Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13]Cl)=[CH:4][CH:3]=1.C1COCC1.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:51]([O-:54])(=[O:53])C.[Na+]>CC([O-])=O.CC([O-])=O.[Pd+2].O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:51]([OH:54])=[O:53])=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: Fc1ccc(Cc2ccccc2CCl)cc1
Agent: [Pd+2]
Agent: [Na+]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccccc1Cc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
[2-(4-fluoro-benzyl)-phenyl]-chloromethane (1 eq.), THF (1 L/mol), water (0.7 L/mol), Pd(OAc)2 (1.3 mol %), dppp (2.6 mol %) and sodium acetate (2.5 eq.) were placed in a inertized reactor. The reaction mixture is placed under a CO pressure of 4 bars and allowed to stir at 80° C. for 20 hours. The organic layer is separated and evaporated under pressure. Toluene (0.75 L/mol) is added to the residue and the carboxylic acid is extracted with a 2 N solution of sodium hydroxide (0.75 L/mol). The black particles of palladium are removed by filtration over Celite. The water layer is placed in a flask and acetic acid (0.9 L/mol) is added. The mixture is warmed up to 80° C. then allowed to spontaneously cool down. The crystallisation starts around 50° C. The crystals are filtered off at room temperature, washed with water and dried to give black [2-(4-fluoro-benzyl)-phenyl]-acetic acid (91%). Treatment of 5 g of black [2-(4-fluoro-benzyl)-phenyl]-acetic acid with charcoal in 25 ml of a mixture of acetic acid and water (7/3) allows the isolation of pure white crystals of [2-(4-fluoro-benzyl)-phenyl]-acetic acid. This step can be performed before the first addition of acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([CH2:6][OH:7])=[C:8]([CH3:10])[CH:9]=1
Reactant: Cc1cc(Cl)cc(C)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Cl)cc(C)c1CO
Temperature: 0 °C

Procedure:
Dissolve 4-chloro-2,6-dimethyl benzaldehyde (5.0 g, 168.64 g/mol) in 100 mL dry MeOH. Cool to 0° C. while stirring under N2. Portionwise add powdered NaBH4 (0.76 g, 37.85 g/mol) over 5 min. Stir at 0° C. for 2 h, monitoring by TLC until aldehyde consumed, then evaporate to a yellow oil. Add H2O (50 mL) and bring to pH 7.0 by addition of saturated NH4Cl. Extract the neutral aqueous layer with CH2Cl2 (3×75 mL) and dry the pooled organic layers over Na2SO4. Filter and concentrate to a yellow oil. Flush through a pad of silica to remove baseline material, then evaporate to a yellow solid (3.0 g) which can be used without further purification. LCMS=171.6 (MH+), 169.6 (M−).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH2:11][O:12][CH2:13][C:14]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:8]2[C:4](=[CH:5][N:6]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:7]=2)[CH:3]=1.[CH:41]1(B(O)O)[CH2:43][CH2:42]1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:41]1([C:2]2[CH:10]=[C:9]([CH2:11][O:12][CH2:13][C:14]3([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]3)[C:8]3[C:4](=[CH:5][N:6]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:38])[CH3:39])[N:7]=3)[CH:3]=2)[CH2:43][CH2:42]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(C3CC3)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Temperature: 100 °C

Procedure:
tert-Butyl 4-(((5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (42 mg, 0.07 mmol), cyclopropyl boronic acid (17.2 mg, 0.2 mmol), and tetrakis(triphenylphosphine) palladium(0) (7.7 mg, 0.007 mmol) were combined in dry tetrahydrofran (2 mL) in a microwave tube and sealed. After flushing the mixture with nitrogen, 0.24 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 100° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated and purified by flash chromatography on silica gel to afford 34 mg (86%). 1H-NMR (CDCl3, 300 MHz) δ 7.86 (s, 1H), 7.32 (m, 1H), 7.14-7.23 (m, 5H), 6.94 (m, 1H), 5.32 (s, 2H), 4.65 (s, 2H), 3.61-3.85 (m, 2H), 3.39 (s, 2H), 3.32-3.38 (m, 2H), 2.95-3.02 (m, 2H), 2.06-2.11 (m, 2H), 1.93-1.96 (m, 1H), 1.71-1.80 (m, 2H), 1.39 (s, 9H), 0.92-0.97 (m, 2H), 0.64-0.78 (m, 4H), 0.13 (s, 9H). Mass spec.: 592.24 (MH)+.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3]Br.O.O.O.O.O.O.O.O.O.[S-2:16].[Na+].[Na+].[S]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.O>[F:1][C:2]([F:6])([F:5])[CH2:3][S:16][S:16][CH2:3][C:2]([F:6])([F:5])[F:1]
Reactant: FC(F)(F)CBr
Reactant: [S-2]
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)CSSCC(F)(F)F
Temperature: 70 °C

