Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1N=[CH:4][N:3]([C:6]([N:8]2[CH:12]=[N:11][CH:10]=[CH:9]2)=[O:7])[CH:2]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:16]=[N:17][C:18]2CCNC[C:23]=2[CH:24]=1>C1COCC1.C(Cl)Cl>[N:8]1([C:6]([N:3]2[CH2:2][CH2:1][C:18]3[N:17]=[CH:16][C:15]([C:14]([F:26])([F:25])[F:13])=[CH:24][C:23]=3[CH2:4]2)=[O:7])[CH:9]=[CH:10][N:11]=[CH:12]1
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(N1CCc2ncc(C(F)(F)F)cc2C1)n1ccnc1
Temperature: 60 °C
Yield: 88.5 %

Procedure:
To a suspension of CDI (0.949 g, 5.86 mmol) in THF (10 mL) was added 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthyridine (0.988 g, 4.88 mmol) and the reaction mixture was heated at about 60° C. for about 16 h. The reaction mixture was cooled at ambient temperature and concentrated in vacuo to afford a light orange solid. The residue was dissolved in DCM (10 mL), washed with water (2×10 mL), and the organic portion was separated, dried over MgSO4, filtered, and concentrated in vacuo to give imidazol-1-yl-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-methanone (1.28 g, 88%) as a yellow solid which was used in subsequent reactions without further purification. RP-HPLC (Table 1, Method d) Rt 2.10 min; m/z: (M+H)+ 297.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([O:19]CC)=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[CH:10][C:11]=1[F:12].[OH-].[Li+]>C1COCC1.C(O)C>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([OH:19])=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)c(F)ccn12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nc2c(OCc3c(F)cccc3F)c(F)ccn2c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
365 mg (0.76 mmol; purity about 76%) of ethyl 8-[(2,6-difluorobenzyl)oxy]-7-fluoro-2-methylimidazo[1,2-a]pyridine-3-carboxylate Example 111A were dissolved in 16.6 ml of THF/ethanol (5:1), 1.14 ml (1.14 mmol) of 1 N aqueous lithium hydroxide solution were added and the mixture was stirred at RT overnight. Another 2.67 ml (2.67 mmol) of 1 N aqueous lithium hydroxide solution were added, and the mixture was stirred at RT overnight. The mixture was concentrated and the aqueous phase was acidified to pH 4 using 6 N hydrochloric acid. A precipitate formed, and the suspension was cooled with ice water. The solid was filtered off and dried under high vacuum. This gave 236 mg of the target compound (87% of theory, purity 94%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].C(O[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17])C.C(N(CC)CC)C>CO>[NH2:19][C:18]1[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH3:2])[N:10]=[CH:14][C:15]=1[C:16]#[N:17]
Reactant: CCOC=C(C#N)C#N
Reactant: Cc1ccccc1NN
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccccc1-n1ncc(C#N)c1N

