Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([CH2:19][O:20][Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:13]=2)[C:9]2[C:4](=[N:5][C:6]([Cl:38])=[CH:7][CH:8]=2)[CH:3]=1.[O:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]1[N:45]1[C:49](B2OC(C)(C)C(C)(C)O2)=[CH:48][CH:47]=[N:46]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[Si:21]([O:20][CH2:19][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([Cl:18])[CH:15]=1)[CH2:11][N:10]1[C:9]2[C:4](=[N:5][C:6]([Cl:38])=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:49]1[N:45]([CH:40]2[CH2:41][CH2:42][CH2:43][CH2:44][O:39]2)[N:46]=[CH:47][CH:48]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](OCc1cc(Cl)cc(Cn2c(Br)cc3nc(Cl)ccc32)c1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
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: COCCOC
Solvent: O
Product: CC(C)(C)[Si](OCc1cc(Cl)cc(Cn2c(-c3ccnn3C3CCCCO3)cc3nc(Cl)ccc32)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.65 g, 0.56 mmol, Strem) was added to a degassed mixture of 2-bromo-1-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-chlorobenzyl]-5-chloro-1H-pyrrolo[3,2-b]pyridine (3.5 g, 5.6 mmol, from Step 1), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.5 g, 9.0 mmol, Aldrich) and Na2CO3 (3.0 g, 28 mmol) in 1,2-dimethoxyethane (60 mL) and Water (10 mL). The mixture was heated at reflux for 2 hours. Additional 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.50 g, 1.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.32 g, 0.28 mmol) were added, and the reaction mixture was heated at reflux until LCMS indicated that the reaction was complete. After cooling to room temperature, the reaction was diluted with water, and the aqueous mixture was extracted with three portions of EtOAc. The combined organic extracts were washed with water, followed by brine, dried over Na2SO4, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-20% EtOAc in hexanes afforded product as a light yellow oil. Yield: (2.73 g, 70%).
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[C:5]([OH:9])(=[O:8])[CH:6]=[O:7]>CC(C)=O>[C:1]([NH:4][CH:6]([OH:7])[C:5]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(N)=O
Reactant: O=CC(=O)O
Solvent: CC(C)=O
Product: CC(=O)NC(O)C(=O)O

Procedure:
A mixture of commercially available acetamide 34 and glyoxylic acid 41 was heated at reflux in acetone to give pure N-acetyl-2-hydroxyglycine 42 as a viscous yellow oil in quantitative yield. The 1H n.m.r. spectrum supported formation of the α-hydroxyglycine derivative 42 with the appearance of a methine (H2) doublet and broad amide (NH) doublet at δ 5.39 and δ 8.65 respectively. Spectroscopic data were in agreement with those reported in the literature.195
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15]>C(Cl)Cl>[N+:1]([C:16]1[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][C:13]=1[CH:14]=[O:15])([O-:4])=[O:2]
Reactant: O=Cc1cccc(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Concentrated nitric acid (29.3 ml) was added dropwise to 500 ml of concentrated sulfuric acid with ice cooling externally while stirring. In addition, 50 g of m-chlorobenzaldehyde was added dropwise to the resulting mixture at 5° C. or less. After stirring was continued at room temperature for 1 hour the reaction mixture was poured onto ice to precipitate solids which were collected by filtration. After washing with water the solids thus-obtained were dissolved in methylene chloride and the methylene chloride layer was washed with a dilute aqueous sodium hydroxide, washed with water and dried over sodium sulfate. Removal of the solvent by distillation gave 62.3 g of 2-nitro-5-chlorobenzaldehyde, m.p. 65°-69° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2C=CC=CC=2)=[CH:8][CH:7]=1)=[N:4][OH:5].Cl>C(Cl)Cl>[F:1][C:2]([F:19])([F:20])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[N:4][OH:5]
Reactant: ON=C(c1ccc(Oc2ccccc2)cc1)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=NO)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 122.9 %

Procedure:
35 g (124 mmol) of 2,2,2-trifluoro-1-(4-phenoxyphenyl)-ethanone oxime (mixture of E- and Z-isomers) prepared according to the method described in example 80.1 is dissolved in 300 ml of methylene chloride. To the solution is added 1.1 ml of conc. HCl and stirred at room temperature for 4.5 hours. The reaction mixture is washed with water and brine, dried over MgSO4, and concentrated, yielding 33.4 g of 2,2,2-trifluoro-1-(4-methoxyphenyl)-ethanone oxime (single isomer) as a white solid. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 7.00-7.12 (m, 4H), 7.19 (t, 1H), 7.39 (t, 2H), 7.57 (d, 2H), 8.95 (s, 1H).