Procedure:
A mixture of 2,2,2-trifluoroethyl bromide (9.8 g), sodium sulphide nonahydrate (14.4 g), sulphur (1.9 g), hexadecyl tributyl phosphonium bromide (1.0 g) and water (18.0 g) was charged to a Carius tube under a nitrogen atmosphere and the tube sealed. The tube was heated to 70° C. for 8 hours, cooled and the contents subjected to steam distillation to give bis-(2,2,2-trifluoroethyl) disulphide as an oil in a yield of 67° C. The product was identified by GC-mass spectroscopy.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].I[CH2:15][CH2:16][O:17][CH3:18].CC(C)([O-])C.[K+].[Cl-].[NH4+]>CN(C)C=O>[CH3:18][O:17][CH2:16][CH2:15][C:2]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[S:3][CH2:4][CH2:5][CH2:6][S:1]1
Reactant: CC(C)(C)OC(=O)C1SCCCS1
Reactant: COCCI
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCC1(C(=O)OC(C)(C)C)SCCCS1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
10.2 g (46.1 mmol) of tert-butyl 1,3-dithiane-2-carboxylate and 12.0 g (64.5 mmol) of 1-iodo-2-methoxyethane were initially charged in 127 ml of dimethylformamide, the mixture was cooled to 0° C. and 6.21 g (55.3 mmol) of potassium tert-butoxide were added. The resulting reaction mixture was stirred at 0° C. for 1 h and at RT for 16 h. The reaction mixture was added to 1.5 l of a 1:2 mixture of ice and saturated aqueous ammonium chloride solution and extracted three times with 300 ml of diethyl ether. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was used for the next step without further purification. Yield: 11.1 g (87% of theory)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.Br[C:36]1[CH:41]=[C:40]([CH3:42])[N+:39]([O-:43])=[C:38]([CH3:44])[CH:37]=1>>[OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:15]=[CH:16][C:17]([C:36]3[CH:41]=[C:40]([CH3:42])[N+:39]([O-:43])=[C:38]([CH3:44])[CH:37]=3)=[CH:18][CH:19]=2)[CH3:13])[CH2:7][CH2:6]1
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccccc4)OC3=O)cc2)cc(C)[n+]1[O-]

Procedure:
The title compound was prepared from (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-2,6-dimethylpyridine-N-oxide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.086, m/z=461.1; 1H NMR (CDCl3) 1.34 (m, 1H), 1.50 (d, 3H), 1.61-1.72 (m, 2H), 1.88-2.00 (m, 2H), 2.18 (m, 1H), 2.22-2.34 (m, 2H), 2.62 (s, 6H), 2.88 (m, 1H), 3.51 (t, 2H), 5.65 (m, 1H), 6.93 (d, 2H), 7.21 (m, 1H), 7.26 (m, 4H), 7.29-7.38 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][C:8]=1[Cl:17].[Li+].[OH-].C1COCC1.CO.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[Cl:17]
Reactant: COC(=O)c1ccc(OCc2cccc(Cl)c2)c(Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(OCc2cccc(Cl)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of compound 27c (662 mg, 2.0 mmol) and LiOH (192 mg, 8 mmol) in a solvent mixture of THF/MeOH/H2O (3/3/3 mL) was stirred at room temperature for 4 h, then acidified with 15% citric acid in H2O. The mixture was extracted with EtOAc (3×), and the combined extracts washed sequentially with water and brine. The extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant crude compound 3b was dried under reduced pressure for 18 h and used in the following reaction without further purification.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]4[CH2:29][CH2:28][NH:27][CH:26]([CH3:30])[C:21]=4[N:22]3[CH3:25])=[CH:18][CH:17]=2)[C:12](=[O:31])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:36](C)=O.[Na+]>CO>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]4[CH2:29][CH2:28][N:27]([CH3:36])[CH:26]([CH3:30])[C:21]=4[N:22]3[CH3:25])=[CH:18][CH:17]=2)[C:12](=[O:31])[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC1NCCc2c1n(C)c1cc(-n3ccc(OCc4ccccc4)cc3=O)ccc21
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc3n2C)CCN1C
Temperature: 25 °C
Yield: 77.2 %

