Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])/[CH:4]=[CH:5]/[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1
Reactant: COC(=O)/C=C/c1ccc(C(=O)O)c2ccccc12
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1ccc(C(=O)O)c2ccccc12
Reaction time: 8 h
Yield: 289.1 %

Procedure:
4-[(1E)-3-(Methyloxy)-3-oxo-1-propen-1-yl]-1-naphthalenecarboxylic acid (for example as prepared for Intermediate 5) (4 g, 5.09 mmol) in 500 mL ethanol was hydrogenated over palladium on carbon (10 wt %, 1 g) for about 2 h. The catalyst was removed by filtration through Celite, the solvent evaporated and the resultant solid left overnight under vacuum to afford the title compound (3.8 g). ES+ve m/z 258 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:26]([O:25][C:23](=[O:24])[CH:22]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1)[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A mixture of tert-butyl 4-oxopiperidine-1-carboxylate 165a (10.0 g, 50.2 mmol) and ethyl 2-(triphenylphosphoranylidene)acetate (26.2 g, 75.3 mmol) in toluene (200 mL) was stirred at 100° C. for 1 h. See FIG. 6. The mixture was concentrated and purified by column chromatography on silica gel (petroleum ether:ethyl acetate=10:1) to afford tert-butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate 165b (12.6 g, 93%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 5.72 (s, 1H), 4.16 (q, J=7.2 Hz, 2H), 3.52-3.45 (m, 4H), 2.94 (t, J=5.6 Hz, 2H), 2.28 (t, J=5.6 Hz, 2H), 1.48 (s, 9H), 1.29 (t, J=7.6 Hz, 3H).
Reaction SMILES: C([O:5]O)(C)(C)C.[C:7]1([CH2:13][CH2:14][CH:15]=[CH:16][CH2:17][OH:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[O:5]1[C@@H:15]([CH2:14][CH2:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@@H:16]1[CH2:17][OH:18]
Reactant: OCC=CCCc1ccccc1
Reactant: CC(C)(C)OO
Product: OC[C@@H]1O[C@H]1CCc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a 1L 3-neck round-bottom flask equipped with a mechanical stirrer, thermocouple and nitrogen inlet was added CH2C12 (350 mL), dried 4 Å molecular sieves (30 g) and L-(+)-diethyl tartrate (7.62 g, 0.037 mol). The resulting mixture was cooled to -20° C. and treated with Ti(O-i-Pr)4 (9.2 mL, 0.031 mol), followed by the addition of t-butylhydroperoxide (4.0 M in CH2Cl2, 182 mL, 0.78 mol) at a rate to maintain the temperature 2 -20° C. Upon complete addition, the reaction mixture was stirred for another 30 min, and then treated with a solution of the allylic alcohol (15) (50 g, 0.31 mol) in CH2C12 (30 mL) at a rate to maintain the temperature at -20° C. The reaction was stirred at the same temperature for 5 h, then filtered into a solution of ferrous sulfate heptahydrate (132 g) and tartaric acid (40 g) in water (400 mL) at 0° C. The mixture was stirred for 20 min, then transferred to a separatory funnel and extracted with t-BuOMe (2×200 mL). The combined organic phase was stirred with 30% NaOH solution containing NaCi, for 1 h at 0° C. The layers were again separated, and the aqueous phase extracted with t-BuOMe. The combined organic phase was washed with brine, dried over MgSO4 and concentrated to yield the title compound (52.8 g) as an amber oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([C:24]1[S:28][C:27]([CH2:29][NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:30]([CH2:29][C:27]1[S:28][C:24]([CH2:22][CH3:23])=[CH:25][CH:26]=1)[C:31]1[CH:32]=[CH:33][C:34]([CH:37]([CH3:38])[CH3:39])=[CH:35][CH:36]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: CCc1ccc(CNc2ccc(C(C)C)cc2)s1
Product: CCc1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)s1
Yield: 48.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.13 g) and [(5-ethylthiophen-2-yl)methyl](4-isopropylphenyl)amine (1.04 g) as starting materials, 5-benzyloxy-N-[(5-ethylthiophen-2-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.01 g) was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1.[OH-].[K+]>N1CCCCC1.C(O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:19]=[C:26]1[C:25]2[C:29](=[CH:30][C:22]([Cl:21])=[CH:23][CH:24]=2)[NH:28][C:27]1=[O:31])([OH:16])=[O:15]
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Reactant: O=C1Cc2ccc(Cl)cc2N1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)O)[nH]c(C=C2C(=O)Nc3cc(Cl)ccc32)c1CCC(=O)O
Temperature: 95 °C
Yield: 72.1 %

