Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:50]([C:52]([C:75]1[CH:80]=[CH:79][C:78](B2OC(C)(C)C(C)(C)O2)=[C:77]([CH3:90])[CH:76]=1)([C:55]1[CH:60]=[CH:59][C:58]([C:61]#[C:62][C:63]2([O:69][Si:70]([CH3:73])([CH3:72])[CH3:71])[CH2:68][CH2:67][S:66][CH2:65][CH2:64]2)=[C:57]([CH3:74])[CH:56]=1)[CH2:53][CH3:54])[CH3:51]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:78]2[CH:79]=[CH:80][C:75]([C:52]([CH2:53][CH3:54])([C:55]3[CH:60]=[CH:59][C:58]([C:61]#[C:62][C:63]4([O:69][Si:70]([CH3:71])([CH3:73])[CH3:72])[CH2:68][CH2:67][S:66][CH2:65][CH2:64]4)=[C:57]([CH3:74])[CH:56]=3)[CH2:50][CH3:51])=[CH:76][C:77]=2[CH3:90])=[CH:7][CH:6]=1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCSCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCSCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
(4-Bromo-phenyl)acetic acid methyl ester (35 mg, 0.15 mmol), palladium acetate (2.3 mg, 0.01 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (8.3 mg, 0.02 mmol), potassium phosphate (65 mg, 0.3 mmol) and water (0.2 mL) were added to a solution of 2-(4-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxy-tetrahydro-thiopyran-4-ylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 136-(4); 60 mg, 0.1 mmol) in toluene (2 mL). The mixture was stirred in a nitrogen atmosphere at 110° C. for two hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the target compound as a colorless oil (55 mg, 88%).
Reaction SMILES: [BH4-].[Na+].[C:3]([N:10]1[CH2:16][C@H:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][C@H:11]1[CH:12]=[O:13])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]>CO>[C:3]([N:10]1[CH2:16][C@H:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH2:14][C@H:11]1[CH2:12][OH:13])([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 105 %

Procedure:
Sodium borohydride (227 mg, 6 mmol) was added at 0° C. to a stirred solution of (2S,4R)-N-BOC-4-(t-butyldimethylsilyloxy)prolinaldehyde (522 mg, 1.58 mmol) in MeOH (10 mL), and the mixture was stirred at rt for 3 h. The reaction was quenched by adding sat. NaHCO3 (20 mL), and the resulting mixture was extracted with EtOAc (3×50 mL). The EtOAc extracts were washed with brine (2×50 mL), and dried (Na2SO4). The solvent was removed in vacuo to give (2S,4R)-N-BOC-4-(t-butyldimethylsilylhydroxy)prolinol (550 mg).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]12[O:16][CH:12]([CH2:13][NH:14][CH2:15]1)[C:11]1[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=1.[OH-].[Na+]>S(=O)(=O)(O)O>[N+:1]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:12]1[O:16][CH:5]2[CH2:15][NH:14][CH2:13]1)([O-:4])=[O:2]
Reactant: c1ccc2c(c1)C1CNCC2O1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc2c(c1)C1CNCC2O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Concentrated nitric acid (10 mL) was added to a mixture of 12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (5.1 g, 32 mmol) and concentrated sulfuric acid (10 mL) at 0° C. The resulting solution was stirred at 0° C. for 30 min before pouring onto ice, adding 10 N NaOH slowly until basic, and extracting with CH2Cl2 (2×25 mL). The combined organic layers were dried over MgSO4, filtered, concentrated and purified with silica gel chromatography (0-30% MeOH in CH2Cl2) to obtain 4-Nitro-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene as a gummy, brown oil (4.2 g, 65%). MS (m/e) 207 (M+1).
Reaction SMILES: [ClH:1].[F:2][C:3]1([F:18])[CH2:5][CH:4]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][NH:13][CH2:12][CH2:11]2.C(OC(=O)[NH:25][C@H:26]([C:28]1[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=1)[CH3:27])(C)(C)C.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[ClH:1].[F:18][C:3]1([F:2])[CH2:5][CH:4]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([CH2:34][C:31]1[CH:32]=[CH:33][C:28]([C@@H:26]([NH2:25])[CH3:27])=[CH:29][CH:30]=1)[CH2:12][CH2:11]2
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C=O)cc1
Reactant: FC1(F)CC1COc1ccc2c(c1)CCNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@H](N)c1ccc(CN2CCc3cc(OCC4CC4(F)F)ccc3C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 800 mg (2.94 mmol) 6-(2,2-difluoro-cyclopropylmethoxy)-1,2,3,4-tetrahydro-isoquinoline hydrochloride (example XXXII.2) and 806 mg (3.23 mmol) [(S)-1-(4-formyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (example II) in 8 mL THF are added 504 μL (8.81 mmol) AcOH and the mixture is stirred at r.t. for 10 min. After that time, the resulting mixture is cooled to 0° C. and 934 mg (4.41 mmol) sodium triacetoxyborohydride are added and the reaction mixture is stirred at r.t. for 2 h. After that time, the reaction is quenched by addition of 500 μl water, the solvent is removed and and the residue is purified by HPLC.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1.[CH2:25]([NH:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>CN(C)C=O>[CH2:25]([N:29]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1)[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCNCCCC
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)cc2C1=O
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)no1
Temperature: 25 °C
Reaction time: 65 h
Yield: 77 %

