Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN(CC)CC.[Cl:14][CH2:15][C:16](Cl)=[O:17]>C1COCC1>[Cl:14][CH2:15][C:16]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)N1CCOCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To the solution of morpholine (10 mmol, 0.872 mL) and Et3N (15 mmol, 2.09 mL) in THF (20 mL) at 0° C. was dropped in chloroacetyl chloride 1 (12 mmol, 0.956 mL). The mixture was stirred at 0° C. for 4 h and then r.t. overnight. The reaction was quenched with H2O and evaporated to dryness. Purification by column chromatography (CH2Cl2/CH3OH=50/1) gave 2-chloro-1-morpholin-4-yl-ethanone 2 (1.62 g, 100%). 2 (1.6 g, 0.98 mmol) was treated with piperazine-1-carboxylic acid t-butyl ester (10 mmol, 1.86 g) in DMF (20 mL) at 70° C. for 12 h in the presence of K2CO3 (3 mmol, 4.14 g). Solvents were evaporated and the crude product was purified by flash chromatography (CH2Cl2/CH3OH=30/1) to give 4-(2-morpholin-4-yl oxo-ethyl)-piperazine-1-carboxylic acid t-butyl ester 4, which was treated with TFA (5 mL) in CH2Cl2 (5 mL) at r.t. for 2 h. Evaporation of all solvents furnished the TFA salt of 1-morpholin-4-yl-2-piperazin-1-yl-ethanone 4 (4.1 g, 93%).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(Br)cc1
Reactant: ClCCN1CCOCC1
Product: Brc1ccc(OCCN2CCOCC2)cc1

Procedure:
reacting 4-(2-chloroethyl)morpholine with 4-bromophenol to yield 4-(2-(4-bromophenoxy)ethyl)morpholine; (2) coupling 4-(2-(4-bromophenoxy)ethyl)morpholine with 6-fluoropyridin-3-yl-3-boronic acid to yield 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.Cl.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: Brc1ccc(OCCN2CCOCC2)cc1