Reaction SMILES: [B].[CH2:2]([CH:4]1[O:6][CH2:5]1)Cl.[CH2:7]([OH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[CH2:2]([O:15][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:4]1[O:6][CH2:5]1
Reactant: ClCC1CO1
Reactant: CCCCCCCCO
Agent: [B]
Product: CCCCCCCCOCC1CO1
Temperature: 0 °C
Yield: 111.8 %

Procedure:
Octanol (130 g) and 2.84 g of a boron trifluorideether complex were cooled to 0° C. while stirring. At a temperature maintained at 0° C., 138.8 g of epichlorohydrin was added dropwise over 1 hour. After completion of dropwise addition, an excess alcohol was distilled off at 100° C. under reduced pressure (13 to 26 Pa). The reaction mixture was cooled to 50° C. and while maintaining the temperature at 50° C., 125 g of a 48% aqueous solution of sodium hydroxide was added dropwise over 1 hour. After stirring for 3 hours, 200 mL of water was added to the reaction mixture to cause separation. The water layer thus obtained was removed and then the residue was washed twice with 100 mL of water, whereby 208 g of crude octyl glycidyl ether was obtained.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=2)=[CH:11][CH:10]=1)C>C(O)C.O>[C:15]1([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:22])=[O:3])=[CH:14][CH:13]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: CCOC(=O)CCCOc1ccc(C2=CCCCCC2)cc1
Solvent: O
Solvent: CCO
Product: O=C(O)CCCOc1ccc(C2=CCCCCC2)cc1

Procedure:
Analogously to the process described in Example 2, using 9.7 g of 4-[p-(1-cycloheptenyl)-phenoxy]-butyric acid ethyl ester as the starting material gives 4-[p-(1-cycloheptenyl)-phenoxy]-butyric acid of melting point 87° -88° C (from ethanol-water).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.C([N:24](CC)CC)C.N>C(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([NH2:24])=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClC(Cl)Cl
Solvent: O
Product: NC(=O)C1(c2ccc(Br)cc2)CC1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
To a −15° C. solution of 1-(4-bromophenyl)cyclopropanecarboxylic acid from Step 2 (1.5 g) in chloroform (60 mL) were slowly added isobutyl chloroformate (900 μL) and triethylamine (1.1 mL). The reaction mixture was stirred at −15° C. for 2 hours. Then it was saturated with ammonia gas and stirred at −15° C. for 10 minutes. The reaction mixture was allowed to stand at room temperature for 1 hour then poured into water (60 mL) and partitioned. The aqueous layer was extracted with dichloromethane (2×160 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by swish using diethyl ether and hexanes to yield the title compound.
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]([O:12][C:13]([N:15]1[C@H:19]([CH:20]=[CH:21][CH2:22][CH2:23][C:24](OCC)=[O:25])[CH2:18][O:17][C:16]1([CH3:30])[CH3:29])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:8]([O:12][C:13]([N:15]1[C@H:19]([CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][OH:25])[CH2:18][O:17][C:16]1([CH3:30])[CH3:29])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCOC(=O)CCC=C[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@H](C=CCCCO)COC1(C)C
Temperature: -12 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
A solution of 11.42 ml of acetic anhydride in 50 ml of dichloromethane is added dropwise at 0°-3° within a period of 25 minutes to a solution of 20.2 g of 2, 16.83 ml of triethylamine and 0.62 g of 4-(dimethylamino)-pyridine in 300 ml of dichloromethane. After 30 minutes,the mixture is washed twice with ice-cold 2N hydrochloric acid and twice with 10% sodium chloride solution. The aqueous phases are extracted with 100 ml of dichloromethane. The organic phases are dried over sodium sulphate and concentrated by evaporation, and the residue is dissolved hotin hexane/ ethyl acetate 4:1. On cooling slowly to approximately 30°there crystallise 1.82 g of racemic (2R*,2S*)-2-formamino-3-acetoxy-4-methyl-4-pentenoic acid ethyl ester having a melting point of 98°-106°. The mother liquor is slowly cooled to -12° C. and kept at that temperature for one hour.Filtration yields 15.04 g of acetate 3, m.p. 73°-75°, [α]D =-75.6° (c=1, CHCl3), analysis by gas chromatography (Chirasil®-L-Val, 160°-180°, 1° per minute): (2R,3S)-isomer 93.5% (Tret =14.5 minutes), (2S,3R)-isomer 2.2% (Tret =14.8 minutes), (2R,3R)-isomer 2.2% (Tret =16.8 minutes), (2S,3S)-isomer 2.1% (Tret =17.1 minutes). 