Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]([NH2:16])=[CH:14][NH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:15]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][NH:13][N:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
4-Amino-1H-pyrazole-3-carboxylic acid (4-fluorophenyl)-amide (500 mg; 2.27 mmol) was dissolved in 5 ml of pyridine, treated with acetic anhydride (240 μl, 2.5 mmol) then stirred at room temperature overnight. The solvent was removed by evaporation then dichloromethane (20 ml) and 2M hydrochloric acid (20 ml) were added. The undissolved solid was collected by filtration, washed with more dichloromethane and water then dried under vacuum. The product was isolated as an off white solid (275 mg). (LC/MS: Rt 2.96, [M+H]+ 262.91).
Reaction SMILES: C=O.[CH:3]1([N:6]2[C:10]3[C:11]([O:29][C@@H:30]([C@@H:32]4[CH2:36][C:35](=[O:37])[NH:34][CH2:33]4)[CH3:31])=[N:12][C:13]([C:15]4[CH:23]=[C:22]5[C:18]([C:19]6([CH2:28][NH:27][CH2:26]6)[C:20](=[O:25])[N:21]5[CH3:24])=[CH:17][CH:16]=4)=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:5][CH2:4]1.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O.C(OCC)(=O)C>[CH:3]1([N:6]2[C:10]3[C:11]([O:29][C@@H:30]([C@@H:32]4[CH2:36][C:35](=[O:37])[NH:34][CH2:33]4)[CH3:31])=[N:12][C:13]([C:15]4[CH:23]=[C:22]5[C:18]([C:19]6([CH2:26][N:27]([CH3:38])[CH2:28]6)[C:20](=[O:25])[N:21]5[CH3:24])=[CH:17][CH:16]=4)=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:5][CH2:4]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C[C@@H](Oc1nc(-c2ccc3c(c2)N(C)C(=O)C32CNC2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](Oc1nc(-c2ccc3c(c2)N(C)C(=O)C32CN(C)C2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Formaldehyde in water (37%, 0.07 mL, 0.89 mmol) was added to a mixture of 6′-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-1′-methylspiro[azetidine-3,3′-indolin]-2′-one 3.85 (42 mg, 0.089 mmol) in 1,2-dichloroethane (1.5 mL). After 15 min, sodium triacetoxyborohydride (78 mg, 0.37 mmol) was added and mixture stirred at room temperature overnight. The reaction mixture was then diluted with water and ethyl acetate. The phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel column chromatography (0-20% methanol in dichloromethane) to afford 6′-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-1,1′-dimethylspiro[azetidine-3,3′-indolin]-2′-one 3.86.
Reaction SMILES: CN(C)C(=O)C.C1(S([O-])(=O)=O)C=CC=CC=1.[CH3:17][S:18]([N:21]1[CH:25]=[C:24]2[CH2:26][NH2+:27][CH2:28][C:23]2=[N:22]1)(=[O:20])=[O:19].[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[C@@H:37]1[C@@H:42]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:41][C:40](=O)[CH2:39][O:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[C@@H:37]1[C@@H:42]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:41][C@@H:40]([N:27]2[CH2:26][C:24]3[C:23](=[N:22][N:21]([S:18]([CH3:17])(=[O:19])=[O:20])[CH:25]=3)[CH2:28]2)[CH2:39][O:38]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(=O)CO[C@@H]1c1cc(F)ccc1F
Reactant: CS(=O)(=O)n1cc2c(n1)C[NH2+]C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])c1ccccc1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(S(C)(=O)=O)nc3C2)CO[C@@H]1c1cc(F)ccc1F
Temperature: 5 °C
Reaction time: 5 h

Procedure:
A vessel was charged with N,N-dimethylacetamide (520.6 kg), 2-(methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-5-ium benzenesulfonate (intermediate 2, 30.0 kg, 86.8 mol), and tert-butyl [(2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl]carbamate (intermediate 1, 31.2 kg, 95.3 mol). After dissolving at room temperature, the solution was cooled to 0-10° C. and sodium triacetoxyborohydride (24 kg, 113 mol) was added in four equal portions every 40 min. The reaction was then allowed to warm to room temperature and stirred an additional 5 h. The solution was then cooled to 5-15° C. and water (672 kg) was added over 1-2 h. The resulting slurry was filtered and the cake washed sequentially with N,N-dimethylacetamide, twice with water, and then n-heptane. The solids were dried under vacuum at 40-60° C. to give tert-butyl {(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][N:14]([C:18]([NH:20][C:21]4[CH:28]=[CH:27][C:24]([CH2:25][Cl:26])=[CH:23][CH:22]=4)=[O:19])[CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH3:30]>CN(C)C=O>[Cl-:26].[CH2:29]([N+:31]1([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([NH:20][C:18]([N:14]3[CH2:13][CH2:12][C:11]4[C:16](=[CH:17][C:8]([C:5]5[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=5)=[CH:9][CH:10]=4)[CH2:15]3)=[O:19])=[CH:22][CH:23]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH3:30]