Procedure:
The first step is a Williamson ether synthesis between 4-bromophenol (131 g) and N-chloroethylmorpholine (1 as the HCl salt; 141 g) using K2CO3 powder (3 to 3.5 equivalents) as the base and having acetonitrile as the solvent. The ingredients were mixed and stirred at reflux overnight with high conversion (96.3-99.1%). After dilution with dichloromethane and heptane, the reaction mixture was filtered and evaporated to give the desired product 2 in essentially a quantitative yield (216 g). Note that with similar substrates (e.g., 4-bromo-3-fluorophenol), conversions (even with extensive heating) were not always so high (e.g., 59.9-98.3%). Both the alkyl chloride and the K2CO3 are preferably purchased from Aldrich. If continued heating does not drive reaction to completion, unreacted bromophenol can readily be removed by dissolving the crude reaction mixture in 4 parts toluene and washing out the phenol with 4 parts 15% aqueous NaOH.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13]C)=O)[C:4]=2[NH:3]1.[CH2:15]([Mg]Br)[CH3:16].[CH2:19](OCC)[CH3:20].Cl>O1CCCC1>[CH2:19]([C:11]([C:10]1[C:4]2[NH:3][C:2](=[O:1])[NH:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)([OH:13])[CH2:15][CH3:16])[CH3:20]
Reactant: CCOCC
Reactant: COC(=O)c1cccc2[nH]c(=O)[nH]c12
Reactant: CC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCC(O)(CC)c1cccc2[nH]c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a suspension of methyl 2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (513 mg, 2.67 mmol) in tetrahydrofuran (5 mL) was added 3M solution of ethyl magnesium bromide in diethyl ether (3.6 ml, 10.7 mmol), and the mixture was stirred at room temperature for 1 hour and refluxed for 20 hours. Addition of 3M solution of ethyl magnesium bromide in diethyl ether (5.3 mL, 16.0 mmol) was followed by refluxing for 30 hours. The reaction mixture was acidified with 6 N hydrochloric acid and extracted with ethyl acetate (X2). The combined organic layer was washed with brine (X1), dried over sodium sulfate and concentrated in vacuo. The resulting solid was washed with diisopropyl ether to give 440 mg (2.00 mmol, 74.8%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:28])[C:11]3[C:20]4[C:19](=[O:21])[NH:18][C:17]([CH:22]([OH:25])[CH:23]=[CH2:24])=[C:16]([CH3:26])[C:15]=4[CH:14]=[CH:13][C:12]=3[N:27]=2)=[C:4]([CH3:29])[CH:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].C(OCC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.CO.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:28])[C:11]3[C:20]4[C:19](=[O:21])[NH:18][C:17]([CH:22]([O:25][C:30](=[O:32])[CH3:31])[CH:23]=[CH2:24])=[C:16]([CH3:26])[C:15]=4[CH:14]=[CH:13][C:12]=3[N:27]=2)=[C:4]([CH3:29])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: C=CC(O)c1[nH]c(=O)c2c(ccc3nc(Nc4ccc(F)cc4C)n(C)c32)c1C
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: C=CC(OC(C)=O)c1[nH]c(=O)c2c(ccc3nc(Nc4ccc(F)cc4C)n(C)c32)c1C
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
To a 500 mL round-bottom flask equipped with a magnetic stir-bar was added 2-(4-fluoro-2-methyl-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (7.8 g, 20 mmole), DCM (100 mL), TEA (3.0 g, 30 mmole), and DMAP (25 mg, 0.2 mmole). To the rapidly stirred suspension at room temperature was added acetic anhydride (2.3 g, 23 mmole). The reaction was complete after 10 minutes as determined by TLC analysis. The mixture was diluted with DCM (100 mL), and washed with saturated aqueous ammonium chloride. The aqueous layer was back-extracted with additional DCM (100 mL). The combined organic fractions were washed with brine (2×100 mL), dried over sodium sulfate, and concentrated in vacuo to give an amorphous orange solid. The crude product was re-dissolved in 5% MeOH/DCM (65 mL). To the stirred solution was added diethyl ether (200 mL), which resulted in the formation of a bright yellow precipitate. The stirred suspension was cooled over a salt/ice bath to −5° C., then filtered to recover the solids. The solids were washed sparingly with diethyl ether and collected to provide acetic acid 1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester (6.94 g, 80.4%) as a yellow powder. 1H NMR (400 MHz, DMSO-d6+TFA) δ 11.35 (br s, 1H), 10.55 (br s, 1H), 7.74 (d, 1H, J=9.0 Hz), 7.70 (d, 1H, J=8.6 Hz), 7.56 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.37-7.34 (m, 3H), 7.25 (td, 1H, J1=2.7 Hz, J2=8.2 Hz), 6.34 (app d, 1H, J=6.3 Hz), 6.17 (ddd, 1H, J1=6.3 Hz, J2=10.2 Hz, J3=16.8 Hz), 5.41 (app d, 1H, J=17.2 Hz), 5.33 (app d, 1H, J=10.2 Hz), 4.18 (s, 3H), 2.32 (s, 3H), 2.12 (s, 3H); ESMS (m/z): 435 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22]>ClCCl>[F:11][C:8]([F:9])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:21](=[O:22])[C:20]([CH3:25])([CH3:24])[CH3:19])=[CH:3][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A solution of dichloromethane (200 mL), 4-aminobenzotrifluoride (32.0 g, 199 mmol) and triethylamine (40 g, 396 mmol) was cooled to 0° C under a dry nitrogen atmosphere. Trimethylacetyl chloride (32.9 g, 273 mmol) was added drop-wise over 2 hours, maintaining the temperature below 10° C. After the addition, the contents were allowed to warm to room temperature for 2 hours. The reaction was washed with water (2×200 mL), saturated ammonium chloride solution (2×200 mL), dried over sodium sulfate and filtered. The solvent was removed in vacuo to afford a white solid, N-(4-trifluoromethylphenyl)-2,2-dimethylpropanamide (48.0 g, 98%): mp 157–159° C. 1H NMR (CDCl3/300 MHz) 7.61 (ab, 4H, J=8.7, Δν=28.6 Hz), 7.47 (br s, 1H), 1.33 (s, 9H). ESHRMS m/z 246.1123 (M+H+, Calc'd 246.1106). Anal. Calc'd for C12H11F3NO: C, 58.77; H, 5.75; N, 5.71. Found: C, 58.28; H, 5.79; N, 5.65.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:17])=O>CN(C=O)C.O1CCOCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([Cl:17])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2ncccc2c1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(Cl)c1ccc2ncccc2c1