Procedure:
A suspension of 1.30 g (0.0037 mol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 15 ml of dimethylformamide was treated with 2.4 g (0.01 9 moll of dibutylamine. After stirring at room temperature for 65 hrs. the orange solution obtained was freed completely from solvent. The residue was chromatographed over silica gel with dichloromethane/methanol 19:1 as the eluent. The product was recrystallized from methanol/ether and there were obtained 1.27 g (77%) of 3-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 137°-140°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[CH:16]1(O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OC1CCCCC1
Reactant: CCOC(=O)CCc1ccc(O)c(Br)c1
Product: CCOC(=O)CCc1ccc(OC2CCCCC2)c(Br)c1

Procedure:
According to the procedure described in the synthesis method of Intermediate 9 in Reference Example 2 (Step e-2), ethyl 3-(3-bromo-4-hydroxyphenyl)propionate and cyclohexanol were reacted and treated to obtain ethyl 3-(3-bromo-4-cyclohexyloxyphenyl)propionate (355 mg). According to the procedure described in the synthesis method of Compound of Example 001 (Preparation Method 4, Step d-1) with the modifications that the reaction was carried out for 17 hours, and the purification was performed by flash column chromatography (hexane:ethyl acetate 8:1), the above product was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (330 mg), 2 M aqueous sodium carbonate (0.9 ml) and (Ph3P)4Pd (105 mg) and treated to obtain the title compound (Intermediate 68, 260 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].[F:41][C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][C:47]=1[C:48]#[N:49].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.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>[Cl:1][C:2]1[CH:3]=[C:4]([C:44]2[CH:45]=[CH:46][C:47]([C:48]#[N:49])=[C:42]([F:41])[CH:43]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:15][CH2:16][CH:17]([O:20][Si:21]([CH:25]([CH3:26])[CH3:27])([CH:22]([CH3:23])[CH3:24])[CH:28]([CH3:30])[CH3:29])[CH2:18][CH2:19]2)[C:10]1=[O:31]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)CC1)(C(C)C)C(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: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C#N)c(F)c4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Yield: 87.2 %

