Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:14][C:15](=[CH:17][CH2:18][CH2:19][CH:20](CC=O)[CH3:21])[CH3:16].C1(C)C=CC=CC=1>O>[C:5]([O:4][CH:1]=[CH:2][CH:20]([CH3:21])[CH2:19][CH2:18][CH:17]=[C:15]([CH3:16])[CH3:14])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=CCCC(C)CC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)OC=CC(C)CCC=C(C)C

Procedure:
167 kg of acetic anhydride and 77 kg of potassium carbonate were heated to 80° in a reaction vessel equipped with an introduction pump and a condenser. 85 kg of (±)-citronellal were then added by means of the introduction pump during 40 min and the mixture was refluxed for 7 hours. After cooling, 100 kg of toluene and 500 l of water were added thereto and after separation of the organic phase the mixture was washed with 100 l of water to give a solution of 3,7-dimethyl-octa-1,6-dien-l-yl acetate in toluene accompanied by minor quantities of a diester of formula ##STR8##
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:12][S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C(Cl)Cl.C([O-])(=O)C.[K+].I[C:46]1[C:47](=[O:74])[C:48]2[CH:49]=[CH:50][N:51]3[C:64](=[O:65])[N:63]([CH2:66][O:67][CH2:68][CH2:69][Si:70]([CH3:73])([CH3:72])[CH3:71])[N:62]=[C:52]3[C:53]=2[O:54][C:55]=1[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[O:65]=[C:64]1[N:51]2[CH:50]=[CH:49][C:48]3[C:47](=[O:74])[C:46]([C:2]4[CH:3]=[CH:4][C:5]([C:8]5([NH:12][S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH2:11][CH2:10][CH2:9]5)=[N:6][CH:7]=4)=[C:55]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[O:54][C:53]=3[C:52]2=[N:62][N:63]1[CH2:66][O:67][CH2:68][CH2:69][Si:70]([CH3:73])([CH3:72])[CH3:71]
Reactant: CC(C)(C)S(=O)NC1(c2ccc(Br)cn2)CCC1
Reactant: C[Si](C)(C)CCOCn1nc2c3oc(-c4ccccc4)c(I)c(=O)c3ccn2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(C)S(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccn5c(=O)n(COCC[Si](C)(C)C)nc45)c3=O)cn2)CCC1
Temperature: 100 °C
Yield: 81.8 %

Procedure:
To a microwave vial were added 2-methyl-propane-2-sulfinic acid [1-(5-bromo-pyridin-2-yl)-cyclobutyl]-amide (33 mg, 0.10 mmol), bis(pinacolato)diboron (30.5 mg, 0.12 mmol, [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with DCM (2.5 mg, 0.003 mmol), potassium acetate (29.4 mg, 0.30 mmol) and DME (1 mL). The reaction mixture was purged using nitrogen and heated in a microwave reactor at 100° C. for 2 h. The reaction mixture was allowed to cool to RT and 7-iodo-8-phenyl-2-(2-trimethylsilanyl-ethoxymethyl)-2H-9-oxa-1,2,3a-triaza-cyclopenta[a]naphthalene-3,6-dione (53.5 mg, 0.10 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dischloropalladium(II), complex with dichloromethane (2.5 mg, 0.003 mmol), sodium carbonate solution (2 M in water, 0.2 mL, 0.4 mmol) and DME (0.5 mL) were added. The reaction mixture was purged using nitrogen and heated in a microwave reactor at 125° C. for 1 h. The reaction mixture was allowed to cool to RT, partitioned between EtOAc and water, and was filtered through a Celite® pad. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in EtOAc) to afford the title compound (54 mg, 82%). LCMS (Method B): RT=4.90 min, [M+H]+=660.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=C(C)[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]1[NH:15][CH2:14][CH2:13][NH:12]1.CC[O:18][C:19]([CH3:21])=[O:20].[NH4+].[OH-].O>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[C:19]([C:21]1[CH:1]=[C:2]([CH3:7])[C:3]([N:10]=[C:11]2[NH:12][CH2:13][CH2:14][NH:15]2)=[C:4]([CH3:9])[CH:5]=1)([OH:18])=[O:20]
Reactant: Cc1cc(C)c(N=C2NCCN2)c(C)c1
Reactant: CCOC(C)=O
Agent: [Cr+6]
Agent: [NH4+]
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C(=O)O)cc(C)c1N=C1NCCN1
Temperature: 0 °C