Procedure:
10.2 g (64.4 mmol) of 2-methylphenylhydrazine hydrochloride are suspended with 7.8 g (64.4 mmol) of ethoxymethylenemalononitrile in 100 ml of methanol, and 26.9 ml (193.3 mmol) of triethylamine are added. The reaction mixture is heated to reflux overnight, during which a clear solution forms. The solution is subsequently distilled off under reduced pressure, and the crude product is purified by column chromatography (silica gel, mobile phase dichloromethane). 10.8 g (85% of theory) of the desired product are obtained.
Reaction SMILES: N1(C(N2C=CN=C2)=O)C=CN=C1.[C:13]([OH:17])(=O)[C:14]#[CH:15].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26](=[O:36])[CH2:27][C:28]1[NH:29][C:30]([CH3:35])=[C:31]([CH2:33][CH3:34])[N:32]=1>C1COCC1>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26]([C:27]1[CH:15]=[CH:14][C:13](=[O:17])[N:29]2[C:30]([CH3:35])=[C:31]([CH2:33][CH3:34])[NH:32][C:28]=12)=[O:36]
Reactant: C#CC(=O)O
Reactant: CCc1nc(CC(=O)c2ccc(F)cc2F)[nH]c1C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCc1[nH]c2c(C(=O)c3ccc(F)cc3F)ccc(=O)n2c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
552 mg (3.40 mmol) of 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole and 199 mg (2.83 mmol) of propiolic acid are dissolved in 25 ml THF. The mixture is stirred for 3 h at rt. To this solution are added 500 mg (1.89 mmol) of 1-(2,4-Difluorophenyl)-2-(4-ethyl-5-methyl-1H-imidazol-2-yl)ethanone (example XIII) and the mixture is refluxed for 24 h. The solvent is evaporated under vacuum and the crude is purified over preparative HPLC (RP18-Column, Eluent: acetonitrile-water-gradient). The regioisomers are isolated after purification over preparative HPLC (Daicel Chiralpak AD, eluent: iso-hexane-ethanol v/v 60:40).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]([NH:16][C:17](=[NH:20])[S:18][CH3:19])=O)[N:7]=3.Cl.[CH:24]([NH:27]N)([CH3:26])[CH3:25]>C(O)(=O)C>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[N:10]([CH:9]=[C:8]([C:14]4[N:27]([CH:24]([CH3:26])[CH3:25])[N:20]=[C:17]([S:18][CH3:19])[N:16]=4)[N:7]=3)[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: CC(C)NN
Reactant: CSC(=N)NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: Cl
Solvent: CC(=O)O
Product: CSc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1

Procedure:
1-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carbonyl)-2-methyl-isothiourea (27 mg, 0.068 mmol) was heated with isopropylhydrazine hydrochloride (23 mg, 0.20 mmol) in acetic acid (0.9 mL) at 100° C. overnight. The mixture was concentrated and the crude residue purified by reverse-phase HPLC to give 240. LCMS EI: 422.1
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1.C[CH2:27][N:28](C(C)C)C(C)C.Cl.C(=N)OC(C)C>CO>[CH:27](=[NH:28])[NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C:9]([NH:11][C@H:12]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([OH:24])=[O:23])[C:15]=3[O:14][B:13]2[OH:25])=[O:10])[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)OC=N
Agent: Cl
Solvent: CO
Product: N=CN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-3-(2-(trans-4-aminocyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid (Example 6) in MeOH was added DIEA (2.5 eq), followed by isopropyl formimidate hydrochloride (1.2 eq). The reaction mixture was stirred at RT overnight. The mixture was then concentrated in vacuo and the crude product was purified using reverse phase HPLC to afford the title compound. ESI-MS m/z 374 (MH)+.
Reaction SMILES: [C:1](=[O:4])(O)[O-].[Na+].O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]=[C:1]=[O:4])[CH3:15])=[CH:10][CH:9]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: O=C([O-])O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@H](N=C=O)c1ccc(Br)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
To a 10 L jacketed reactor was charged 241 g of sodium bicarbonate (2.87 mol, 2.30 equiv) and 5 L of deionized water. The resulting solution was agitated for 10-20 min, until the solids dissolved (homogeneous). To the clear solution was charged 250 g (1.25 mol, 1.00 equiv) of (S)-(−)-1-(4-bromophenyl)ethylamine as a solution in 1.00 L of dichloromethane. An additional 4 L of dichloromethane was charged to the reactor. The biphasic solution was agitated and cooled to Tint=2-3° C. Triphosgene (126 g, 424 mmol, 0.340 equiv) was charged to the reactor in approximately two equal portions ˜6 min apart. It should be noted that a slight exotherm was noted upon the addition of triphosgene. The resulting murky solution was agitated at Tint=2-5° C. for 30 min, at which point HPLC analysis indicates >99 A % conversion (220 nm). The dichloromethane layer was cut and dried with anhydrous sulfate. The resulting solution was passed through a celite plug and concentrated to ˜1.5 L which fine particles of a white solid developed. The solution was filtered and concentrated to a thick oil via reduced pressure to produce 239 g of 1-bromo-4-((S)-1-isocyanato-ethyl)-benzene (93.7 wt %, 79.4% yield). 1H-NMR spectroscopy (400 MHz, CD2Cl2) δ 7.53 (d, J=11.4 Hz, 2 H), 7.26 (d, J=8.2 Hz, 2 H), 4.80 (q, J=6.7 Hz, 1H), 1.59 (d, J=6.7 Hz, 3 H). The material was used in Step 3 without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=CC=1)([O-])=O.[F:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[C:16]1=[N:17][CH:18]=[CH:19][CH:20]=[C:15]1[CH2:14]2>C1(C)C(C)=CC=CC=1.[Pd]>[F:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[C:16]1=[N:17][CH:18]=[CH:19][CH:20]=[C:15]1[CH2:14]2.[CH2:4]1[NH:1][CH2:7][CH2:8][CH2:9]1
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Pd]
Agent: Fc1ccc2c(c1)Cc1cccnc1-2
Solvent: Cc1ccccc1C
Product: C1CCNC1