Reactant: Cc1ccc(-c2ccc3c(c2)CN(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: CCN1CCCCC1
Solvent: CN(C)C=O
Product: CC[N+]1(Cc2ccc(NC(=O)N3CCc4ccc(-c5ccc(C)cc5)cc4C3)cc2)CCCCC1
Product: [Cl-]

Procedure:
A solution of 4-(7-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinolin-2-ylcarbonylamino)benzyl chloride (0.2 g) and 1-ethylpiperidine (0.21 ml) in dimethylformamide (5 ml) was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was evaporated to remove the solvent and was mixed with ethyl acetate, and the precipitate was collected by filtration to obtain 1-ethyl-1-(4-((7-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinolin-2-yl)carbonylamino)benzyl)piperidinium chloride (compound 30) (0.24 g) as a light red, amorphous substance.
Reaction SMILES: [Zn:1].[N+:2]([O-:5])([OH:4])=[O:3]>O>[N+:2]([O-:5])([O-:4])=[O:3].[Zn+2:1].[N+:2]([O-:5])([O-:4])=[O:3]
Reactant: [Zn]
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=[N+]([O-])[O-]
Product: [Zn+2]

Procedure:
The zinc-loaded organic 13 is fed to the solvent stripping stage 14 where it is mixed with recycle nitric acid 15 obtained from scrubber 16 to form a zinc nitrate solution by virtue of water 18 being fed to scrubber 16 to form nitric acid by combining with NOx (g) 19A formed during thermo-hydrolysis at stage 19.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]2[CH:27]=[CH:26][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([Cl:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[O:13])=[CH:10][C:9]=2Br)[CH2:3]1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C(Cl)Cl.CCCCCC>[NH2:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]2[CH:27]=[CH:26][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([Cl:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[O:13])=[CH:10][C:9]=2[C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)[CH2:3]1
Reactant: OB(O)c1cncnc1
Reactant: N[C@H]1CN(c2ccc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2Br)C[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: COCCOC
Product: N[C@H]1CN(c2ccc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2cncnc2)C[C@@H]1O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
4-((3S,4S)-3-amino-4-hydroxypyrrolidin-1-yl)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)benzamide (Stage 245.1, 60 mg, 0.121 mmol), 5-pyrimidineboronic acid (22.46 mg, 0.181 mmol) and Na2CO3 aq. (0.181 mL, 0.362 mmol) were added to a vial containing DME (1.5 mL) under argon atmosphere. PdCl2(dppf)-(CH2Cl2) (5.92 mg, 7.25 μmol) was added. The RM was stirred at 80° C. for 2 h, then filtered through Hyflo® and the solvent was evaporated off under reduced pressure to give the crude product which was purified by preparative HPLC (Condition 14). Fractions containing the product were combined, treated with sat. aq. Na2CO3 and the MeCN was removed. The aq. residue was extracted with DCM and the combined extracts were dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to give a residue that was suspended in DCM/n-hexane. The obtained solid was filtered off and washed with n-hexane then purified by SFC. The residue diluted with sat. aq. Na2CO3 (20 mL) and DCM (20 mL). Aq. phase was extracted with DCM (2×10 mL) and with EtOAc (3×10 mL). The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to afford the title product as a beige solid. HPLC (Condition 10) tR=5.77 min, UPLC-MS (Condition 3) tR=0.79 min, m/z=476.1/478.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.65-2.73 (m, 2H) 3.09-3.15 (m, 1H) 3.21-3.30 (m, 2H) 3.71-3.79 (m, 1H) 5.00 (d, J=3.50 Hz, 1H) 6.95 (d, J=8.99 Hz, 1H) 7.34 (d, J=8.20 Hz, 2H) 7.83-7.90 (m, 3H) 7.94 (dd, J=8.60, 2.30 Hz, 1H) 8.86 (d, J=0.78 Hz, 2H) 9.17 (d, J=1.17 Hz, 1H) 10.10 (s, 1H).