Procedure:
2-(2,4,6-Trimethylphenylimino)imidazolidine (2.03 g) is dissolved in glacial acetic acid (50 ml) and cooled as 5.0 g of chromium trioxide is added in small portions. The solution is then heated to 50° in an oil bath for 4 hours when the reaction is complete as shown by tlc [silica gel, EtOAc/iPA/2 N NH4OH (2:5:1 v/v/v). The mixture is poured into water and ice (500 ml) and the resultant precipitate is filtered and washed with water. Recrystallization from ethyl acetate gives pure product, m.p. 116°-117° C. (1.35 g, 76%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[OH:6].[H-].[Na+]>C1COCC1.[Ni]>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C@@H:5]2[CH2:4][CH2:3][CH2:2][O:6]2)=[CH:8][CH:9]=1
Reactant: O[C@@H](CCCCl)c1ccc(Br)cc1
Agent: [Ni]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc([C@@H]2CCCO2)cc1
Yield: 75 %

Procedure:
A solution of [S]-1-chloro-4-(4-bromophenyl)-4-butanol (50 mmol) in THF (25 ml) was added to a cooled suspension (0° C.) of NaH (55 mmol) in THF (50 ml). After being stored for 2 h at 25C, the reaction mixture was quenched with water, brought to pH 6 with concentrated HCl, and extracted with ether (2×50 ml). The organic phase was dried over H2SO4, filtered and all volatiles removed under reduced pressure. The residue was distilled to provide the product in 75% yield, 98% ee as determined on a chiral capillary column of Ni(HFN-IR-Cam)2.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][CH:7]1[C:39](=[O:40])[N:9]2[C:10]([C:23]([O:25]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:24])=[C:11](/[CH:14]=[CH:15]/[S:16][C:17]3[N:21]([CH3:22])[N:20]=[N:19][N:18]=3)[CH2:12][S:13][C@H:8]12>O.C(O)=O>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[NH:6][CH:7]1[C:39](=[O:40])[N:9]2[C:10]([C:23]([OH:25])=[O:24])=[C:11](/[CH:14]=[CH:15]/[S:16][C:17]3[N:21]([CH3:22])[N:20]=[N:19][N:18]=3)[CH2:12][S:13][C@H:8]12
Reactant: Cn1nnnc1S/C=C/C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(Nc3ncc[nH]3)[C@H]2SC1
Solvent: O
Solvent: O=CO
Product: Cn1nnnc1S/C=C/C1=C(C(=O)O)N2C(=O)C(Nc3ncc[nH]3)[C@H]2SC1

Procedure:
A solution of the hydrochloried/hydrofluoride salt of diphenylmethyl 7-(imidazol-2-yl)amino-3-[2-(1-methyltetrazol-5-ylthio)-trans-vinyl]ceph-3-em-4-carboxylate (300 mg.) in a mixture of water (2 ml.) and formic acid (2 ml.) was heated to 40°-45° for 1.75 hours. The solvent was evaporated and the residue dissolved in the minium amount of a mixture of CH2Cl2, methanol and water. Precipitation by addition of isopropanol gave 7-(imidazol-2-yl)amino-3-[2-(1-methyltetrazol-5-ylthio)-trans-vinyl]ceph-3-em-4-carboxylic acid as a salt (73 mg.) having the following n.m.r. in d6DMSO+CD3COOD: 3.62 (m, 2H); 3.90 (s, 3H); 5.1 (d, 1H); 5.5 (d, 1H); 6.7 (d, 1H); 7.2 (d, 1H); 6.75 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[F:32][C:33]1[CH:34]=[C:35]([S:40]([NH2:43])(=[O:42])=[O:41])[CH:36]=[CH:37][C:38]=1[F:39]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:43][S:40]([C:35]3[CH:36]=[CH:37][C:38]([F:39])=[C:33]([F:32])[CH:34]=3)(=[O:41])=[O:42])=[O:24])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1ccc(F)c(F)c1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(F)c(F)c3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 3,4-difluorobenzenesulfonamide: 1H-NMR (CDCl3) δ 7.84-7.70 (2H, m), 7.47-7.21 (10H, m), 6.07 (1H, br.s), 3.50-3.43 (2H, m), 2.85 (2H, t, J=6.3 Hz), 2.32 (3H, s), 2.22 (3H, s).
Reaction SMILES: Cl[Si:2]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[C:6]1([SiH:2]2[CH2:5][CH2:4][CH2:3]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cl[Si]1(c2ccccc2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: c1ccc([SiH]2CCC2)cc1