Procedure:
To a solution of 4-(benzyloxy)-1-(1,9-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride (205 mg, 0.470 mmol) in CH3OH (8 mL) was added formaldehyde (53 μL, 0.71 mmol) and NaBH(OAc)3 (200 mg, 0.94 mmol). The reaction was stirred at room temperature until complete and then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and washed with H2O and 5% aqueous LiCl and dried over Na2SO4. The organic solution was filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) to give 4-(benzyloxy)-1-(1,2,9-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one as a white solid (0.15 g, 77%). The free base was converted to the HCl salt to give the title compound (147 mg, 90%) as an off-white powder: 1H NMR (500 MHz, CD3OD) δ 7.58-7.55 (m, 2H), 7.47-7.34 (m, 6H), 6.99 (d, J=8.5, 1.0 Hz, 1H), 6.28 (dd, J=7.5, 2.5 Hz, 1H), 6.11 (d, J=2.5 Hz, 1H), 5.18 (s, 2H), 4.27 (q, J=6.5 Hz, 1H), 3.69 (s, 3H), 3.36-3.33 (m, 1H), 3.10-2.96 (m, 2H), 2.84-2.80 (m, 1H), 2.65 (s, 3H), 1.51 (d, J=6.5 Hz, 3H); ESI MS m/z 414 [M+H]+; HPLC (Method A)>99% (AUC), tR=13.0 min.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH2:22]([OH:24])[CH3:23].[Na]>O>[CH2:22]([O:24][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19])[CH3:23]
Reactant: CCO
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Agent: [Na]
Solvent: O
Product: CCOc1c(C(F)(F)F)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12
Temperature: 25 °C

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole (3.0 grams; 0.09 mole) was added to about 100 milliliters of ethanol, and the mixture was then refluxed overnight (3.0 grams) and the starting material was recovered. Sodium (.42 gram; 0.018 mole) was added to 100 milliliters of ethanol, and the recovered 4-chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole was added at room temperature and the resulting reaction mixture was stirred at room temperature over a weekend. TLC showed only the starting material, so the reaction mixture was heated to reflux and refluxed overnight. The reaction mixture was then poured into water, acidified, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and solvent removed by evaporation to obtain the desired 4-ethoxy-7-nitro-2,5-bis(trifluoromethyl)benzimidazole. After recrystallization from a mixture of ethanol and water, it melted at 144°-46°C. Analysis, Calc.: C, 38.50; H, 2.06; N, 12.24 Found: C, 38.65; H, 2.26; N, 12.36
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([CH:13]([CH3:15])[CH3:14])[C:6]=2[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2C1CCCCO1.CCN(C(C)C)C(C)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:24]3[N:32]=[CH:31][N:30]=[C:29]4[C:25]=3[N:26]=[CH:27][NH:28]4)[CH3:11])[N:7]([CH:13]([CH3:14])[CH3:15])[C:6]=2[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CC(C)n1c([C@H](C)N)nc2ccc(F)c(-c3ccccn3)c21
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1c([C@H](C)Nc2ncnc3[nH]cnc23)nc2ccc(F)c(-c3ccccn3)c21
Temperature: 90 °C
Yield: 9.2 %

Procedure:
(S)-1-(6-Fluoro-1-isopropyl-7-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine (0.18 g, 0.6 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (145 mg, 0.60 mmol) and DIPEA (543 μL, 3.0 mmol) were added and the reaction mixture heated at 90° C. for 16 hours. The reaction mixture was loaded onto an SCX column to remove the THP group. The column was washed with MeOH and the product was eluted with 2M NH3 in MeOH. The product fractions were collected, concentrated in vacuo and the resultant residue was subjected to flash chromatography (SiO2, eluting with 0-10% methanol in DCM) to give 409 as a white solid (23 mg, 10%). LCMS (Method K): RT 2.94 min [M+H]+ 417. 1H NMR (DMSO-d6, 400 MHz): δ 12.69 (1H, br s), 8.69 (1H, d, J=4.4 Hz), 8.17 (1H, br s), 8.13 (1H, s), 7.93 (1H, td, J=7.8, 1.8 Hz), 7.66 (1H, dd, J=8.8, 5.0 Hz), 7.64 (1H, br s), 7.62 (1H, d, J=7.8 Hz), 7.47 (1H, ddd, J=7.7, 4.9, 1.1 Hz), 7.11 (1H, dd, J=10.2, 8.9 Hz), 5.90-5.78 (1H, m), 4.11-3.87 (1H, m), 1.62 (3H, d, J=6.6 Hz), 1.35-1.15 (6H, m)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([CH2:23][CH3:24])[CH:3]=1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[CH2:23]([C:4]1[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=2)[CH:7]=[CH:6][C:5]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=2[C:13]=1[CH3:22])(=[O:10])=[O:11])[CH3:24]
Reactant: CCc1cc(Br)ccc1NS(=O)(=O)c1sc2ccc(F)cc2c1C
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CCc1cc(-c2ccncc2)ccc1NS(=O)(=O)c1sc2ccc(F)cc2c1C
Yield: 25.1 %