Reaction SMILES: N[C:2]1[S:3][C:4]([C:14]2[N:23]=[CH:22][C:21]3[N:20]([CH3:24])[C:19](=[O:25])[C@@H:18]([CH2:26][CH3:27])[N:17]([CH:28]([CH3:30])[CH3:29])[C:16]=3[N:15]=2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1.[Cu](C#N)[C:32]#[N:33].N(OCCC(C)C)=O>C(#N)C>[CH2:26]([C@H:18]1[N:17]([CH:28]([CH3:29])[CH3:30])[C:16]2[N:15]=[C:14]([C:4]3[S:3][C:2]([C:32]#[N:33])=[N:6][C:5]=3[C:7]3[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=3)[N:23]=[CH:22][C:21]=2[N:20]([CH3:24])[C:19]1=[O:25])[CH3:27]
Reactant: N#C[Cu]C#N
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3sc(N)nc3-c3ccc(F)cc3)nc2N1C(C)C
Agent: CC(C)CCON=O
Solvent: CC#N
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3sc(C#N)nc3-c3ccc(F)cc3)nc2N1C(C)C
Reaction time: 1 h

Procedure:
To a solution of (R)-2-(2-amino-4-(4-fluorophenyl)thiazol-5-yl)-7-ethyl-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 318, 0.25 g, 0.586 mmol) and copper cyanide (0.054 g, 0.598 mmol) in 19 mL of anhydrous acetonitrile, isoamyl nitrite (0.1 ml, 0.751 mmol) was added. The reaction was placed in an oil bath set at 90° C. under condenser with N2 (g) inlet. The reaction mixture was stirred for 1 h, then cooled and quenched with water and extracted with EtOAc. The organic phase was collected, dried with sodium sulfate, filtered and concentrated. The resulting material was purified by preparative HPLC to give the title compound. LCMS: 437.1 m/z (M+H)+; ret. Time: 7.85 min (Analytical Method A). 1H NMR (CDCl3) δ: 7.83 (s, 1H), 7.69 (d, J=6 Hz, 1H), 7.67 (d, J=6 Hz, 1H), 7.15 (d, J=8 Hz, 1H), 7.13 (d, J=8 Hz, 1H), 4.33-4.28 (m, 1H), 4.20-4.14 (m, 1H), 3.37 (s, 3H), 2.07-2.02 (m, 1H), 1.94-1.85 (m, 1H), 1.24 (d, J=7 Hz, 3H), 1.13 (d, J=7 Hz, 3H), 0.84 (t, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21]COC)[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(CO[Si](C)(C)C(C)(C)C)cccc1OCOC
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(O)cccc1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Yield: 41.5 %

Procedure:
Ethyl 2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-(methoxymethoxy)benzoate (Intermediate 177, 950 mg, 2.68 mmol) was dissolved in dichloromethane (30 ml), the solution was cooled to 0° C. and trifluoroacetic acid (2 ml) was added. After 3 h stirring at 0° C. water (20 ml) was added at 0° C. and two phases were separated. The organic layer was dried over Na2SO4 and evaporated in vacuo to afford a colourless oil that was purified by flash chromatography (Biotage system) on silica gel using cyclohexane to cyclohexane/ethyl acetate 7:3 as eluents affording the title compound (0.345 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][N:6]=1)=[O:4].[H-].[Na+].[CH3:18][Si:19]([CH2:22][CH2:23][O:24][CH2:25]Cl)([CH3:21])[CH3:20]>C1COCC1.CCOC(C)=O>[C:10]1([C:8]2[N:7]([CH2:25][O:24][CH2:23][CH2:22][Si:19]([CH3:21])([CH3:20])[CH3:18])[N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:9]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccccc2)n(COCC[Si](C)(C)C)n1