Procedure:
The 1-chloro-1-phenyl-1-silacyclobutane was reacted with lithium aluminum hydride in ethyl ether to obtain 1-phenyl-1-silacyclobutane. The 1-chloro-1-phenyl-1-silacyclobutane (8.4 g, 46 mmole) in 10 ml diethyl ether was added dropwise to 0.87 g 23 mmole of lithium aluminum hydride in 10 ml diethyl ether at ±5° C. The reaction mixture warmed gradually to room temperature. The mixture was stirred over 12 hours. The mixture was hydrolyzed with 3N hydrochloric acid. After separation, the water layer was extracted with 2×20 ml of ethyl ether. The combined organic layer was dried over anhydrous sodium sulfate. Removal of solvent and fractional distillation gave 1-phenyl-1-silacyclobutane. b.p. 70°-72° C./20 mm Hg, 6.3 g, 92% yield was obtained. 1H NMR (δ) 1.39 (m, 4H), 2.31 (m, 2H), 5.25 (m, 1H), 7.46 (m, 3H), 7.70 (m, 2H). 13C NMR (δ) 12.71, 19.67, 127.98, 129.88, 134.35, 135.19, 29Si NMR (δ) -1.80.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[N:7]=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]1[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:33]([NH:40][C:19](=[O:21])[C:18]1[CH:17]=[CH:16][C:15]([N:3]2[C:2](=[O:1])[C:6]3[N:7]=[N:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:5]=3[NH:4]2)=[CH:23][CH:22]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1ccc(-n2[nH]c3c(nnc4ccccc43)c2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(3-oxo-1,3-dihydro-2H-pyrazolo[4,3-c]cinnolin-2-yl)benzoic acid (52 mg, 0.17 mmol) was mixed with DMF (2 ml). Diisopropylethylamine (22 mg, 29 μl, 0.17 mmol) and benzylamine (18.2 mg, 18.6 μl, 0.17 mmol) were added followed by HBTU (64.5 mg, 0.17 mmol). The mixture was stirred at room temperature for 4 h. The product was purified by preparative HPLC. The title compound was isolated as a red solid (6.6 mg, 0.02 mmol, 10%). LCMS: m/z 396 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1.C1C[O:29]CC1.C(#N)C>CCOC(C)=O>[OH:29][C:2]([CH3:25])([CH3:1])[CH2:11][CH2:10][C:9]1[C:4](=[O:3])[C:5]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)=[C:6]([CH3:14])[C:7](=[O:13])[C:8]=1[CH3:12]
Reactant: Cc1c(O)c(C)c(-c2ccc(C(F)(F)F)cc2)c2c1CCC(C)(C)O2
Reactant: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1=C(CCC(C)(C)O)C(=O)C(c2ccc(C(F)(F)F)cc2)=C(C)C1=O