Procedure:
Under nitrogen, a 1 L round bottom flask, equipped with septum and drying tube attached to a gas scrubber setup, was charged with 25.4 g (146.5 mmol) quinoline-6-carboylic acid. 1,4-Dioxane (250 mL) was added along with 10 drops of DMF. Inside a glovebox, oxalyl chloride (25.1 g, 197.8 mmol, 1.35 eq) was weighed into a septum vial. The vial was closed, removed from the glovebox, and the weighed oxalyl chloride was added, under nitrogen, to the reaction, in portions, via syringe. The reaction was stirred until most of the gas development ceased. The reaction remained stirring at room temperature overnight. The volatiles were removed using a rotary evaporator. Trace HCl was removed by addition of several aliquots of dry toluene, which were consecutively evaporated using the rotary evaporator. The final product was obtained in form of a colorless to slightly yellow powder (28.0 g, 146.4 mmol, 100%). 1H-NMR: (500 MHz, CDCl3) δ 9.35 (dd, J=5.2, 1.5 Hz, 1H), 9.09 (d, J=8.5 Hz, 1H), 9.09 (d, J=9.0 Hz, 1H), 9.01 (d, J=2.0 Hz, 1H), 8.64 (dd, J=9.1, 2.0 Hz, 1H), 8.14 (dd, J=8.4, 5.2 Hz, 1H); 13C-NMR (126 MHz, CDCl3) δ 122.92, 123.90, 128.21, 133.44, 133.79, 134.55, 140.95, 146.44, 147.11, 166.69.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[OH:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.[NH2:21][OH:22].C([O-])(=O)C.[NH4+]>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[N:21][OH:22])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[OH:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: NO
Reactant: CC(=O)N1CCC(C(=O)c2cc(F)ccc2O)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Product: CC(=O)N1CCC(C(=NO)c2cc(F)ccc2O)CC1
Yield: 65.6 %

Procedure:
A mixture of 12.7 g of 1-acetyl-4-(5-fluoro-2-hydroxybenzoyl)piperidine, 6.6 g of hydroxylamine hydrochloride, 11.0 g of ammonium acetate and 200 ml of ethanol-ether was heated under reflux for 10 hrs. After cooling, most of the ethanol was removed under reduced pressure. The resultant suspension was diluted with water and extracted with dichloromethane. The dichloromethane was evaporated in vacuo to given an oil. The oil was dissolved in ethyl acetate and cyclohexane was added to precipitate a solid. The solid was recrystallized from ethyl acetate to give 8.8 g (65.4%) of product, mp, 181°-183°. The chromatogram showed 2 spots.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C(Cl)Cl.O>[Si:13]([O:12][CH2:11][CH2:10][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCn1cc([N+](=O)[O-])cn1
Temperature: 70 °C
Yield: 92.5 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a reflux condenser and magnetic stirrer was purged with nitrogen and charged with 4-nitro-1H-pyrazole (500 mg, 4.42 mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane (2.12 g, 8.85 mmol), cesium carbonate (5.76 g, 17.7 mmol) and anhydrous DMF (5 mL). After heating at 70° C. for 1 h, the mixture was cooled to room temperature and diluted with methylene chloride (50 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with methylene chloride (2×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a 92% yield (1.11 g) of 116a as a white solid: mp 63-64° C.; 1H NMR (500 MHz, CDCl3) d 8.20 (s, 1H), 8.08 (s, 1H), 4.24 (t, 2H, J=4.5 Hz), 3.95 (t, 2H, J=4.5 Hz), 0.84 (s, 9H), −0.04 (s, 6H).
Reaction SMILES: Cl.[NH:2]=[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:6]=[C:5]([CH3:18])[S:4]1.N1CCCCC1.C(N(CC)CC)C.[F:32][C:33]([F:37])=[C:34](F)F.CN(C)C=[O:41]>>[F:32][CH:33]([F:37])[C:34]([N:2]=[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[CH:6]=[C:5]([CH3:18])[S:4]1)=[O:41]
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Reactant: FC(F)=C(F)F
Reactant: CN(C)C=O
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCN(CC)CC
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(F)F)s1
Temperature: 50 °C
Reaction time: 13 h
Yield: 93 %