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of 5-phenyl-1H-pyrazole-3-carboxylic acid methyl ester (250 mg, 1.236 mmole) in THF (5 mL) was added NaH (60% dispersion in mineral oil, 60 mg, 1.500 mmole) portionwise at RT. After gas evolution had ceased SEMCl (0.263 mL, 1.484 mmol) was added. After stirring overnight the mixture was diluted with EtOAc, filtered through a pad of Celite washing with EtOAc, and concentrated. Flash column (Biotage-SNAP-25 g SiO2, 0-20% EtOAc/hexanes) gave methyl 5-phenyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-3-carboxylate (380 mg, 92%) as a clear oil. 1H NMR (399 MHz, CDCl3): δ 7.64 (dd, J=7.3, 1.9 Hz, 3 H); 7.46 (d, J=7.4 Hz, 3 H); 6.94 (s, 1 H); 5.49 (s, 2 H); 3.96 (s, 3 H); 3.80-3.71 (m, 3 H); 0.97-0.88 (m, 2 H); 0.02 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:28]=1)[CH3:2].C(OO)(=[O:36])C.C(O)(=O)C.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(OCC)(=O)C.O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[CH:12][C:11]=3[N+:10]([O-:36])=[CH:9][C:8]=2[N:28]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC(C)(C)O
Reactant: CC(=O)OO
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCOCc1nc2c[n+]([O-])c3cc(OCCNC(=O)OC(C)(C)C)ccc3c2n1CC(C)(C)O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-{[2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate (2.9 g, 6.32 mmol) was dissolved in ethyl acetate (25 mL). 32% Peracetic acid in acetic acid (1.99 mL, 9.48 mmol) was added to the solution and the mixture was heated to 50° C. for 2 hours. Another 0.5 mL of the peracetic acid solution (2.37 mmol) was added and the reaction was stirred for 1 hour. A solution of sodium metabisulfite in water (1.5 g in 3.0 mL) was added in two portions and the reaction mixture was stirred for 10 minutes. The heat was then removed and the solution was brought to pH≈10 with saturated aqueous sodium carbonate (˜15 mL). The resulting precipitate was filtered, washed with ethyl acetate (10 mL) and water (10 mL), and dried under vacuum to afford 2.8 g of tert-butyl 2-{[2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-5-oxido-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethylcarbamate as a white paper-like solid with some water remaining.
Reaction SMILES: C(O)(=O)C.Br[CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[CH2:9][CH:10]=O.[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16]>C(O)C.O>[CH3:16][CH:15]([CH3:17])[CH2:14][N:18]1[CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[CH:7]=[CH:6]1
Reactant: CC(C)(CC=O)CCBr
Reactant: CC(C)CN
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(C)CN1C=CC(C)(C)CC1
Yield: 92.7 %

Procedure:
Acetic acid was added to a mixture of ethanol (40 ml) and water (20 ml) until the pH was 4. 5-Bromo-3,3-dimethylpentanal (19.3 g, 0.1 mol) was added to the mixture, which was then cooled to 0°-5° C. and purged with nitrogen. Isobutylamine (7.3 g, 0.1 mol) was added over 5 minutes to the solution stirring under an atmosphere of nitrogen. After 3 hours stirring at 0°-5° C., most of the ethanol was removed under reduced pressure, the residue then diluted with water (20 ml) and the solution taken to pH 10 with solid potassium carbonate. The mixture was extracted with ether (3×50 ml), the organic layer dried over anhydrous MgSO4 and concentrated to yield a pale yellow oil (15.5 g, 93%) which was essentially pure by 1H NMR spectroscopy. A pure colourless liquid (13.0 g, 78%) was obtained after vacuum distillation, b.p. 50°-53° C./2 mm Hg. The 1H NMR spectrum was found to be the same as for material prepared by the procedure hereafter described in Example 25 Part (C).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]1[NH:17][C:18]2[C:23]([C:24]=1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[CH:22][CH:21]=[C:20]([C:31]([O:33]C)=[O:32])[CH:19]=2)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:35](Br)[CH:36]=[CH2:37]>CN(C=O)C.C1COCC1.CO.[OH-].[Na+]>[CH2:37]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([C:31]([OH:33])=[O:32])[CH:19]=2)[C:24]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[C:16]1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:10]=1[C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH:36]=[CH2:35]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cnccc3C(=O)OC(C)(C)C)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CN(C)C=O