Procedure:
The purified residue containing 2,2,5,7-tetramethyl-8-(4-(trifluoromethyl)phenyl) chroman-6-ol from the above reaction (60 mg) was dissolved in THF/acetonitrile (1:1, 2 ml) and cooled in an ice-water bath. To the resulting solution was added dropwise an aqueous solution of ceric ammonium nitrate (170 mg, 310 μmol in 1 mL) until a reddish color persisted. When the titration endpoint was reached, the mixture was diluted in 5 mL EtOAc, washed once with brine (2 mL). The remaining organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography (5→25% EtOAc/hexanes) producing 80 mg of 2-(3-hydroxy-3-methylbutyl)-3,5-dimethyl-6-(4-(trifluoromethyl)phenyl)cyclohexa-2,5-diene-1,4-dione, a yellow oil. 1H NMR (CDCl3, 400 MHz) 7.67 (d, 2H), 7.26 (d, 2H), 2.60 (m, 2H), 2.11 (s, 3H), 1.92 (s, 3H), 1.54 (m, 2H), 1.25 (s, 6H) ppm.
Reaction SMILES: C([O:8][C:9](=[O:25])[C@@H:10]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)C1C=CC=CC=1.O1CCCC1.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[C:21]([O:20][C:18]([NH:17][C@@H:10]([CH2:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)[C:9]([OH:25])=[O:8])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1nccs1)C(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1nccs1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 100 mL round bottom flask was charged with 2-(S)-tert-butoxycarbonylamino-3-thiazol-2-yl-propionic acid benzyl ester (370 mg, 1.02 mmol), tetrahydrofuran (9.0 mL), water (0.9 mL), and lithium hydroxide (48 mg, 1.14 mmol) and the resulting mixture was stirred at room temperature for 6 h. The resulting mixture was then neutralized with 10% citric acid and extracted with ethyl acetate (100 mL), and dichlormethane (100 mL). The organic layers were dried with MgSO4, filtered, and concentrated in vacuo to yield (S)-2-(tert-butoxycarbonylamino)-3-(thiazol-2-yl)propanoic acid. MS (ES+) 273 (M+1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:21]4[CH2:22][NH:23][CH2:24][CH2:25][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)=[C:5]([C:26]([F:29])([F:28])[F:27])[CH:4]=1.C(N(C(C)C)CC)(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CN(C=O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:21]4[CH2:22][N:23]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:24][CH2:25][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)=[C:5]([C:26]([F:29])([F:27])[F:28])[CH:4]=1
Reactant: O=C(c1n[nH]c2c1CNCC2)N1CCC(c2ccc(F)cc2C(F)(F)F)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4ccc(F)cc4C(F)(F)F)CC3)c2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.6 %

Procedure:
To a solution of (4-(4-fluoro-2-(trifluoromethyl)phenyl) piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone hydrochloride (38 mg, 0.088 mmol) and diisopropylethylamine (35 μL, 0.20 mmol) in DMF (2.0 mL) was added methanesulfonyl chloride (9 L, 0.12 mmol). The mixture was stirred for 16 h at ambient temperature. The solvent was removed under reduced pressure and the residue diluted with H2O (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The obtained solids were chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 100% (10% CH30H in CH2Cl2 with 0.01% NH4OH) in CH2Cl2) and freeze dried to give (4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone as a white solid (4 mg, 10%): 1H NMR (300 MHz, DMSO-d6) δ 13.05 (s, 1H), 7.73-7.69 (m, 1H), 7.57-7.46 (m, 2H), 5.28-5.24 (m, 1H), 4.70-4.65 (m, 1H), 4.38-4.33 (m, 2H), 3.51-3.45 (m, 2H), 3.22-3.10 (m, 2H), 2.94 (s, 3H), 2.84-2.70 (m, 3H), 1.73 (br s, 4H); ESI MS m/z 475 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3](=[O:36])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:63][C:64]1[CH:65]=[C:66](B(O)O)[CH:67]=[CH:68][C:69]=1[O:70][CH3:71]>>[F:63][C:64]1[CH:65]=[C:66]([C:2]2[C:3](=[O:36])[C:4]3[C:9]([C:10]=2[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:27][CH2:28]2)[CH:5]=3)[CH:67]=[CH:68][C:69]=1[O:70][CH3:71]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCN(C(=O)OC(C)(C)C)CC4)cc3C2=O)cc1F