20.64 g of anhydrous potassium carbonate are added at -16° to a solution of (2R,3S)-2-formylamino-3-acetoxy-4-methyl-4-pentenoic acid ethyl ester (3) in 400 ml of absolute ethanol. After stirring at -18° to -11° C. for 4 hours, 500 ml of buffer solution (1 molar, phosphate, pH=7) are added dropwise. The mixture is stirred at roomtemperature for 30 minutes and extracted three times with 350 ml of dichloromethane each time. The organic phases are dried over sodium sulphate and concentrated by evaporation, and the residue is chromatographed on 1 kg of silica gel using hexane/ethyl acetate 1:2 as eluant, yielding 9.8 g of alcohol 1.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[N:17][C:16]([C:19](O)=[O:20])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6].S(Cl)(Cl)=O.O[NH:33][C:34](=[NH:38])[CH2:35][CH2:36][CH3:37].C(N(CC)CC)C>C(Cl)(Cl)Cl.CN(C=O)C.ClCCl>[CH2:35]([C:34]1[N:38]=[C:19]([C:16]2[N:17]=[N:18][C:13]([N:10]3[CH2:9][CH2:8][N:7]([C:5]([C:4]4[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=4[C:2]([F:27])([F:26])[F:1])=[O:6])[CH2:12][CH2:11]3)=[CH:14][CH:15]=2)[O:20][N:33]=1)[CH2:36][CH3:37]
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CCCC(=N)NO
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCc1noc(-c2ccc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)nn2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a suspension of 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (0.500 g, 1.314 mmol) in chloroform, one drop of DMF was added followed by the addition of thionyl chloride (0.5 mL). The mixture was heated at reflux overnight. The clear solution was evaporated to dryness under vacuum to get a pale yellow syrup. This syrup was then dissolved in anhydrous dichloromethane (1 mL) and transferred to a solution containing N-hydroxybutyramidine (0.134 g, 1.314 mmol) and triethylamine (0.5 mL) in dichloromethane (5 mL) at 0° C. The mixture was warmed up to room temperature and stirred for another 30 minutes. The solvent was removed in vacuo. The crude mixture was suspended in 1,4-dioxane-water (1:1, 9 mL) containing cesium carbonate (0.3 g) and heated at reflux overnight, cooled, concentrated and diluted with water (10 mL), extracted with ethyl acetate. The organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography and recrystallization from ethyl acetate-hexanes. The title compound was obtained as a white solid in 39% yield (0.228 g). m.p. 226° C. 1H NMR (300 MHz, CDCl3) 7.98 (d, J=9.6 Hz, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.65-7.50 (m, 2H), 7.34 (d, J=7.4 Hz, 1H), 6.97 (d, J=9.6 Hz, 1H), 4.11-3.98 (m, 1H), 3.96-3.70 (m, 5H), 3.34 (t, J=5.1 Hz, 2H), 2.77 (t, J=7.4 Hz, 2H), 1.90-1.75 (m, 2H), 0.99 (t, J=7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 172.6, 171.1, 167.7, 159.2, 139.7, 134.1, 132.4, 129.5, 127.8, 127.2, 126.9, 126.8, 111.3, 46.3, 44.5, 44.1, 41.2, 27.9, 20.4, 13.7. MS (ES+) m/z 447.0 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](O)=O.[NH2:10][C:11]1[C:12](=[O:33])[N:13]([CH2:30][CH2:31][CH3:32])[C:14](=[O:29])[N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[C:16]=1[NH2:17]>>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:15]2[C:16]3[N:17]=[C:7]([CH2:6][C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[NH:10][C:11]=3[C:12](=[O:33])[N:13]([CH2:30][CH2:31][CH3:32])[C:14]2=[O:29])=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: O=C(O)Cc1cccs1
Reactant: CCCn1c(=O)c(N)c(N)n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Product: CCCn1c(=O)c2[nH]c(Cc3cccs3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
By the method of Example 2, 2-thiopheneacetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(thiophen-2-yl)methyl]xanthine. By the method of Example 3, this substance is alkylated with a mixture of 1,2-dichloroethane, sodium carbonate and 2-(ethylamino)ethanol to yield 7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(thiophen-2-yl)methyl]xanthine. By the method of Example 4 this substance is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propyl-8-[(thiophen-2-yl)methyl]xanthine free base. The corresponding dihydrochloride salt is then made on exposure to an excess of hydrogen chloride in solution.