Procedure:
5-Formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (281 mg), 6-chloro-2-oxindole (168 mg) and piperidine (2 drops) in ethanol (2 mL) were stirred at 90° C. for 2 hours. Potassium hydroxide (537 mg) was added to the mixture and it was then stirred at 95° C. for and additional hour. The reaction mixture was cooled and concentrated. The residue was dissolved into water and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 270 mg (72%) of 4-(2-carboxy-ethyl)-3-methyl-5-(6-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C:10]([C:20](O)=[O:21])=[C:11]([CH2:15][O:16][CH2:17][CH2:18][Cl:19])[NH:12][C:13]=1[CH3:14])=[O:7])#[N:2].CCN=C=NCCCN(C)C.Cl.[C:42]1([CH:48]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:49][CH2:50][NH2:51])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl>[C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C:10]([C:20](=[O:21])[NH:51][CH2:50][CH2:49][CH:48]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[C:11]([CH2:15][O:16][CH2:17][CH2:18][Cl:19])[NH:12][C:13]=1[CH3:14])=[O:7])#[N:2]
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)O)=C(COCCCl)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)NCCC(c2ccccc2)c2ccccc2)=C(COCCCl)N1

Procedure:
250 mg (0.560 mmol) of 2-(2-chloroethoxy) methyl-4-(3-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid 5-(2-cyanoethyl) ester, 110 mg (0.570 mmol) of WSC hydrochloride and 120 mg (0.570 mmol) of 3,3-diphenylpropylamine were stirred at room temperature for 15 hours in 4 ml of dichloromethane. After evaporating dichloromethane under reduced pressure, 0.1 N hydrochloric acid was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/1) to obtain the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([C:11]([C:13]2[CH:22]=[C:21]([CH3:23])[C:16]3[NH:17][C:18](=[O:20])[O:19][C:15]=3[CH:14]=2)=[O:12])[CH:5]=1.I[CH3:25]>CN(C=O)C>[Cl:3][C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([C:11]([C:13]2[CH:22]=[C:21]([CH3:23])[C:16]3[N:17]([CH3:25])[C:18](=[O:20])[O:19][C:15]=3[CH:14]=2)=[O:12])[CH:5]=1
Reactant: Cc1nc(Cl)cc(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
59 mg (1.4 mmol) sodium hydride (55%, suspension in mineral oil) were added at RT to 0.37 g (1.2 mmol) 6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 5.0 mL DMF. The reaction mixture was stirred for 30 min at RT. Then 0.10 mL (1.60 mmol) iodomethane were added and the mixture was stirred for 1 h at RT. Then another 0.10 mL (1.60 mmol) iodomethane were added and the mixture was stirred overnight at RT. The reaction mixture was diluted with ice water and the precipitate formed was suction filtered. The residue was washed with water and dried i. vac.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:26][NH:27][CH3:28]>>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH2:6][N:27]([CH3:28])[CH3:26])=[C:4]([F:11])[CH:3]=1
Reactant: CNC
Reactant: O=Cc1c(F)cc(Br)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CN(C)Cc1c(F)cc(Br)cc1F
Yield: 80 %

Procedure:
According to procedure for the synthesis of Example A211A, by using 4-bromo-2,6-difluorobenzaldehyde (500 mg, 2.26 mmol), sodium triacetoxyborohydride (959 mg, 4.52 mmol) and 2M dimethylamine solution (2.626 mL, 4.52 mmol) to give the title compound as a colorless oil (452 mg, 79%). 1H NMR (400 MHz, CDCl3) δ 7.09 (d, J=6.8 Hz, 2H), 3.54 (s, 2H), 2.26 (s, 6H); MS ESI 249.9 [M+H]+, calcd for [C9H10BrF2N+H]+ 249.0.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:22][CH3:23])[C:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:24])[CH:3]=1.[NH3:25]>CO>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([C:10]2[C:9]([S:22][CH3:23])=[N:8][N:7]3[C:2]([NH2:25])=[CH:3][C:4]([CH3:24])=[N:5][C:6]=23)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(S(=O)(=O)c2c(SC)nn3c(Cl)cc(C)nc23)cc1
Reactant: N
Solvent: CO
Product: COc1ccc(S(=O)(=O)c2c(SC)nn3c(N)cc(C)nc23)cc1