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using t-butyl 4-(3-(2-bromo-3-(3,5-difluorophenyl)-1-oxo-1H-inden-6-yloxy)propyl)piperazine-1-carboxylate obtained in Step 1 of Example 104 as a starting material instead of 6-(2-morpholino ethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 3-fluoro-4-methoxyphenylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound.
Reaction SMILES: Cl.[CH:2]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]#[N:18]>ClC1C=CC=CC=1>[CH:2]1([NH:8][C:17]([NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH3:9])=[NH:18])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccccc1NC#N
Reactant: NC1CCCCC1
Agent: Cl
Solvent: Clc1ccccc1
Product: Cc1ccccc1NC(=N)NC1CCCCC1
Reaction time: 8 h
Yield: 26.5 %

Procedure:
A suspension of cyclohexylamine hydrochloride (310 mg, 2.28 mmol) and (2-methylphenyl)cyanamide (365 mg, 2.76 mmol) in dry chlorobenzene was heated at 125°-135° for 4 hrs. The solvent was evaporated in vacuo with heating, and the residue partitioned between CH2Cl2 and 20-8 ml 10% HCl. The aqueous extracts were made alkaline to pH 9-9.5, and the white precipitate collected after standing at 4° C. overnight. Two recrystallizations from EtOH/H2O gave 140 mg (22%) of white needles, mp 145°-146°, 1H (CD3OD) 1.149-2.054 (m, 10 H), 2.164 (s, 3 H), 3.50 (m, 1 H), 6.875 (d, 1H, J=7.5 Hz), 6.968 (t, 1H, J=7.5 Hz), 7.118 (t, 1H, J=7.5 Hz), 7.177 (d, 1H, J=7.5 Hz). Anal. Calcd for C14H21N3 : C, 72.69; H, 9.15; N, 18.16. Found: C, 72.72; H, 9.24; N, 18.18.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]2[C:3]=1[CH2:4][N:5]([CH:13]([CH3:15])[CH3:14])[C:6]2=[O:12].[N:16]([O-])=O.[Na+].[Sn](Cl)Cl>Cl.O>[ClH:11].[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][NH2:16])=[C:3]2[C:7]=1[C:6](=[O:12])[N:5]([CH:13]([CH3:15])[CH3:14])[CH2:4]2
Reactant: O=N[O-]
Reactant: CC(C)N1Cc2c(N)ccc(Cl)c2C1=O
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CC(C)N1Cc2c(NN)ccc(Cl)c2C1=O
Temperature: 5 °C
Reaction time: 0.75 h

Procedure:
A stirred solution of 4.0 grams (0.018 mole) of 4-amino-7-chloro-2-(1-methylethyl)isoindolin-1-one in 40 mL of concentrated hydrochloric acid was cooled in an ice-water bath, and a solution of 1.2 grams (0.018 mole) of sodium nitrite in 20 mL of water was added dropwise while maintaining the reaction mixture temperature under 5° C. Upon completion of addition, the reaction mixture was stirred for about 45 minutes, then a solution of 8.8 grams (0.039 mole) of tin(II) chloride in 20 mL of concentrated hydrochloric acid was added dropwise while still maintaining the reaction mixture temperature under 5° C. After this time the reaction mixture was stirred for about one hour at 5° C., then it was filtered to collect, after drying, 4.6 grams of subject compound, mp 186° C., dec. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1I>>[NH2:15][C:7]1[C:6]([C:4]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[F:17])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: Fc1ccccc1I
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCSc1ncc(C(=O)c2ccccc2F)c(N)n1

Procedure:
The same procedure was used as described in Example 2, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methylamide (from Example 1) and a solution of 2-fluorophenylilithium (˜3 equiv, freshly prepared from 1-fluoro-2-iodobenzene as in Example 2A), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2-fluoro-phenyl)-methanone. MS (M+H)+: 278.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([CH:15]=[N:16]O)=[C:10]3[CH2:9][N:8]([CH3:18])[C:7](=[O:19])[C:6]=2[CH:20]=1>C(OC(=O)C)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]#[N:16])=[C:10]3[CH2:9][N:8]([CH3:18])[C:7](=[O:19])[C:6]=2[CH:20]=1
Reactant: CN1Cc2c(C=NO)ncn2-c2ccc(F)cc2C1=O
Solvent: CC(=O)OC(C)=O
Product: CN1Cc2c(C#N)ncn2-c2ccc(F)cc2C1=O