Procedure:
This product was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-ethyl-phenyl)-amide (0.10 g) and 4-pyridineboronic acid (0.043 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.25 ml) and 2 M aqueous sodium carbonate solution (0.9 ml) with tetrakis(triphenylphosphine)palladium (0.013 g) to obtain the title compound (0.025 g) as a yellowish foam. MS (ISP): 427.3 (M+H)+
Reaction SMILES: [C:1]([CH:3]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]([CH3:18])([CH3:17])[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)#[N:2].[O-]CC.[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(O)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][C:3]1([C:1]#[N:2])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]([CH3:18])([CH3:17])[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:29]
Reactant: CC1(C)c2ccccc2C(C#N)c2ccccc21
Reactant: CCOC(=O)CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC1(C#N)c2ccccc2C(C)(C)c2ccccc21
Yield: 89.5 %

Procedure:
9-cyano-10,10-Dimethyl-9,10-dihydroanthracene [9] (0.8 g, 3.42 mmol) was added to sodium ethoxide prepared from Na metal (0.110 g, 4.80 mmol) and ethanol (10 mL) and heated under reflux for one hour leading to the development of a greenish brown solution. The solution was then cooled in an ice bath and ethyl bromoacetate (0.80 g, 4.80 mmol) was added dropwise via a syringe. The resulting mixture was then heated at reflux (4 h) and filtered. The solid residue was washed with ether (25 mL). Water (25 mL) was added to the filterate and the organic layer was separated. The aqueous layer was once again extracted with ether (25 mL). The combined ether extracts were washed with water, brine, dried (MgSO4) and evaporated under reduced pressure to give an oil which was purified by medium pressure liquid chromatography using pet. ether: EtOAc (9:1) as eluent to give 0.978 g (74%) of the product as a colorless oil. 1H NMR (CDCl3)d: 0.98-1.06 (t, 3H, CH3), 1.64-1.67 (d, J=9Hz, 3H, CH3), 1.71-1.74 (d, J=9 Hz, 3H, CH3), 3.04-3.07 (d, J=9Hz, 2H, CH2), 3.86-3.94 (q, 2H, CH2), 7.29-7.77 (m, 8H, Ar—H). 13C NMR (CDCl3)d: 14.39, 33.85, 35.21, 38.37, 52.29, 61.38, 123.17, 127.53, 127.84, 128.17, 129.48, 130.97, 143.23, 167.97.
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:5]=[C:6]([C@H:9]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[N:16](COCC[Si](C)(C)C)[CH:15]=2)=[O:13])[CH3:10])[O:7][CH:8]=1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH2:3][C:4]1[N:5]=[C:6]([C@H:9]([NH:11][C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=5)[N:25]([CH3:33])[N:24]=4)[N:21]=3)[NH:16][CH:15]=2)=[O:13])[CH3:10])[O:7][CH:8]=1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1nc(CC#N)co1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1nc(CC#N)co1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyanomethyl-oxazol-2-yl)-ethyl]-amide (36 mg, 0.063 mmol) was dissolved in dichloromethane (0.4 ml) and trifluoroacetic acid (0.20 ml, 2.6 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.4 ml) and ethylenediamine (0.26 ml, 3.8 mmol) was added. The yellow solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resultant suspension was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 18 mg (65%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyanomethyl-oxazol-2-yl)-ethyl]-amide as an off-white powder. MS: (M+Na)+=467; 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 12.93 (br. s., 1H), 9.12 (s, 1H), 8.66 (d, J=8.3 Hz, 1H), 8.50 (s, 1H), 8.46 (dd, J=8.9, 5.4 Hz, 1H), 8.06 (t, J=1.0 Hz, 1H), 7.69 (dd, J=9.7, 2.1 Hz, 1H), 7.12 (td, J=9.0, 2.3 Hz, 1H), 5.44-5.56 (m, 1H), 4.15 (s, 3H), 3.92 (d, J=1.3 Hz, 2H), 1.68 (d, J=7.0 Hz, 3H).
