(Br)cc4[nH]3)ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: O=C(c1c(F)cc(F)cc1F)c1c[nH]c2c(=O)n(Cc3nc4ncc(-c5ccc[nH]5)cc4[nH]3)ccc12
Temperature: 135 °C
Yield: 8.2 %

Procedure:
A microwavable vial was charged with 6-[(6-bromo-1H-imidazo[4,5-b]pyridin-2-yl)methyl]-3-(2,4,6-trifluorobenzoyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (20 mg, 0.04 mmol), [1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]boronic acid (12.6 mg, 0.06 mmol), cesium carbonate (39 mg, 0.119 mmol), bis(triphenylphosphine)palladium(II) chloride (2.8 mg, 3.98 umol) and acetonitril/water (0.6/0.2 ml). The vial was sealed, purged by 3 cycles of freeze-pump-thaw. The resultant suspension was heated to 135° C. by microwave irradiation for 15 min. LCMS showed complete consumption of the starting material and formation of the desired product. The reaction mixture was diluted with acetonitrile, and filtered through a 0.45 micron membrane filter and then concentrated to dryness under reduced pressure. The crude reaction mixture was purified by HPLC on Xbridge (C18 5u particle size, 30×75 mm) preparative column eluting with a linear gradient of 15-40% acetonitrile/water (0.01% NH4OH) at 70 ml/min. to give the title compound (1.6 mg, 8%). MS (ESI): m/z 489 (M+H). 1H-NMR (500 MHz, d6-DMSO): δ 11.35 (br. s, 1H), 8.61 (s, 1H), 8.03 (s, 1H), 7.89 (s, 1H), 7.58 (d, 1H), 7.36 (m, 2H), 7.00 (d, 1H), 6.86 (s, 1H), 6.54 (s, 1H), 6.11 (s, 1H), 5.47 (s, 2H),
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[C:4]=1[C:13](=[O:19])[C:14]([N:16]([CH3:18])[NH2:17])=[O:15])[CH3:2].[F:20][C:21]([F:28])([F:27])[C:22](=O)[CH2:23][S:24][CH3:25].O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[C:4]=1[C:13](=[O:19])[C:14]([N:16]([CH3:18])[N:17]=[C:22]([CH2:23][S:24][CH3:25])[C:21]([F:28])([F:27])[F:20])=[O:15])[CH3:2]
Reactant: CCc1cc(CC)c(C(=O)C(=O)N(C)N)c(CC)c1
Reactant: CSCC(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(CC)c(C(=O)C(=O)N(C)N=C(CSC)C(F)(F)F)c(CC)c1
Temperature: 25 °C
Yield: 50 %

Procedure:
To a 100 ml volume three-necked flask, 1-[2-(2,4,6-triethylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-40) (3.01 g) was added, and to the mixture was added dropwise a solution of 1,1,1-trifluoro-3-methylsulfanyl-2-propanone (7-0-2) (2.10 g) in toluene (27 g), followed by the addition of para-toluenesulfonic acid monohydrate (0.030 g). The resulting mixture was stirred under reflux for 40 minutes. Then, the reaction mixture was cooled to room temperature, poured into water (30 ml), and extracted with ethyl acetate (50 ml) 3 times. The resulting organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (chloroform) to give 2.31 g of 1-[2-(2,4,6-triethylphenyl)-2-oxoacetyl]-2-(1,1,1-trifluoro-3-methylsulfanyl-2-propylidene)-1-methylhydrazine ((4-46)-(1)-40).