Procedure:
In an analogous manner to that described in Example 4, from 7-chloro-3-(4-methoxy-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 3-(4-methoxy-benzenesulphonyl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p.>230°.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:11]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:10]([CH3:16])=[N:9][CH:8]=1)=O.C(=O)(O)O.[C:22]1([NH:28][C:29]([NH2:31])=[NH:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C[O-].[Na+].O>CC(N(C)C)=O>[NH:28]([C:29]1[N:31]=[C:5]([C:7]2[N:11]([CH:12]3[CH2:13][CH2:14][CH2:15]3)[C:10]([CH3:16])=[N:9][CH:8]=2)[CH:4]=[CH:3][N:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N=C(N)Nc1ccccc1
Reactant: Cc1ncc(C(=O)C=CN(C)C)n1C1CCC1
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ncc(-c2ccnc(Nc3ccccc3)n2)n1C1CCC1
Temperature: 160 °C
Yield: 33.6 %

Procedure:
5-(3-Dimethylaminoprop-2-en-1-oyl)-1-cyclobutyl-2-methylimidazole (Method 37; 466 mg, 2 mmol), phenylguanidine hydrogen carbonate (434 g, 2.2 mmol) and sodium methoxide (238 mg, 4.4 mmol) were suspended in anhydrous DMA (5 ml) and the mixture heated at 160° C. for 3 hours. The reaction mixture was allowed to cool to ambient temperature and poured into water (50 ml). The solution was extracted EtOAc (2×50 ml). The combined extracts were washed with water (2×50 ml) and then brine (2×50 ml), dried and the volatiles removed by evaporation. The residue was triturated with ether, collected by filtration and air dried to give the title compound (205 mg, 35%) as a brown solid. NMR: 1.63 (m, 2H), 2.35 (m, 4H), 2.53 (s, 3H), 5.5 (m, 1H), 6.96 (d, 2H), 7.28 (m, 4H), 7.70 (d, 2H), 8.39 (d, 1H), 9/45 (s, 1H); m/z 306.
Reaction SMILES: [C:1]([NH:4][O:5][CH2:6][C:7]([NH2:9])=[S:8])(=[O:3])[CH3:2].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)(O)O.C([O-])(=O)C.[Na+]>C(O)(=O)C.C(OC(=O)C)(=O)C>[C:1]([N:4]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:9][C:7](=[S:8])[CH2:6][O:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NOCC(N)=S
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1OCC(=S)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.9 %

Procedure:
1.48 g (10 millimoles) of alpha-(acetylaminooxy)-thioacetamide are dissolved in a mixture of 10 ml of acetic acid and 1.3 ml of acetic anhydride, thereafter 1.3 ml (13 millimoles) of freshly distilled benzaldehyde and then 0.5 ml of concentrated sulfuric acid are added. The mixture is stirred for 3 hours at room temperature, then 2.8 g of crystalline sodium acetate are added, stirred for 10 minutes, thereafter the solvent is evaporated under vacuum. The residue is dissolved in 30 ml of ethyl acetate, the solution is extracted with 20 ml of water. The organic layer is dried over anhydrous sodium sulfate then evaporated to dryness. The residue is crystallized from ethanol at a temperature of +5° C. 1.25 g (52.9%) of crystalline title product are obtained. M.p.: 172°-174° C. Rf (A)=0.43.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[C:5]([NH2:18])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:26][C:27]([F:35])([F:34])[C:28]([F:33])([F:32])[C:29](O)=O>O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]2[NH:18][C:29]([C:28]([F:33])([F:32])[C:27]([F:35])([F:34])[F:26])=[N:19][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2)cc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc3[nH]c(C(F)(F)C(F)(F)F)nc3cc2Cl)cc1
Yield: 52 %