Procedure:
A solution of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline hydrochloride (1.47 g, 5.0 mmol), piperidine (0.64 g, 7.5 mmol) and triethylamine (1.77 g, 17.5 mmol) in N,N-dimethylformamide (10 ml) charged in a reaction flask was reacted with tetrafluoroethylene, which was made to flow intothe flask (ca. 0.7 liter/hr), with vigorous stirring at 50° C. for 13 hours. After cooling to an ambient temperature, the reaction mixture was poured into ice-water, and extracted with diethyl ether. The ether layer was washed with water and then brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography, which afforded 2-difluoroacetylimino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1.56 g, 4.6 mmol, yield 93%).
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[CH:2].[C:10]([C:13]1[CH:14]=[C:15](/[CH:18]=[C:19]2\[C:20](=[O:30])[NH:21][C:22]3[C:27]\2=[C:26](I)[C:25]([F:29])=[CH:24][CH:23]=3)[NH:16][CH:17]=1)(=[O:12])[CH3:11]>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.CN(C=O)C.CCN(CC)CC>[C:10]([C:13]1[CH:14]=[C:15](/[CH:18]=[C:19]2\[C:20](=[O:30])[NH:21][C:22]3[C:27]\2=[C:26]([C:2]#[C:1][C:3]2([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[C:25]([F:29])=[CH:24][CH:23]=3)[NH:16][CH:17]=1)(=[O:12])[CH3:11]
Reactant: C#CC1(O)CCOCC1
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(C#CC4(O)CCOCC4)c32)c1

Procedure:
Using Method C above, 4-Ethynyl-tetrahydro-pyran-4-ol (0.16 g1 1.26 mmol) (Example 85A) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (0.2 g, 0.50 mmol) (Example 90B above) using (Ph3P)4Pd (58.4 mg) and Cul (9.6 mg) as catalyst in DMF (15 mL) and Et3N (15 mL) as solvent at 85° C. for 18 h. (Yield 102 mg, 52%).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH:18]=C)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.C[N+]1([O-])CC[O:26]CC1.S(=O)(O)[O-].[Na+]>C1COCC1.O.CC(O)(C)C.O=[Os](=O)(=O)=O>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH:18]=[O:26])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCN(CC(C)(C)C)c1ccc(C#N)c(C(F)(F)F)c1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CC(C)(C)CN(CC=O)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 81.3 %