Procedure:
The process typically involves the addition of 1.1 molar equivalents of the enamine to 1 molar equivalent of bromopropylamine hydrobromide in dimethylformamide at elevated temperature until the exothermic reaction is initiated wherein the temperature is kept at 90°-120° C. for several hours. The product is isolated by a combination of acidification and ether washing followed by basification and ether extractions. Evaporation yields the tetrahydroimine product such as: ##STR60## The tetrahydroimine product is aromatized in xylene and nitrobenzene and 10% palladium on charcoal according to Parcell and Hauch, ibid. The resulting product, e.g., 7-fluoro-5H-indeno[1,2-b]pyridine (which may be further derivatized according to Method V) is derivatized according to Methods II and IV to yield the corresponding spiro-derivatives such as spiro-(7-fluoro-5H-indeno[1,2-b]pyridin-5,5-thiazolidine)-2',4'-dione; spiro-(7-fluoro-5H-inden[1,2-b]pyridin-5,5'-(oxazolidine-2',4'-dione and spiro-(7-fluoro-5H-indeno[1,2-b]pyridin-5,3'-succinimide. Oxidation (Method VII) of 5H-indeno[1,2-b]pyridine or its derivatives according to the method of Sprinzak, J. Amer. Chem. Soc., 80, 5449 (1958) yields the corresponding 5-one or ketone derivative, which may be further derivatized according to Method V. When reacted in accordance with Method I, the ketone will yield a spiro-hydantoin derivative such as spiro-(7-fluoro-5H-indeno[1,2-b]pyridin-5,5'-imidazolidine)-2',5'-dione. Any of the aforementioned spiro derivatives may be further derivatized, e.g., nitrated, in accordance with Method VI. See Examples XVIII, XI and XII.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].[C:17](Cl)(=[O:26])[C:18]1[C:19]([O:24][CH3:25])=[CH:20][CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNc1ncccc1NC(=O)c1ccccc1OC
Reaction time: 8 h
Yield: 30.4 %

Procedure:
A solution of N-(3-nitro-2-pyridinyl)glycine ethyl ester (64.4 g, 0.286 mole) in 900 ml of tetrahydrofuran was hydrogenated in a 2-liter Parr bottle over 5% palladium on carbon (6.5 g) at room temperature for 1 hour. The reaction mixture was dried over magnesium sulfate and filtered through a Celite pad. A 235-ml portion of the filtrate was used in this reaction. Under nitrogen atmosphere, o-anisoyl chloride (9.72 g, 0.057 mole) and triethylamine (6.33 g, 0.063 mole) were added dropwise simultaneously to the above-stirred filtrate at room temperature. The reaction mixture was allowed to stir overnight. The reaction mixture was filtered, and the filtrate was treated with Florisil® (30 g), and evaporated to a solid. The solid was recrystallized from hot tetrahydrofuran (minimum). The solid was filtered off, washed with cold tetrahydrofuran, and dried under high vacuum at room temperature to give 5.7 g of title compound, mp 111°-12° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:11](Cl)(=[O:15])[CH:12]([CH3:14])[CH3:13]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)c1ccccc1
Product: CC(C)C(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The procedure of Example 3 was followed for the reaction of 67g (0.5 mole) of tert-butylbenzene with 53.3g (0.5 mole) of isobutyryl chloride. Obtained after high vacuum concentration was 88g of a clear liquid; ir (film) 3.4 (m), 5.95 (s), 8.2 (s), 10.2 (s) microns; nmr (CDCl3) 7.65 (4H, d of d) 3.50 (1H, quintet), 1.28 (9H, s) 1.15(6H, d) ppm. A VPC analysis indicated one pure product.
Reaction SMILES: C(OC=[C:6](C)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)(=O)C.CC(CC1C=CC2OCOC=2C=1)C=[O:21]>>[C:7]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)(=[O:21])[CH3:6]
Reactant: CC(C=O)Cc1ccc2c(c1)OCO2
Reactant: CC(=O)OC=C(C)Cc1ccc2c(c1)OCO2
Product: CC(=O)c1ccc2c(c1)OCO2