Procedure:
To a solution of 5-chloro-4-iodo-2-nitroaniline (5.0 g, 16.75 mmol) in dioxane (200 ml) was added water (20 ml), Pd(PPh3)4 (924 mg, 0.80 mmol), K3PO4 (7.0 g, 32.98 mmol) and [4-(trifluoromethyl)phenyl]boronic acid (6.3 g, 33.17 mmol) with stirring overnight at 100° C. under nitrogen. The resulting mixture was concentrated under vacuum and dissolved in water (250 ml), extracted with ethyl acetate (3×200 ml) and the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give the residue, which was re-crystallized from 50% ether in hexane to afford 5-chloro-2-nitro-4-[4-(trifluoromethyl)phenyl]aniline as a yellow solid (4.2 g, crude). Next, to a solution of 5-chloro-2-nitro-4-[4-(trifluoromethyl)phenyl]aniline (3.7 g, crude) in ethanol (300 ml) and hydrogen chloride (3.0 ml) was added Zn powder (4.55 g, 70.0 mmol) in several bacthes with stirring for 20 min at room temperature. The resulting solution was stirred for 7 h at 85° C. The solids were filtered out and the filtrate was concentrated under vacuum to give a residue, which was dissolved in water (100 ml). The mixture was adjusted to pH 7 with saturated aqueous sodium carbonate, extracted with ethyl acetate (3×300 ml) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue that was purified by a silica gel column eluted with 10% to 50% ethyl acetate in petroleum ether to produce 4-chloro-5-[4-(trifluoromethyl)phenyl]benzene-1,2-diamine as brown oil (2.9 g,). Finally, the solution of 4-chloro-5-[4-(trifluoromethyl)phenyl]benzene-1,2-diamine (150 mg, 0.52 mmol) in pentafluoropropanoic acid (1 ml) was stirred overnight at 80° C. The result mixture was diluted with water (50 ml) and adjusted to pH 7 with saturated aqueous sodium carbonate. The resulting solution was extracted with ethyl acetate (3×50 ml), combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column eluted with 0.5% to 6.5% ethyl acetate in petroleum ether to produce 5-chloro-2-(pentafluoroethyl)-6-[4-(trifluoromethyl)phenyl]-1H-1,3-benzodiazole as a white solid (112.6 mg, 52%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[F:27][C:28]1[C:36]2[C:35](=O)O[C:33](=O)[C:32]=2[CH:31]=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[CH2:35][N:23]([C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:17][CH2:16]3)[CH:21]=1)[CH2:33]2
Reactant: O=C1OC(=O)c2c(F)cccc21
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5Cc6cccc(F)c6C5)c4)CC3)cccc2n1

Procedure:
Prepared from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 4-fluoro-2-benzofuran-1,3-dione according to Method I.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[C:25]([F:28])([F:27])[F:26]>[F-].[Cs+].Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@@H:21]([OH:22])[C:25]([F:28])([F:27])[F:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Product: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](O)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.7 %

Procedure:
To (2S,3R)-3-(tert-butyldimethylsilanyloxy)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (7C) (2.10 g, 6.38 mmol) was added trimethyl(trifluoromethyl)silane (800 μL, 6.57 mmol) and cesium fluoride (dried under high vacuum at 130° C. for 12 h) (10.0 mg, 0.066 mmol). The reaction was stirred at rt for 24 h then heated to 50° C. for 5 h. After cooling to rt, 4N HCl (ca. 10 mL) was added and the reaction was stirred overnight. The brown aqueous solution was decanted and the remaining waxy yellow solid was dried under high vacuum overnight then recrystallized from hexane to provide (2R,3R)-3-(tert-butyldimethylsilanyloxy)-2-[(1R)-(2,2,2-trifluoro-1-hydroxyethyl)]-pyrrolidine-1-carboxylic acid tert-butyl ester (7D) (1.19 g) as a white solid. The mother liquor was concentrated and purified via flash chromatography eluting with 5-20% EtOAc/hexane to provide (2R,3R)-3-(tert-butyldimethylsilanyloxy)-2-[(1S)-(2,2,2-trifluoro-1-hydroxy-ethyl)]-pyrrolidine-1-carboxylic acid tert-butyl ester (7E) (192 mg) as an oil and a mixture of (2R,3R)-3-(tert-butyldimethylsilanyloxy)-2-[(1R)-(2,2,2-trifluoro-1-hydroxy-ethyl)]-pyrrolidine-1-carboxylic acid tert-butyl ester (7D) and starting material (306 mg). The latter was recrystallized from hexane to provide additional (2R,3R)-3-(tert-butyldimethylsilanyloxy)-2-[(1R)-(2,2,2-trifluoro-1-hydroxy-ethyl)]-pyrrolidine-1-carboxylic acid tert-butyl ester (7D) (100 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](Cl)[N:10]=2)[CH2:5][C:4]([CH3:19])([CH3:18])[NH:3]1.[CH:21]1([C:24]2[CH:25]=[C:26]([NH2:36])[CH:27]=[C:28]([N:31]3[CH:35]=[N:34][N:33]=[N:32]3)[C:29]=2[F:30])[CH2:23][CH2:22]1>CC(O)C>[CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:36][C:26]3[CH:27]=[C:28]([N:31]4[CH:35]=[N:34][N:33]=[N:32]4)[C:29]([F:30])=[C:24]([CH:21]4[CH2:23][CH2:22]4)[CH:25]=3)[N:10]=2)[CH2:5][C:4]([CH3:19])([CH3:18])[NH:3]1
Reactant: CC1(C)CC(Nc2nc(Cl)ncc2C#N)CC(C)(C)N1
Reactant: Nc1cc(C2CC2)c(F)c(-n2cnnn2)c1
Solvent: CC(C)O
Product: CC1(C)CC(Nc2nc(Nc3cc(C4CC4)c(F)c(-n4cnnn4)c3)ncc2C#N)CC(C)(C)N1
Temperature: 60 °C
Yield: 34.8 %