Procedure:
Purge with nitrogen for 10 minutes a mixture of (R)-trifluoro-methanesulfonic acid 3,5-dichloro-4-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (0.18 g, 0.28 mmol), 3-fluoro-4-cyanophenylboronic acid (0.055 g, 0.33 mmol), sodium carbonate (0.089 g, 0.84 mmol) in THF (10 mL) and water (3 mL). Add Pd(PPh3)4 (0.016 g, 0.01 mmol) to the mixture. Stir the reaction at 80° C. for 1 hour. Cool the reaction, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica gel column with 0% to 50% ethyl acetate in hexanes gradient to afford 0.151 g of the titled product. MS (m/z): 617 (M+).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12]([C:13](=O)[C:14](C)(C)C)[C:11](=[O:19])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C([Li])CCC.BrCC#[N:34]>C1COCC1.CCCCCC>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]2[CH2:9][CH2:10][C:11](=[O:19])[N:12]2[CH2:13][C:14]#[N:34])=[CH:3][CH:2]=1
Reactant: CC(C)(C)C(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Reactant: N#CCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CCN1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1.5 g (5.97 mmol) (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1, R1═H) is dissolved in 15 ml dry THF and cooled to −78° C. After the addition of 4.13 ml butyl lithium in hexane (1.59 M) the yellow solution is stirred at −78° C. for 30 min. Subsequently, 475 l (855 mg, 7.16 mmol) bromoacetonitrile is added and the mixture is warmed up to room temperature overnight. The reaction is then quenched on addition of 10 ml saturated NH4Cl solution followed by the addition of 6 ml water and the mixture is extracted with 2×40 ml ethyl acetate. The combined organic layers are separated, dried over MgSO4, filtered and evaporated. The resulting residue is purified by column chromatography (dichloromethane:methanol=99:1) to give ((S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidin-1-yl)acetonitrile (1-a, R1=cyanomethyl) as off-white solid. NMR (400 MHz, DMSO-d6, /ppm): 7.65 (m, 4H); 7.47 (t, J=7.4, 2 H); 7.40 (m, 3H); 4.57 (d, J=17.7, 1H); 4.44 (d, J=17.7, 1H); 3.91 (m, 1H); 3.19 (dd, J=3.9, 13.8, 1H); 2.70 (dd, J=9.2, 13.8, 1H); 2.18 (m, 2H); 1.95 (m, 1H); 1.77 (m, 1H). MS (ESI, m/e) 291 [M+H]+. IR (solution in CH2Cl2, /cm−1): 3025; 2985; 2257; 1697; 1688; 1486; 1421; 1323; 1271; 1182; 760; 699.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([Cl:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[N+:18]([O-])([O-:20])=[O:19].[K+]>>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([Cl:12])[C:8]([N+:18]([O-:20])=[O:19])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1c(Cl)ccc(C(=O)O)c1Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c(Cl)c(C(=O)O)cc([N+](=O)[O-])c1Cl

Procedure:
30 g of 2,4-dichloro-3-methylbenzoic acid are initially introduced into 83 ml of concentrated H2SO4. 16.7 g of KNO3 are added in portions, while cooling with ice. The mixture is subsequently warmed at 50° for a further 2 hours and then poured onto ice. The nitro compound is isolated and recrystallized from toluene. Melting point: 152°-4°, yield: 24 g.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([C:11]([F:14])([F:13])[F:12])=[CH:5][C:6]([O:8]CC)=O.[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=1[CH2:24][N:25]=[C:26]=[O:27].O>CN(C)C=O>[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=1[CH2:24][N:25]1[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:26]1=[O:27]
Reactant: CCOC(=O)C=C(N)C(F)(F)F
Reactant: O=C=NCc1cc(Cl)cc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1Cc1cc(Cl)cc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 53.4 %