Procedure:
In the step (2), 1-acetoxy-2-methyl-3-(3,4-methylenedioxyphenyl)-1-propene represented by the following formula (3) which has been obtained in the step (1) is subjected to hydrolysis reaction or to transesterification reaction with an alcohol to obtain a crude product of 1-acetyl-3,4-methylenedioxybenzene represented by the following formula (4) and 2-methyl-3-(3,4-methylenedioxyphenyl)propanal represented by the following formula (5), and then the resulting reaction mixture is further subjected to distillative purification, to thereby obtain 2-methyl-3-(3,4-methylenedioxyphenyl)propanal having a content of 1-acetyl-3,4-methylenedioxybenzene of from 50 to 3000 ppm.
Reaction SMILES: [NH2:1][C:2]1[N:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([O:17]CC3C=CC=CC=3)[CH:14]=[CH:13][C:11]=2[CH:12]=1)=[O:5].C(=O)(O)[O-].[Na+].O>FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[CH:12]=1)=[O:5]
Reactant: Nc1ncccc1C(=O)NCc1cc2ccc(OCc3ccccc3)cc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncccc1C(=O)NCc1cc2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
To a trifluoroacetic acid solvent of 2-amino-N-(6-benzyloxy-benzofuran-2-ylmethyl)-nicotinamide (323 mg, 865 mmol) described in Example 58 at 0° C., which was stirred at room temperature for 3 hours. Sodium bicarbonate and water were added to the reaction solution at 0° C. followed by extraction with ethyl acetate. The organic layer was washed with sat. NaCl followed by drying by adding anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (219 mg, 89%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH2:9][CH3:10])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH:11]([O:13][CH2:14][CH2:15]Cl)=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:11]([O:13][CH2:14][CH2:15][N:4]1[C:3](=[O:8])[C:2]([CH3:1])([CH2:9][CH3:10])[NH:6][C:5]1=[O:7])=[CH2:12]
Reactant: C=COCCCl
Reactant: CCC1(C)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=COCCN1C(=O)NC(C)(CC)C1=O
Reaction time: 0.58 h

Procedure:
A mixture of 71.04 g (0.5 mol) of 5-methyl-5-ethylhydantoin, 55.94 g (0.5 mol+5% excess) of 2-chloroethyl vinyl ether, 36.28 g (0.25 mol+5% excess) of anhydrous potassium carbonate and 150 ml of dimethylformamide is stirred, analogously to Example 1, for 4 hours and 35 minutes at 122°-129° C. After completion of the reaction, the reaction mixture is filtered and the clear filtrate is concentrated on a rotary evaporator at 80° C. under vacuum from a waterpump. The residue is taken up in 200 ml of acetone, 2 g of active charcoal are added and the mixture is kept at the boil for 15 minutes. It is then filtered and the filtrate is concentrated on a rotary evaporator at 60° C. under vacuum from a waterpump. The residue is freed from non-volatile constituents at 60° C. and 0.5 mm Hg and 86.9 g (81.9% of theory) of a yellowish, viscous crude product are obtained. This is purified by distillation in a high vacuum and 80.34 g (75.7% of theory) of the desired product, of boiling point 132° C./0.2 mm Hg, are obtained.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4](/[CH:7]=[CH:8]/[CH2:9]O)=[CH:5][CH:6]=1.[CH3:11][C:12]([CH3:16])=[CH:13][CH:14]=[O:15].C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:11][C:12]([CH2:16][CH2:9][CH:8]=[CH:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)=[CH:13][CH:14]=[O:15]
Reactant: OC/C=C/c1ccccc1
Reactant: CC(C)=CC=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(=CC=O)CCC=Cc1ccccc1
Yield: 81 %