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[C:43]([CH:46]1[CH2:50][CH:49]([C@@H:51]2[CH2:55][C@H:54]([SH:56])[CH2:53][N:52]2[C:57]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=2)=[O:58])[CH2:48][N:47]1[C:70]([O:72][CH2:73][C:74]1[CH:79]=[CH:78][C:77]([N+:80]([O-:82])=[O:81])=[CH:76][CH:75]=1)=[O:71])(=[O:45])[NH2:44]>>[C:43]([CH:46]1[CH2:50][CH:49]([C@@H:51]2[CH2:55][C@H:54]([S:56][C:18]3[C@H:19]([CH3:42])[C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]4[C:22]=3[C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])[CH2:53][N:52]2[C:57]([O:59][CH2:60][C:61]2[CH:62]=[CH:63][C:64]([N+:67]([O-:69])=[O:68])=[CH:65][CH:66]=2)=[O:58])[CH2:48][N:47]1[C:70]([O:72][CH2:73][C:74]1[CH:79]=[CH:78][C:77]([N+:80]([O-:82])=[O:81])=[CH:76][CH:75]=1)=[O:71])(=[O:45])[NH2:44]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: NC(=O)C1CC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CC(C(N)=O)N(C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 82.9 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (174 mg, 0.29 mmol) and (2S,4S)-2-[2-carbamoyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer I (160 mg, 0.28 mmol, compound of Reference Example 13) to obtain p-nitrobenzyl (1R,5S,6S)-2-[(2S,4S)-2-[2-carbamoyl-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate diastereomer I (223 mg, yield: 82.9%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[N:21]=[C:20]4[NH:25][C:26](=[O:28])[NH:27][C:19]4=[CH:18][C:17]=3[CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+](C1C=CC(OCCCS(C2C=CC(Cl)=CC=2)(=O)=O)=CC=1C=C1NC(=O)NC1=O)([O-])=O>>[C:5]1([S:8]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[N:21]=[C:20]4[NH:25][C:26](=[O:28])[NH:27][C:19]4=[CH:18][C:17]=3[CH:16]=2)(=[O:10])=[O:9])[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: O=c1[nH]c2cc3cc(OCCCS(=O)(=O)c4ccc(Cl)cc4)ccc3nc2[nH]1
Agent: O=C1NC(=O)C(=Cc2cc(OCCCS(=O)(=O)c3ccc(Cl)cc3)ccc2[N+](=O)[O-])N1
Product: O=c1[nH]c2cc3cc(OCCCS(=O)(=O)c4ccccc4)ccc3nc2[nH]1

Procedure:
1,3-Dihydro-7-[3-[(4-chlorophenyl)sulfonyl]propoxy]-2H-imidazo[4,5-b]quinolin-2-one was analogously prepared from 5-[[2-nitro-5-[3-[(4-chlorophenyl)sulfonyl]propoxy]phenyl]methylene]-2,4-imidazolidinedione.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:22]3[NH:23][CH:24]=[CH:25][CH:26]=3)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[Br:27][CH2:28][CH2:29][CH2:30]Br>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]=[C:11]([C:22]3[NH:23][CH:24]=[CH:25][CH:26]=3)[N:10]([CH2:30][CH2:29][CH2:28][Br:27])[C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:15][CH:16]=1
Reactant: BrCCCBr
Reactant: COc1ccc(-c2nc(-c3ccc[nH]3)[nH]c2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2nc(-c3ccc[nH]3)n(CCCBr)c2-c2ccc(OC)cc2)cc1

Procedure:
4,5-Bis(4-methoxyphenyl)-2-(2-pyrrolyl)-1-(3-bromopropyl)imidazole is prepared analogously to Example 22 by reacting 4,5-bis(4-methoxyphenyl)-2-(2-pyrrolyl)-imidazole with 1,3-dibromopropane. Melting point 97° C.