Procedure:
A mixture of 4-(2,2,6,6-tetramethylpiperidin-4-ylamino)-2-chloropyrimidine-5-carbonitrile (112 mg, 0.380 mmol, 1 equiv), 3-cyclopropyl-4-fluoro-5-(1H-tetrazol-1-yl)benzenamine (100 mg, 0.456 mmol, 1.2 equiv), and PTSA monohydrate (58 mg, 0.304 mmol, 0.8 equiv) in IPA (4 mL) were heated to 60° C. for 5 days. After cooling to ambient temperature, the crude mixture was concentrated to dryness. The residue was taken in ice-cold water and EtOAc then adjusted to ca. pH 12-14 with 1N NaOH. The aqueous and organic layers were partitioned, and the aqueous layer was extracted with EtOAc (1×150 mL). The combined organic extracts were dried (Na2SO4), filtered, and the solvent removed under vacuum. The crude product was submitted to the analytical department for purification by reverse-phase HPLC using 0.1% formic acid as a modifier in water and acetonitrile (compound unstable in TFA). The product as the formate salt was taken in ice-cold water and EtOAc then adjusted to ca. pH 12-14 with 1N NaOH. The aqueous and organic layers were partitioned, and the aqueous layer was extracted with EtOAc (2×150 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to give desired compound (63 mg, 35%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]([CH2:16][CH2:17][C:18]([OH:20])=O)[C:5]=2[CH:4]=1.O=S(Cl)[Cl:23]>CO.O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]([CH2:16][CH2:17][C:18]([Cl:23])=[O:20])[C:5]=2[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2c(c1)C(CCC(=O)O)c1ccccc1-2
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)C(CCC(=O)Cl)c1ccccc1-2
Reaction time: 2 h

Procedure:
3-(2-Methoxyfluoren-9-yl)propionic acid (1.6 g, 5.2 mmol) was charged with SOCl2 (20 mL, in excess) at room temperature. The reaction mixture was boiled for 2 hr. The reaction was monitored by TLC (silica RP-18, 70% methanol/water). The excess of thionyl chloride was removed under reduced pressure, the residue (an oil) was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH:29]=[O:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[O-:32][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([OH:32])=[O:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2C=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2C(=O)O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2-formylphenyl)-L-phenylalanine methyl ester (104 mg) was dissolved in acetone (700 μL) by warming up to about 40° C. A warm (40° C.) solution of KMnO4 (61.2 mg) in a mixture of acetone (900 μL) and water (130 μL) was then added over a 1 h period and the resulting mixture was stirred at that temperature for an additional 2 h. The mixture was filtered through Celite and washed with acetone. The filtrate was taken up with water and acidified to approximately pH 2 with 1N HCl, and extracted with EtOAc. The combined extracts were dried (MgSO4) and evaporated. The residue was purified through a silica gel column using toluene then a gradient of toluene/EtOAc (20:1 to 3:1) as an eluent to give N-(2,6-dichlorobenzoyl)-4-(2-carboxyphenyl)-L-phenylalanine methyl ester (85.0 mg). ESMS: m/z 472 (MH+).