Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:12]([C:21]2[CH:26]=[C:25]([C:27]3[N:28]=[N:29][NH:30][N:31]=3)[CH:24]=[CH:23][N:22]=2)[N:11]=[CH:10]1.Br[CH2:33][O:34][C:35](=[O:37])[CH3:36].CC([O-])(C)C.[K+].O>CN(C=O)C>[C:35]([O:34][CH2:33][N:29]1[N:30]=[N:31][C:27]([C:25]2[CH:24]=[CH:23][N:22]=[C:21]([C:12]3[N:11]=[CH:10][N:9]([CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:13]=3[C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH:26]=2)=[N:28]1)(=[O:37])[CH3:36]
Reactant: Fc1ccc(-c2c(-c3cc(-c4nn[nH]n4)ccn3)ncn2Cc2ccccc2Cl)cc1
Reactant: CC(=O)OCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCn1nnc(-c2ccnc(-c3ncn(Cc4ccccc4Cl)c3-c3ccc(F)cc3)c2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 8.3 %

Procedure:
To a solution of 2-[1-[(2-chlorophenyl)methyl]-5-(4-fluorophenyl)imidazol-4-yl]-4-(2H-tetrazol-5-yl)pyridine (50 mg, 0.12 mmol, Example 137) in DMF (5 mL) was added acetic acid bromomethyl ester (20 mg, 0.12 mmol), t-BuOK (27 mg, 0.24 mmol) and KI (40 mg, 0.24 mmol) at 0° C., then the mixture was stirred for 72 hr at rt, H2O was added, extracted with EA, dried, concentrated and purified by HPLC to give the title compound (5 mg, 8.6%). 1H NMR (300 MHz, CD3OD): δ 2.13 (3H, s), 5.38 (2H, s), 6.55 (2H, s), 6.97-6.98 (1H, m), 7.23-7.49 (7H, m), 7.85 (1H, s), 8.10 (1H, d, J=6.0 Hz), 8.28 (1H, m), 8.64 (1H, m). [M+H] Calc'd for C25H19ClFN7O2, 504. Found, 504.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Si:16]([O:23][CH2:24][C:25]1[CH:30]=[C:29](O)[CH:28]=[C:27]([NH:32][C:33]2[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[N:34]=2)[N:26]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(Cl)(Cl)Cl.Cl>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:29]1[CH:28]=[C:27]([NH:32][C:33]2[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[N:34]=2)[N:26]=[C:25]([CH2:24][O:23][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:30]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(O)cc(Nc2ccn(COCC[Si](C)(C)C)n2)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OCc1cc(OS(=O)(=O)C(F)(F)F)cc(Nc2ccn(COCC[Si](C)(C)C)n2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
9.7 ml of trifluoromethanesulfonic anhydride was added to a mixture of 12.9 g of 2-(((tert-butyl(dimethyl)silyl)oxy)methyl)-6-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyridin-4-ol, 14.2 g of 4-(dimethylamino)pyridine and 290 ml of chloroform at 0° C. The resulting mixture was stirred for 2 hours at room temperature and then diluted with ethyl acetate. The resulting solution was charged with 100 ml of 0.1 mol/l hydrochloric acid at 0° C. The organic layer separated was washed with saturated sodium bicarbonate, water and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=10/1 to 1/1) to give the title compound.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.Cl[Si](C)(C)C.Cl[C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[C:19]1([C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:4][CH2:3][CH2:1][OH:2])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethanolamine (5 g, 82 mmol) and triethylamine (11.4 ml, 8.28 g, 82 mmol) were dissolved in dry tetrahydrofuran (50 ml). Chlorotrimethylsilane (10.4 ml, 8.90 g, 82 mmol) was added over five minutes and the mixture was stirred for 30 minutes. The white solid was removed by filtration and washed with dry tetrahydrofuran. The combined filtrate and washings were stirred and triethylamine (11.4 ml, 8.28 g, 82 mmol) was added followed by chlorotriphenylmethane (22.8 g, 82 mmol). The mixture was stirred at ambient temperature for two hours, when it was filtered and the filtrate cooled to 0° C. for 30 minutes. Following a further filtration the liquors were stirred with methanol (60 ml) for fifteen minutes. The solvent was removed under vacuum and the residue crystallised from hot ethyl acetate. The resulting white solid was dried under vacuum at room temperature for 16 hours before triturating successively with diethyl ether (twice) and acetone (twice). The residue was heated with boiling acetone (700 ml) for ten minutes before the solid was collected by filtration, washed with cold acetone and dried under vacuum for four hours to give N-(triphenylmethyl)ethanolamine.
Reaction SMILES: C1(C[O:8][C:9](=[O:46])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:13]=[C:12]([O:27][CH2:28][CH2:29][CH2:30][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][CH3:45])[CH:11]=2)C=CC=CC=1.[H][H]>[Pd]>[CH2:28]([O:27][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:13]=1)[C:9]([OH:46])=[O:8])[CH2:29][CH2:30][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][CH3:45]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccccc2)cc(C(=O)O)c1
Yield: 94.3 %