Procedure:
To a solution of 4-[(2,2-dimethylpropyl)(2-propen-1-yl)amino]-2-(trifluoromethyl)benzonitrile (1.46 g, 4.95 mmol) in THF/water (20:1, 45 mL) at rt was added a solution of OsO4 (1.02 g of a 2.5 wt % solution in t-BuOH, 0.10 mmol) in THF/water (20:1, 5 mL), followed by NMO (1.22 g, 10.4 mmol) in one portion. The resulting mixture was stirred 22 hours at rt, cooled to 0° C. and sodium bisulfite (0.300 g) was added in one portion. The mixture was stirred 1 h, filtered through a pad of Celite (EtOAc wash) and the filtrate/washings were partitioned between EtOAc/water (required addition of NaCl to separated layers). The aqueous layer was extracted with EtOAc (×1), combined organics were washed with brine and concentrated in vacuo. The residue was dissolved in acetone (50 mL), a solution of NalO4 (2.22 g; 10.4 mmol) in water (20 mL) was added, the mixture was stirred two hours at rt and partially concentrated in vacuo to an aqueous residue. The residue was partitioned between EtOAc/water and the aqueous layer was further extracted with EtOAc (×1). Combined organics were washed (water, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 1.20 g of the title compound as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 7.57 (d, J=8.8 Hz, 1H), 6.96 (d, J=2.5 Hz, 1H), 6.74 (dd, J=8.9, 2.7 Hz, 1H), 4.31 (s, 2H), 3.33 (s, 2H), 1.02 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][CH2:22][O:23][CH3:24])[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([OH:19])=O)[CH2:15][C:4]=2[CH:3]=1.Cl.[F:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[NH:35][C:34](=[O:37])[C:33]([CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[CH:32]2>>[Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][CH2:22][O:23][CH3:24])[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([N:41]3[CH2:42][CH2:43][CH:38]([C:33]4[C:34](=[O:37])[NH:35][C:36]5[C:31]([CH:32]=4)=[CH:30][CH:29]=[CH:28][C:27]=5[F:26])[CH2:39][CH2:40]3)=[O:19])[CH2:15][C:4]=2[CH:3]=1
Reactant: COCCN1Cc2c(cc(Br)c3[nH]ncc23)C[C@@H](CC(=O)O)C1=O
Reactant: O=c1[nH]c2c(F)cccc2cc1C1CCNCC1
Agent: Cl
Product: COCCN1Cc2c(cc(Br)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(c3cc4cccc(F)c4[nH]c3=O)CC2)C1=O
Yield: 56 %

Procedure:
[(S)-4-Bromo-9-(2-methoxy-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-acetic acid (100 mg, 0.25 mmol) and 8-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (85 mg, 0.30 mmol) were combined in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10$$ -tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as white solid in 56% yield. High resolution MS m/e (M+H)+=624.1631.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N+:12]([O-])=O)=[O:5])[CH2:3][CH2:2]1.[H][H]>[Pd].C1(C)C=CC=CC=1>[CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])=[O:5])[CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: O=C(c1ccccc1[N+](=O)[O-])C1CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: Nc1ccccc1C(=O)C1CC1
Yield: 73.9 %

Procedure:
A mixture of the 23.6% toluene solution of o-nitrophenyl cyclopropyl ketone obtained in Example 7 (232.3 g, 0.286 mole ketone) and 2.86 g of 5% Pd/C catalyst is placed under H2 at 32-56 psig in a Parr hydrogenator. The hydrogen uptake is monitored and when the reaction is complete, the reaction mixture is filtered and concentrated in vacuo to give the title product, 39.5 g, 86.3% pure by HPLC analysis (73.9% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.C(O)C.[S:12]([O-:15])([O-:14])=[O:13].[Na+:16].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:12]([O-:15])(=[O:14])=[O:13])[N:3]=1.[Na+:16]
Reactant: Clc1cccc(Cl)n1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])c1cccc(Cl)n1
Temperature: 170 °C
Yield: 29.1 %

Procedure:
Into a 50 ml autoclave, 2.22 g (15 mmol) of 2,6-dichloropyridine and 4.5 ml of ethanol were introduced and dissolved. To the solution, 2.27 g (18 mmol) of sodium sulfite dissolved in 18 ml of water, was added, and after sealing, the mixture was heated in an oil bath of 170° C. for 12 hours. After completion of the reaction, the mixture was cooled, and after an addition of 30 ml of water, extracted with methylene chloride (30 ml×3 times). The aqueous layer was distilled under reduced pressure, and 200 ml of ethanol was added. The mixture was heated. After filtering off insoluble precipitates, the filtrate was distilled under reduced pressure to obtain 0.94 g (30%) of sodium 2-chloropyridine-6-sulfonate as crystalline solid. Purification was conducted by recrystallization from ethanol. The physical property values are shown below.