Procedure:
Under a nitrogen atmosphere, a stirred suspension of 0.62 gram (0.015 mole) of 60% sodium hydride (in mineral oil) in 30 mL of N,N-dimethylformamide was cooled to below 7° C., and a solution of 2.8 grams (0.015 mole) of ethyl 3-amino-4,4,4-trifluoro-2-butenoate in 15 mL of N,N-dimethylformamide was added dropwise at a rate to maintain the reaction mixture below 7° C. Upon completion of the addition the reaction mixture was stirred for about 45 minutes, during which time the reaction mixture temperature was about 2°-4° C. After this time a solution of 3.2 grams of 2,3,5-trichlorophenylmethyl isocyanate in 10 mL of N,N-dimethylformamide was added dropwise at a rate to maintain the reaction mixture temperature at about 2°-4° C. Upon completion of the addition the reaction mixture was stirred for about 10 minutes at 2°-4° C. and then warmed to 70°-85° C., where it was stirred for 3 hours. After this time the reaction mixture was allowed to cool to ambient temperature, where it stirred for about 16 hours. The reaction mixture was then poured into water, and the mixture was extracted with ethyl acetate. The extract was then washed with one portion of water. The water layer and the wash were combined and acidified with concentrated hydrochloric acid. The resultant solid was collected by filtration, yielding, when dried, 0.5 gram of solid. To collect additional product, the ethyl acetate extract was again washed, this time with five 150 mL portions of water. The combined washes were acidified with concentrated hydrochloric acid. The resultant solid was collected by filtration. The solid was dissolved in ethyl acetate and washed with water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding a solid residue. The solid was combined with the 0.5 gram of material collected above, yielding 2.7 grams of 3-(2,3,5-trichlorophenylmethyl)-6-trifluoromethyluracil, mp 199°-202° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].S(Cl)([Cl:15])(=O)=O>ClCCl>[Cl:15][C:2]([CH3:4])([CH3:3])[C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CC(=O)C(C)(C)Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of ethyl isobutyrylacetate (2 g, 12.6 mmol) in dichloromethane (12 mL) at 0° C. was added a 1M solution of sulfuryl chloride in dichloromethane (13.9 mL, 13.9 mmol). The reaction mixture was warmed to 25° C. and stirred for 2.5 h. The reaction mixture was diluted with dichloromethane (80 mL) and washed in turn with water (2×60 mL) and brine (75 mL). The organic extract was dried (MgSO4), filtered, concentrated to yield ethyl 2-chloroisobutyrylacetate (2.8 g, 66% product, 34% ethyl isobutyrylacetate) as a yellow oil which was used as is in the step below.
Reaction SMILES: [CH3:1][O-:2].[Na+].F[C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[C:8]([OH:10])=[O:9].Cl>CO.CS(C)=O>[CH3:1][O:2][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(F)c1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: COc1cc(C(=O)O)ccc1C(F)(F)F
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
28% Sodium methoxide in methanol (50 ml) was added to a solution of 3-fluoro-4-(trifluoromethyl)benzoic acid (20.8 g) in dimethylsulfoxide (200 ml). The mixture was stirred at 90° C. for 3.5 hours. After cooling at room temperature, the resulting mixture was poured into ice-water (1.5 l) and made acidic with diluted hydrochloric acid. After being stirred for 30 minutes, the resulting precipitates were collected by filtration and air-dried to give a colorless powder of 3-methoxy-4-(trifluoromethyl)benzoic acid (22.95 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([CH2:20][CH3:21])[CH2:18][OH:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](OCC)(=[O:32])[CH3:31]>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:30]([O:19][CH2:18][C:17]([NH:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])([CH2:20][CH3:21])[CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)(=[O:32])[CH3:31]
Reactant: CCC(CO)(CCc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCC(CCc1ccc(OCc2ccccc2)cc1)(COC(C)=O)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 4-(4-benzyloxyphenyl)-2-tert-butoxycarbonylamino-2-ethylbutanol (24 g) in pyridine (200 ml) and acetic anhydride (32 ml) was allowed to stand at room temperature overnight. Ethyl acetate was added to the reaction mixture and the mixture was washed with water, a dilute hydrochloric acid, an aqueous sodium hydrogencarbonate solution and a saturated brine in order, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:1) to give the subject compound (13 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][N:14]1[CH:18]=[C:17]([C:19]2[CH:20]=[CH:21][C:22]3[CH2:23][C@H:24]4[C@@H:29]([C:30]=3[CH:31]=2)[CH2:28][CH2:27][CH2:26][NH:25]4)[CH:16]=[N:15]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:25]3[CH2:26][CH2:27][CH2:28][C@@H:29]4[C:30]5[CH:31]=[C:19]([C:17]6[CH:16]=[N:15][N:14]([CH3:13])[CH:18]=6)[CH:20]=[CH:21][C:22]=5[CH2:23][C@H:24]34)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: Cn1cc(-c2ccc3c(c2)[C@H]2CCCN[C@H]2C3)cn1
Product: Cn1cc(-c2ccc3c(c2)[C@H]2CCCN(C(=O)c4ccc5[nH]cnc5c4)[C@H]2C3)cn1
Yield: 78 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-6-(1-methyl-1H-pyrazol-4-yl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1. Yield: 78% of theory; LC (method 1): tR=2.35 min; Mass spectrum (ESI+): m/z=398 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1)[CH2:6][CH3:7])C.[OH-].[Na+]>C(O)C.O>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([CH:5]([CH2:6][CH3:7])[C:4]([OH:17])=[O:3])=[CH:9][CH:10]=1)(=[O:16])[CH3:15]
Reactant: CCOC(=O)C(CC)c1ccc(C(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(C(=O)O)c1ccc(C(C)=O)cc1
Yield: 123.8 %