Procedure:
A mixture of 14.6 g of 3-(octadecyloxy)-5-(3-phenoxypropoxy)benzoic acid phenylmethyl ester and 3 g of 10% palladium on carbon was shaken in a hydrogen atmosphere at room temperature for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated to a solid which was recrystallized from ether-hexane to give 11.8 g (95% yield mp 79°-81°) of 3-(octadecyloxy)-5-(3-phenoxypropoxy)benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[CH2:33]([O:35][C:36]([C:38]1([NH2:44])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37])[CH3:34]>>[CH2:33]([O:35][C:36]([C:38]1([NH2:44])[CH2:39][CH2:40][N:41]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][C:4]=3[C:29]([F:31])([F:32])[F:30])[N:8]=[CH:9]4)[C:18](=[O:26])[N:19]=2)[CH2:42][CH2:43]1)=[O:37])[CH3:34]
Reactant: CCOC(=O)C1(N)CCNCC1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CCOC(=O)C1(N)CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
4-Amino-1-{5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidine-4-carboxylic acid ethyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and 4-amino-piperidine-4-carboxylic acid ethyl ester following General Procedure B.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].Cl[CH2:13][CH2:14][C:15]([N:18]=CC1C=CC=CC=1)([CH3:17])[CH3:16]>>[NH2:18][C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11]
Reactant: O=C1CCc2ccccc2N1
Reactant: CC(C)(CCCl)N=Cc1ccccc1
Product: CC(C)(N)CCN1C(=O)CCc2ccccc21

Procedure:
Prepared analogously to the method described for Example 6a) from 15.7 g (107 mmol) of 3,4-dihydroquinolin-2-one and 24.9 g (119 mmol) of (3-chloro-1,1-dimethylpropyl)-(1-phenylmethylidene)amine. Unlike in the method mentioned above, the product is precipitated not as the maleate but as the hydrochloride. Yield: 6.9 g (24%, hydrochloride); melting range: 200° C.-203° C.
Reaction SMILES: Cl.[NH:2]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Cl:19][C:20]1[CH:29]=[CH:28][C:23]([CH:24]=[CH:25][CH2:26]Cl)=[CH:22][CH:21]=1>C(#N)C>[Cl:19][C:20]1[CH:29]=[CH:28][C:23](/[CH:24]=[CH:25]/[CH2:26][N:2]2[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4][CH2:3]2)=[CH:22][CH:21]=1
Reactant: ClCC=Cc1ccc(Cl)cc1
Reactant: O=C1CCCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CCCN(C/C=C/c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48.3 %

Procedure:
4-Perhydroazepinone hydrochloride (2.5 g, prepared according to Synth. Commun. 1992, 1249-1258) was suspended in acetonitrile (80 ml); diisopropylethylamine (4.4 ml) and 4-chlorocinnamyl chloride (2.7 g) were successively added at room temperature and the resulting reaction mixture was stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue purified by silica gel chromatography (eluent cyclohexane:ethyl acetate 6:4) to afford 1-(trans-3-(4-chlorophenyl)allyl)-perhydroazepin-4-one (1.84 g) as a foam. MS (ES+) 264/266 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][CH2:5][N:6]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:11][CH:10]=[CH:9][N:8]=1.P(Cl)(Cl)(Cl)=O>O>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:29])[CH3:1])[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:12]=2[N:13]=1
Reactant: CN(C)CCCN(c1ccccc1)c1ncccc1NC(=O)c1ccccc1F
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)CCCN1c2ccccc2C(c2ccccc2F)=Nc2cccnc21
Yield: 38.8 %