Product: C=CCn1c(-c2cnccc2C(=O)OC(C)(C)C)c(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (19.5 mg of 60% dispersion in mineral oil, 0.488 mmol) in DMF (2 mL), methyl 2-(4-(tert-butoxycarbonyl)pyridin-3-yl)-3-cyclohexyl-1H-indole-6-carboxylate (100 mg, 0.222 mmol) was added and the reaction mixture was stirred at rt for 10 min. Allyl bromide (0.040 mL, 0.466 mmol) was then added, and the reaction mixture was stirred at rt for 3 hr. It was then quenched by the addition of water and acidified using 1N HCl solution. A yellowish precipitate formed which was collected by filtration to give the crude ester product in sufficient purity to proceed to the next step. This material was then dissolved in a THF/Methanol mixture (3 mL/3 mL) and 2N NaOH solution (2 mL) was added. The reaction mixture was heated at 100° C. under microwave conditions for 15 min. It was then concentrated and the pH was adjusted to 4–5 using 1N HCl solution. This mixture was then extracted using ethyl acetate and the organic layer was dried with MgSO4, filtered and evaporated and the resultant residue was purified using Prep. reverse phase HPLC to afford the title compound as a yellow solid, (50 mg, 44% yield two steps). MS m/z 516(MH+); 1H NMR (500 MHz, CD3OD) □ ppm 1.22–1.48 (m, 13 H) 1.70–2.02 (m, 5 H) 2.15 (m, 1 H) 2.37 (m, 1 H) 3.88 (dd, J=16.63, 5.04 Hz, 1 H) 4.13 (m, 1 H) 4.51 (m, 1 H) 4.76 (m, 1 H) 4.87 (m, 1 H) 5.04–5.21 (m, 3 H) 5.79 (m, 1 H) 5.97 (m, 1 H) 7.58 (d, J=5.80 Hz, 1 H) 7.78 (m, 1 H) 7.90 (d, J=8.24 Hz, 1 H) 8.13 (s, 1 H) 8.50 (s, 1 H) 8.67 (d, J=5.80 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([CH2:10][O:11][C:12](=[O:32])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:8]O)[N:5]=[N:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:52]=[N+]=[N-].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.[C].[Pd].C1C=CC=CC=1>[CH3:1][C:2]1[N:6]([CH:7]([CH2:10][O:11][C:12](=[O:32])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:8][NH2:52])[N:5]=[N:4][N:3]=1
Reactant: [N-]=[N+]=N
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)n1nnnc1C
Agent: [Pd]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)n1nnnc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a stirred solution of 1.02 g (2.25 mM) of 2-(5-methyl-1H-tetrazol-1-yl)-3-octadecylcarbamoyloxypropanol Vi2, 885 mg (3.38 mM) of triphenylphosphine, and 1.9 ml (3.38 mM) of 1.8 mM benzene solution of hydrazoic acid in 50 ml of tetrahydrofurane at -50° C. is added 0.53 ml (3.38 mM) of diethyl azodicarboxylate dropwise and the mixture is raised to room temperature during 2 hr. Subsequently, 150 mg of 10% palladium carbon is added to the mixture which is stirred under hydrogen gas for 30 minutes. After 10% palldium carbon filtered off, the solvent is evaporated. The residue obtained is purified by column silica gel chromatography using ethyl acetate-choroform/methanol (9/1) mixture as an eluent and 0.82 g (81% yield) of the title compound is obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[CH3:12][N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][CH2:19][NH2:20].[Na]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][NH:20][CH2:19][CH2:18][CH:14]1[CH2:15][CH2:16][CH2:17][N:13]1[CH3:12]