Procedure:
A mixture of 187 parts of cinnamic alcohol, 360 parts of 3,3-dimethylacrolein and 550 parts of toluene is heated with 33 parts of glacial acetic acid in a V4A steel stirred vessel having a capacity of 5 liters for six hours at 140° C. at a pressure of 2 atmospheres, the water forming being continuously removed as an azeotropic mixture with toluene. The product is distilled. 149 parts of 3-methyl-7-phenyl-2,6-heptadien-1-al is obtained having a boiling point of 118° to 120° C. at 10-3 mm. The yield is 81% of theory (based on cinnamic alcohol) at a conversion of 66%.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][OH:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>ClCCl>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1COS(C)(=O)=O
Reaction time: 1 h

Procedure:
To a solution of (2S,4R)-4-(tert-butyldimethylsilyloxy)-1-(tert-butoxycarbonyl)-2-hydroxymethylpyrrolidine (5.3 g) and methanesulfonyl chloride (1.49 ml) in dichloromethane (40 ml) was added dropwise triethylamine (3.2 ml) at 0° C. After one hour, the reaction mixture was washed in turn with 1N-hydrochloric acid, water and brine. The organic layer was dried over magnesium sulfate, and evaporated to give an oil, which was chromatographed on silica gel (250 ml) eluting with a mixture of hexane and ethyl acetate (2:1, V/V) to give (2S,4R)-4-(tert-butyldimethylsilyloxy)-1-(tert-butoxycarbonyl)-2-methanesulfonyloxymethylpyrrolidine (6.06 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH:8]2[N:10]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH:4]([CH2:5][O:6][CH2:7]2)[CH2:3]1.[N+](=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N-]>C(Cl)Cl.CCOC(C)=O.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][O:1][CH:2]1[CH2:3][CH:4]2[N:10]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH:8]([CH2:7][O:6][CH2:5]2)[CH2:9]1)[CH3:28]
Reactant: O=C(OCc1ccccc1)N1C2COCC1CC(O)C2
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)COC1CC2COCC(C1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of benzyl 7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate O (200 mg, 0.72 mmol) in DCM (4 mL) was added ethyl 2-diazoacetate (202 mg, 1.44 mmol) and Rhodium(II) acetate (319 mg, 0.72 mmol) at 0° C. The resulting mixture was stirred at room temperature for overnight, and then diluted with EtOAc. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and brine and dried (Na2SO4). The organic solvent was removed in vacuo to give the crude product, which was purified by column chromatography to give the intermediate benzyl 7-(2-ethoxy-2-oxo-ethoxy)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (144 mg, 55%). LC/MS: calc'd 364 (MH+), exp 364 (MH+).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl:19][C:20]1[C:21]([C:49]2[CH:50]=[C:51]3[C:55](=[CH:56][C:57]=2[F:58])[N:54]([CH2:59][CH2:60][OH:61])[CH:53]=[CH:52]3)=[CH:22][C:23]2[N:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:39])=[C:33]([CH:38]=3)[C:34]([O:36]C)=[O:35])[N:25](COCC[Si](C)(C)C)[C:24]=2[CH:48]=1>C1COCC1.CCOC(C)=O>[Cl:19][C:20]1[C:21]([C:49]2[CH:50]=[C:51]3[C:55](=[CH:56][C:57]=2[F:58])[N:54]([CH2:59][CH2:60][OH:61])[CH:53]=[CH:52]3)=[CH:22][C:23]2[N:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:39])=[C:33]([CH:38]=3)[C:34]([OH:36])=[O:35])[NH:25][C:24]=2[CH:48]=1
Reactant: COC(=O)c1cc(Oc2nc3cc(-c4cc5ccn(CCO)c5cc4F)c(Cl)cc3n2COCC[Si](C)(C)C)ccc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(Oc2nc3cc(-c4cc5ccn(CCO)c5cc4F)c(Cl)cc3[nH]2)cc1C(=O)O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
TBAF (1 M in THF) (2 mL, 2 mmol) was added to a solution of methyl 5-[(6-chloro-5-[6-fluoro-1-(2-hydroxyethyl)-1H-indol-5-yl]-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]-2-methylbenzoate in THF (2 mL). The reaction was heated at 80° C. for 3 h. Volatiles were removed and the residue was dissolved in MeOH (4 mL) and treated with 2.5 N aqueous NaOH (1.5 mL). The reaction was stirred at 45° C. for 1 h, then at rt overnight. Reaction mixture was diluted with EtOAc and washed with 1 M aqueous HCl and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. Chromatography over silica eluting with 8% MeOH/DCM afforded the title compound as a beige solid. 1H NMR (500 MHz, CD3OD): δ 7.86 (d, 1H), 7.48 (s, 1H), 7.44-7.37 (m, 3H), 7.33 (s, 1 H), 7.27 (d, 1H), 7.23 (d, 1H), 6.46 (d, 1H), 4.25 (t, 2H), 3.88 (t, 2H), 2.61 (s, 3H). LC-MS: m/e 480.2 (M+H)+ (1.79 min).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]([C:5](F)=[O:6])[C:3]=1[C:14](F)=[O:15].C(=O)([O-])[O-:18].[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4]2[C:5](=[O:18])[O:6][C:14](=[O:15])[C:3]=12
Reactant: O=C(F)c1c(F)c(F)c(F)c(F)c1C(=O)F
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Yield: 93.4 %