Procedure:
A solution of 8.5 g (0.022 mole) of N-[2-[[3-(dimethylamino)propyl]phenylamino]-3-pyridinyl]-2-fluorobenzamide in 26 g (0.173 mole) of phosphorus oxychloride was refluxed under nitrogen atmosphere for 16 hr. The cooled reaction mixture was poured over ice, diluted with water, and extracted twice with diethyl ether. The acidic portion was made basic with sodium hydroxide pellets, cooled with ice and extracted twice with methylene chloride. The combined methylene chloride layers were washed in sequence with water and saturated sodium chloride, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from isopropyl alcohol-isopropyl ether using charcoal treatment to yield 3.2 g (39%) of a bright-yellow solid, m.p. 92°-94° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH3:17].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:16][CH3:17]
Reactant: Oc1ccccc1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In DMF (120 ml) was dissolved 2-bromophenol (12 g). To the mixture was added potassium carbonate (12.5 g) and then was added iodoethane (6.7 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=12/1) to give 1-bromo-2-ethoxybenzene (12.2 g).
Reaction SMILES: FC1C(O[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)=[O:10])=C(F)C(F)=C(F)C=1F.[CH3:37][O:38][CH2:39][CH2:40][NH2:41]>>[CH3:37][O:38][CH2:39][CH2:40][NH:41][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[N:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=1)=[O:10]
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc32)cc1
Reactant: COCCN
Product: COCCNC(=O)c1ccc2c(c1)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
The title compound was prepared from 2-oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid pentafluorophenyl ester and 2-methoxyethylamine according to Procedure K: mp>230° C.; Anal. Calcd for C18H19N5O5S: C, 51.79; H, 4.59; N, 16.78. Found: C, 51.69; H, 4.54; N, 16.72.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]=1[C:19]([F:22])([F:21])[F:20])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[Cl:29][C:30]1[N:31]=[C:32](Cl)[C:33]2[CH:38]=[CH:37][N:36]([CH3:39])[C:34]=2[N:35]=1.O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:29][C:30]1[N:31]=[C:32]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:19]([F:20])([F:21])[F:22])[CH:6]=2)[C:33]2[CH:38]=[CH:37][N:36]([CH3:39])[C:34]=2[N:35]=1
Reactant: CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F
Reactant: Cn1ccc2c(Cl)nc(Cl)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1ccc(-c2nc(Cl)nc3c2ccn3C)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 6 h
Yield: 73.8 %

Procedure:
2-[4-ethoxy-3-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (188 mg), Na2CO3 (217 mg), and tetrakis(triphenylphosphine)palladium (0) (29 mg) were added to a mixture of 2,4-dichloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (100 mg), dioxane (2 mL), and water (0.3 mL) in an argon atmosphere, and the reaction mixture was stirred at 100° C. for 6 hours. After the reaction mixture was cooled to room temperature, extraction thereof was performed using EtOAc, and the extract was washed with water and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=9:1 to 7:3), whereby 2-chloro-4-[4-ethoxy-3-(trifluoromethyl)phenyl]-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (130 mg) was obtained as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:34])[CH3:33])=[N:9]2)=[CH:4][CH:3]=1.[C:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:38])[CH3:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:35])[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:42]3[CH2:43][CH2:44][N:39]([C:36](=[O:38])[CH3:37])[CH2:40][CH2:41]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH:32]([CH3:33])[CH3:34])=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2=NC(C)(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)c(OC(C)C)c1
Reactant: CC(=O)N1CCNCC1
Product: COc1ccc(C2=N[C@@](C)(c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(C(C)=O)CC2)c(OC(C)C)c1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-acetyl-piperazine (Aldrich) to give the title compound. LC-MS: 623.2 [(M+H)+]
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Cl:21])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1.[OH-].[K+]>C(O)C.O>[Cl:21][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][O:8][CH2:7]2)[C:3]([OH:22])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: COC(=O)C(CC1CCOC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCOC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-3-yl)-propionic acid methyl ester (729 mg, 2.10 mmol) in ethanol (20 mL) was treated with a solution of potassium hydroxide (694 mg, 10.51 mmol) in water (7 mL). The reaction was stirred for 3 h at 25° C., concentrated in vacuo to remove the ethanol, and then was acidified to pH=2 with a 1N aqueous hydrochloric acid solution. The resulting mixture was then extracted with methylene chloride 3×10 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-3-yl)-propionic acid (654 mg, 94%) as a white foam: (ES)+-HRMS m/e calcd for C14H17ClO5S (M+Na)+ 355.0377. found 355.0382.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[CH:11][CH:12]=2)[C:7]=1[CH2:19][CH2:20][CH2:21][CH3:22])=[O:5])[CH3:2].CI.[C:25](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH3:25])[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[CH:11][CH:12]=2)[C:7]=1[CH2:19][CH2:20][CH2:21][CH3:22])=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCCCc1c(C(=O)OCC)cc(O)c2ccc(OC)cc12
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCCCc1c(C(=O)OCC)cc(OC)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 64 h
Yield: 78.7 %