Procedure:
Part C--To a solution of 4-acetylphenylbutyric acid ethyl ester (50.0 g, 0.21 mol) in ethanol (1250 mL) was added, dropwise, a solution of sodium hydroxide (50.0 g) in water (1250 mL). All was stirred at reflux over 4 hours. The solution was concentrated to half volume and then acidified to a pH equal to 1.0 using hydrochloric acid (1N). The resulting precipitate was collected and washed with water to give 4-acetylphenylbutyric acid (53.76 g, 0.26 mol, 99%) as a white solid. mp=50°-52° C.;
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[OH-].[Na+]>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(O)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Yield: 104 %

Procedure:
1-Benzyl-4-methyl-piperidin-4-ol (4.81 g, 23.4 mmol, 1.00 equiv) was added to a suspension of AlCl3 (15.62 g, 117 mmol, 5.00 equiv) in benzene (100 mL) at room temperature under argon. The mixture was stirred at reflux for 24 hours, then cooled and poured cautiously into ice water (100 g of ice plus 50 mL of water). The aqueous phase was adjusted to pH 11-12 by addition of 6 N aqueous NaOH at 0° C., and extracted with EtOAc (3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, hexane-Et2O 19:1 to 9:1 followed by hexane-EtOAc 3:1) to give 3.23 g (52%) of brown oil, which was characterized, spectroscopically.
Reaction SMILES: [NH3:1].F[C:3]1[C:8]([C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=[CH:7][CH:6]=[C:5]([F:16])[N:4]=1.O>C(N)=O>[NH2:1][C:3]1[C:8]([C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])=[CH:7][CH:6]=[C:5]([F:16])[N:4]=1
Reactant: N
Reactant: CCCCOC(=O)c1ccc(F)nc1F
Solvent: O
Solvent: NC=O
Product: CCCCOC(=O)c1ccc(F)nc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.9 %

Procedure:
To a mechanically stirred solution of ammonia (14 grams (g)) in formamide (300 milliliter (ml)) was added all at once butyl 2,6-difluoropyridine-3-carboxylate (29 g, 0.135 mole). The resulting mixture was stirred overnight at room temperature. The mixture was then poured into water (1500 ml) and the product was filtered. After washing with several portions of water, the solid was dissolved in chloroform, dried (MgSO4) and the solvent evaporated. The resulting solid (26 g, m.p.=84°-120° C.) was separated via preparative high pressure liquid chromatography (8:2 hexane-acetone) to give first the desired butyl 2-amino-6-fluoropyridine-3-carboxylate (10 g) which after recrystallization from hexane had a m.p.=88.5°-90.5° C. Eluting second was the isomeric butyl 6-amino-2-fluoropyridine-3-carboxylate (9 g) which after recrystallization from toluene had a m.p.=132.5°-134° C.