Reaction SMILES: [Mg].Br[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1.[Cl:9][C:10]1[S:14][C:13]([S:15]([NH:18][C@H:19]([CH:24]=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])(=[O:17])=[O:16])=[CH:12][CH:11]=1.[NH4+].[Cl-]>C1COCC1>[Cl:9][C:10]1[S:14][C:13]([S:15]([NH:18][C@H:19]([C@H:24]([CH:8]2[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]2)[OH:25])[C@@H:20]([CH3:21])[CH2:22][CH3:23])(=[O:17])=[O:16])=[CH:12][CH:11]=1
Reactant: BrC1=CCCCC1
Reactant: CC[C@H](C)[C@@H](C=O)NS(=O)(=O)c1ccc(Cl)s1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NS(=O)(=O)c1ccc(Cl)s1)[C@@H](O)C1C=CCCC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a two dram vial containing magnesium turnings (60 mg, 2.5 mmol) suspended in THF (3 mL) was added 2-bromocyclohexene (288 μL, 2.5 mmol) followed by 5-chlorothiophene-2-sulfonyl isoleucinal (1 mL of a 1 M THF solution, 1 mmol, example 118). The vial was capped and agitated at 50° C. for 18 h. The vial was cooled and sat. aqueous NH4Cl (1 mL) was added. The vial was vortexed and the organic layer was transferred into a tarred vial and the aqueous layer was extracted with EtOAc (1 mL). The combined organics were concentrated in vacuo and the residue was submitted to semipreparative RP-HPLC using the conditions below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][CH2:26][C:27]12[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2)=[O:23].Cl>CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][CH2:26][C:27]12[CH2:28][CH:29]3[CH2:30][CH:31]([CH2:32][CH:33]([CH2:35]3)[CH2:34]1)[CH2:36]2)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)c(C(=O)NCCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NCCC12CC3CC(CC(C3)C1)C2)c1cc(CN2CCNCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-[[4-chloro-3-[[(2-tricyclo[3.3.1.13,7]dec-1-ylethyl)amino]carbonyl]phenyl]methyl]-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester, (Example 18b, 0.270 g) was dissolved in methanol (3 ml), 4N HCl in dioxane (2 ml) was added and the mixture stirred for 14 h at room temperature. The solvent was removed under vacuum and the resulting solid was triturated with ether to afford the title compound as a white powder (0.207 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH:12]([CH3:17])[CH2:13][C:14]([OH:16])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:19]([N:21]1[C:29]2[C:24](=[CH:25][C:26]([NH2:30])=[CH:27][CH:28]=2)[C:23]([CH3:31])=[C:22]1[CH3:32])[CH3:20].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:18])[CH2:11][CH:12]([CH3:17])[CH2:13][C:14]([NH:30][C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:21]([CH2:19][CH3:20])[C:22]([CH3:32])=[C:23]3[CH3:31])=[O:16])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCn1c(C)c(C)c2cc(N)ccc21
Reactant: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(C)c(C)c2cc(NC(=O)CC(C)CC(=O)Nc3ccc(C#N)cc3)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.8 %

Procedure:
To a solution of the compound obtained in Step 1 (510 mg, 2.07 mmol), 1-ethyl-2,3-dimethyl-1H-indol-5-amine (390 mg, 2.07 mmol) and DIEA (1.085 mL, 6.21 mmol) in DMF (8 mL) was added HATU (1181 mg, 3.11 mmol), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane) to give the title compound (533 mg, 1.280 mmol, 61.8%) as a white powder.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)=O.O.[NH2:18]N>C(O)C>[N+:13]([C:9]1[CH:8]=[C:7]([C:5]2[CH:4]=[CH:3][NH:2][N:18]=2)[CH:12]=[CH:11][CH:10]=1)([O-:15])=[O:14]
Reactant: CN(C)/C=C/C(=O)c1cccc([N+](=O)[O-])c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2cc[nH]n2)c1
Reaction time: 5 h
Yield: 100.9 %

Procedure:
2.5 g (11 mmol) of (2E)-3-(dimethylamino)-1-(3-nitrophenyl)prop-2-en-1-one were dissolved in 25 ml of ethanol and 2.3 ml of hydrazine hydrate 98% (46 mmol) were added. The resulting solution was refluxed under stirring for 5 hours. The solvent was then evaporated and the crude was dissolved with dichloromethane and washed with water. The organic layer was dried over sodium sulphate and the solvent removed in vacuo. The residue was then triturated with diisopropylether and collected by filtration, giving 2.1 g of the title compound (98%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([O:8]C(OC(C)(C)C)=O)=O)([CH3:4])[CH3:3].[NH2:16][OH:17].O>C(Cl)Cl>[C:6]([NH:16][OH:17])([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:8]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NO
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NO
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Boc anhydride (5.91 g, 0.026 mole) was added in one portion to a stirred solution of amino alcohol in anhydrous DCM (150 mL), and the reaction mixture stirred at ambient temperature under argon for 4.5 h. Water (200 mL) was added to the reaction mixture and the organic layer separated. The organic layer was washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated to give N-boc amino alcohol as a colorless liquid that became a colorless glass upon standing. The material was used without further purification. Yield: 9.0 g (quantitative); LCMS: (+) ESI: m/z=368 [M+Na]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:14])=[C:6]([C:12]=1[CH3:13])[C:7]([O:9]CC)=[O:8].C(O)C.[OH-].[Na+].Cl>O>[OH:14][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:12]([CH3:13])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1c(O)ccc(Br)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(Br)ccc(O)c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1A (20.2 g, 0.078 mol), ethanol (150 ml) and an aqueous sodium hydroxide (12 g, 0.3 mol in 100 ml water) is heated under reflux with stirring for 16 hours. The reaction mixture is cooled to room temperature, diluted with water (600 ml) and acidified with concentrated hydrochloric acid. The precipitate is collected and washed with water yielding 18.45 g (100%) white crystals with a melting point of 163-165° C.
Reaction SMILES: C(=O)([O-])[O-].[NH4+:5].[NH4+].[CH3:7][O:8][C:9](=[O:26])[CH:10]([CH:24]=O)[N:11]([CH:22]=O)[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1>C1(C)C(C)=CC=CC=1>[CH3:7][O:8][C:9]([C:10]1[N:11]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:22]=[N:5][CH:24]=1)=[O:26]
Reactant: COC(=O)C(C=O)N(C=O)C1CCCc2ccccc21
Reactant: [NH4+]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1C
Product: COC(=O)c1cncn1C1CCCc2ccccc21
Temperature: 70 °C

Procedure:
33.0 g of ammonium carbonate are added at room temperature to a solution of 15.5 g of N,α-bis-formyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)glycine methyl ester in 300 ml of xylene. The mixture is heated to 70° C. for 1 hour then the temperature is raised to 120° C. for 3 hours. After concentration the 1-(1,2,3,4-tetrahydronaphthalen-1-yl)-5-imidazolecarboxylic acid methyl ester precipitates from the solution, having a melting point of 63° C.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27](C(F)(F)F)=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[F:35][C:36]([F:47])([F:46])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>>[F:35][C:36]([F:47])([F:46])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:14]1[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:4]([OH:3])=[O:34])[C:11]([C:36]([F:47])([F:46])[F:35])=[C:12]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:13]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccccc2C(F)(F)F)cc(-c2ccccc2)c1C(F)(F)F

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 2-trifluoromethyl-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.86-0.97 (m, 6H), 1.54 (dt, J=13.39, 6.63 Hz, 1H), 1.75-1.85 (m, 1H), 2.01 (ddd, J=13.94, 7.95, 7.70 Hz, 1H), 3.78 (t, J=7.83 Hz, 1H), 7.36 (s, 1H), 7.38 (d, J=7.34 Hz, 1H), 7.45-7.53 (m, 2H), 7.56-7.62 (m, 2H), 7.67-7.78 (m, 5H); Calcd for C26H22ClF6O2 (M+Na) 503.44, Found 503.