Procedure:
A solution of 1-butyl-4-hydroxy-7-methoxy-2-naphthalenecarboxylic acid ethyl ester (6.5 g) and methyl iodide (7 mL) in acetone (65 mL) containing potassium carbonate (5 g) was stirred at room temperature for 64 hours. After the reaction mixture was filtered, the filtrate was concentrated to dryness and the residue was partitioned between dichloromethane (150 mL) and water (100 mL). The dried (MgSO4) organic layer was evaporated and the residual material crystallized from 2-propanol to yield 5.35 g of 1-butyl-4,7-dimethoxy-2-naphthalenecarboxylic acid ethyl ester, mp 44°-45° C. Anal. Calcd for C19H24O3 : C, 72.13; H, 7.64 Found: C, 72.03; H, 7.78
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][C:16]([OH:18])=O)[CH:9]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[NH2:29][C:30]1([C:41]([O:43][CH3:44])=[O:42])[CH2:35][CH2:34][C:33]([O:39][CH3:40])([CH2:36][O:37][CH3:38])[CH2:32][CH2:31]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][C:16]([NH:29][C:30]3([C:41]([O:43][CH3:44])=[O:42])[CH2:31][CH2:32][C:33]([O:39][CH3:40])([CH2:36][O:37][CH3:38])[CH2:34][CH2:35]3)=[O:18])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COCC1(OC)CCC(N)(C(=O)OC)CC1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: COCC1(OC)CCC(NC(=O)Cc2cc(-c3ccc(Cl)cc3)ccc2C)(C(=O)OC)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
574 mg (2.20 mmol) of (4′-chloro-4-methylbiphenyl-3-yl)acetic acid (EP 2029531 A1 and US 2009/298828 A1) were dissolved in 0.9 g (12.5 mmol) of thionyl chloride. The reaction mixture was stirred at 80° C. for 1 h and then concentrated. The residue was dissolved in 5 ml of acetonitrile. 816 mg (5.90 mmol) of potassium carbonate were added to 390 mg (1.69 mmol) of the compound from Example 24A in 10 ml of acetonitrile. With ice-cooling, the solution of the acid chloride was added dropwise, and the mixture was stirred at room temperature overnight. The mixture was then concentrated, the residue was taken up in ice-water and extracted repeatedly with dichloromethane, and the combined organic phases were washed repeatedly with 1N aqueous hydrogen chloride solution and saturated aqueous sodium bicarbonate solution, dried over sodium sulphate, filtered and concentrated. This gave 570 mg of the title compound as a diastereomer mixture which were reacted without further purification.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=O)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:30])=[N:5]1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([O:23][C:24]([CH3:29])([CH3:28])[C:25]([N:44]5[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]5)=[O:27])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:30])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(C)C(=O)O)cc2OCC3)n(C(C)C)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)(C)C(=O)N4CCN(C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To a suspension of 2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-2-methylpropionic acid from Example 45 (0.0922 mmol) in DMF (2 mL) were added DIPEA (47 ul, 0.277 mmol), 1-methylpiperazine (31 uL, 0.277 mmol), HOBt (19 mg, 0.138 mmol) and EDCI (27 mg, 0.138 mmol) and the reaction mixture was stirred at RT for 2 h. Additional EDCI (50 mg) was added and the reaction mixture was stirred at RT for 18 h. The mixture was then partitioned between EtOAc and water. The aqueous layer was further extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% MeOH in DCM) affording 250 as a white solid (28 mg, 60% over three steps). LCMS: RT 2.92 min [M+H]+ 494.1. 1H NMR (DMSO, 400 MHz): δ 8.29 (1H, d, J=8.97 Hz), 7.83 (1H, s), 6.64 (1H, dd, J=8.98, 2.60 Hz), 6.42 (1H, d, J=2.57 Hz), 5.88-5.76 (1H, m), 4.47 (4H, s), 3.75-3.44 (4H, m), 2.24 (3H, s), 2.19 (2H, s), 2.06-1.94 (5H, m), 1.58 (6H, s), 1.44 (6H, d, J=6.59 Hz)
Reaction SMILES: Br[CH2:2][C:3]1([CH3:15])[CH2:7][C:6]2[C:8]([CH3:14])=[CH:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[C:16]1([CH:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O>[CH3:15][C:3]1([CH2:2][N:27]2[CH2:28][CH2:29][CH:24]([NH:23][CH:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:25][CH2:26]2)[CH2:7][C:6]2[C:8]([CH3:14])=[CH:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1
Reactant: Cc1cc(C)c2c(c1C)OC(C)(CBr)C2
Reactant: c1ccc(C(NC2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(C)c2c(c1C)OC(C)(CN1CCC(NC(c3ccccc3)c3ccccc3)CC1)C2
Temperature: 177 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
A suspension of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethylbenzofuran (1.0 g), N-(diphenylmethyl)-4-piperidinamine (1.5 g), and potassium carbonate (0.77 g) in N,N-dimethylacetamide (4 mL) was stirred under argon gas at 177° C. for 4 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) to provide the title compound (1.5 g). Yield 97%.