Procedure:
1.65 g (6 mmol) of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde-3-oxime are heated to boiling under reflux for 4.5 hours in 15 ml of acetic acid anhydride and the mixture is evaporated. The residue is taken up in 100 ml of chloroform and the solution is washed once with saturated sodium hydrogen carbonate solution and once with water. The chloroform solution is dried over magnesium sulphate and concentrated. After column chromatography and recrystallisation from ethyl acetate, there is obtained 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile of melting point 236°-237° C.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:13])[C:10]([CH3:12])=C)=[CH:6][C:5]([F:14])=[CH:4][N:3]=1.O.[CH:16](Cl)(Cl)Cl.CO>CN(C)C=O.C(N(CC)CC)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:14][C:5]1[CH:6]=[C:7]2[C:2]([C:12]([CH3:16])=[CH:10][C:9](=[O:13])[NH:8]2)=[N:3][CH:4]=1
Reactant: ClC(Cl)Cl
Reactant: C=C(C)C(=O)Nc1cc(F)cnc1Cl
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(=O)[nH]c2cc(F)cnc12
Temperature: 110 °C
Reaction time: 0.67 h

Procedure:
To a solution of 1.1 g of N-(2-chloro-5-fluoropyridin-3-yl)-2-methylacrylamide in 10 mL of N,N-dimethylformamide, 1.5 mL of triethylamine and 0.13 g of bis(tri-tert-butylphosphine)palladium(0) were added, and the mixture was stirred at 110° C. for 3 hours 40 minutes under a nitrogen flow. Thereto was further added 0.13 g of bis(tri-tert-butylphosphine)palladium(0), and the mixture was stirred for 2 hours. Thereto was further added 0.13 g of bis(tri-tert-butylphosphine)palladium(0), and the mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature, the solvent was then distilled off under reduced pressure, and diisopropyl ether and ethyl acetate were added to the resultant residue, the solid was filtered off, and washed with ethyl acetate, to the solid thus obtained, water, chloroform and methanol were added, the organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the resultant residue, diisopropyl ether was added, and the solid was filtered off to obtain 0.25 g of 7-fluoro-4-methyl-1,5-naphthyridin-2(1H)-one as a light brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])=[C:8]([CH:19]=1)[O:9][CH2:10][CH:11]([OH:18])[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)([O-:3])=[O:2].[C:27](Cl)(=[O:29])[CH3:28]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:20]([F:26])([F:25])[C:21]([F:22])([F:23])[F:24])=[C:8]([CH:19]=1)[O:9][CH2:10][CH:11]([O:18][C:27](=[O:29])[CH3:28])[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)([O-:3])=[O:2]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OCC(O)CN2CCCC2)c1
Solvent: ClCCl
Product: CC(=O)OC(COc1cc([N+](=O)[O-])ccc1C(F)(F)C(F)(F)F)CN1CCCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Dissolved 1-(5-nitro-2-pentafluoroethyl-phenoxy)-3-pyrrolidin-1-yl-propan-2-ol (3.5 g) in CH2Cl2 (15 ml) added TEA (2.55 ml) and cooled to 0° C. Acetyl chloride (781.3 μl) was added dropwise, forming a suspension. The mixture was warmed to RT and stirred for 1.5 h. Additional acetyl chloride (200 μl) was added and the mix was stirred for another h. The mixture was diluted with CH2Cl2 and washed with sat. NaHCO3. The organic layer was removed, washed with brine and back extracted with CH2Cl2. Dried the combined organic layers over Na2SO4, filtered and concentrated in vacuo. The residue was purified over silica gel column (5:94.5:0.5 MeOH: CH2Cl2:NH4OH) to provide acetic acid 2-(5-nitro-2-pentafluoroethyl-phenoxy)-1-pyrrolidin-1-ylmethyl-ethyl ester as a yellow brown oil.