Reactant: CN1CCCC1CCN
Reactant: O=Cc1cc2ccccc2o1
Agent: [Na]
Solvent: ClCCl
Product: CN1CCCC1CCNCc1cc2ccccc2o1
Yield: 32.1 %

Procedure:
Experimental condition analogous to Example 5, from 2-benzofurancarboxaldehyde 0.14 g (1.1 mmol), 2-(1-methyl-pyrrolidin-2-yl)-ethylamine 0.14 g (1 mmol), and sodium triacethoxyborohydride 0.31 g (1.5 mmol), in 10 mL Dichloromethane. Purification using silica chromatography, elution with dichloromethane-methanol-ammonium hydroxide, 9-1-0.25, gave 83 mg of compound.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH2:27][CH:28]2[CH2:31][CH2:30][CH2:29]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[N:32]1[O:36][N:35]=[C:34]2[C:37]([CH2:41][CH2:42][CH2:43][CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[CH:38][CH:39]=[CH:40][C:33]=12.Cl>>[N:32]1[O:36][N:35]=[C:34]2[C:37]([CH2:41][CH2:42][CH2:43][CH:44]3[CH2:49][CH2:48][N:47]([CH2:1][C@@H:3]4[C@@H:7]([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[CH2:6][N:5]([C@H:14]([CH2:27][CH:28]5[CH2:29][CH2:30][CH2:31]5)[C:15]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=5)=[O:16])[CH2:4]4)[CH2:46][CH2:45]3)=[CH:38][CH:39]=[CH:40][C:33]=12
Reactant: c1cc(CCCC2CCNCC2)c2nonc2c1
Reactant: COc1ccc(COC(=O)[C@@H](CC2CCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Agent: Cl
Product: COc1ccc(COC(=O)[C@@H](CC2CCC2)N2C[C@H](CN3CCC(CCCc4cccc5nonc45)CC3)[C@@H](c3ccccc3)C2)cc1
Yield: 40.7 %

Procedure:
The title compound was prepared from 20 mg (0.07 mmol) of 2-(R)-(3-(R)formyl-4-(S)-phenylpyrrolidin-1-yl)-3-(cyclobutyl)propanoic acid, (4-methoxy)benzyl ester (from EXAMPLE 19, Step F) and 13.7 mg (0.04 mmol) of 4-(3-(benzofurazanyl)propyl)piperidine.HCl (from EXAMPLE 117, Step B) using a procedure analogous to that described in EXAMPLE 1, Step J to provide 10.6 mg (35%) of the title compound: RF: 0.36 (1:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 0.80-3.32 (m, 33H), 3.80 (s, 31), 5.04-5.13 (m, 2H), 6.88 (d, J=8.6, 21), 7.15-7.37 (m, 8H), 7.51 (s, 1H), 7.73 (d, J=9.3, 1H).
Reaction SMILES: [Li][C:2]([CH3:5])([CH3:4])[CH3:3].CCCCC.F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:19][CH2:20][C:21]([CH3:24])([CH3:23])[N:22]=1>C1COCC1>[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:19][CH2:20][C:21]([CH3:24])([CH3:23])[N:22]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: [Li]C(C)(C)C
Reactant: CC1(C)COC(c2ccccc2F)=N1
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC1(C)COC(c2ccccc2C(C)(C)C)=N1
Reaction time: 0.33 h
Yield: 93 %

Procedure:
A 1.7M solution of t-BuLi in pentane (161 mL, 274 mmol) was added dropwise to a solution of 2-(2-fluorophenyl)-4,4-dimethyl-2-oxazoline [cf. Meyers A. I. and Williams B. E., Tetrahedron Letters, 223-226(1978)] (48.0 g., 249 mmol) in THF (320 mL), maintaining the reaction temperature between −45 and −40° C. with a dry-ice/acetone cooling bath. The resulting reaction mixture was maintained at ≦−40° C. with a dry-ice/acetonitrile bath, and monitored to completion by GLC over 20 min. This mixture was poured onto ice and extracted three times with ether. These extracts were combined, dried (MgSO4), concentrated and distilled under vacuum to afford 56.87 g of 2-(2-tert-butylphenyl)-4,4-dimethyl-2-oxazoline, a 93% yield.