Procedure:
Into a 500 ml glass reactor equipped with a reflux condenser and a stirrer, 100 g (0.413 mol) of the 3,4,5,6-tetrafluorophthaloyldifluoride separated by distillation from the mixture of Example 2, 43.8 g (0.413 mol) of sodium carbonate and 200 g of xylene were charged, and the mixture was reacted at 130° C. for 1.5 hours with vigorous stirring. Then, the inorganic substance was removed by filtration, and the residue was separated by distillation to obtain 84.9 g of tetrafluorophthalic anhydride. The yield was 93.4%.
Reaction SMILES: [ClH:1].[F:2][C:3]1([F:23])[CH2:11][N:10]2[C@H:5]([CH2:6][CH:7]([NH:14][C@H](C3C=CC=CC=3)C)[CH2:8][C:9]2([CH3:13])[CH3:12])[CH2:4]1.[H][H]>CO>[ClH:1].[F:23][C:3]1([F:2])[CH2:11][N:10]2[C@H:5]([CH2:6][CH:7]([NH2:14])[CH2:8][C:9]2([CH3:13])[CH3:12])[CH2:4]1
Reactant: [H][H]
Reactant: C[C@H](NC1C[C@@H]2CC(F)(F)CN2C(C)(C)C1)c1ccccc1
Agent: Cl
Solvent: CO
Product: CC1(C)CC(N)C[C@@H]2CC(F)(F)CN21
Reaction time: 39 h

Procedure:
A MeOH (20 ml) solution of (8aR)-2,2-difluoro-octahydro-5,5-dimethyl-N—((S)-1-phenylethyl)indolizin-7-amine hydrogen chloride and Pd(OH)2—C (20% on activated carbon, 50% wet, 0.2 g) was hydrogenated in a Parr flask under 45 psi of hydrogen. Additional Pd(OH)2—C was added (˜0.2 g) was added at 16 hours and 24 hours, and the reaction went to completion at 39 hours monitored by LC-MS. Solid was removed by filtration through a short Celite column, washing with MeOH. Filtrate was collected, solvent was removed in vacuo. Compound (8aR)-2,2-difluoro-octahydro-5,5-dimethylindolizin-7-amine hydrogen chloride was obtained as an off-white solid and was used directly in next reaction: 0.56 g; LRMS] (M+H) m/z 204.99.