Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[S:10][CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](OB(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>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.C(O)C>[N+:14]([C:13]1[CH:12]=[CH:11][S:10][C:9]=1[C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1)([O-:16])=[O:15]
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccsc1Br
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=[N+]([O-])c1ccsc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.5 %

Procedure:
To 50 ml of toluene, 1 g of 2-bromo-3-nitrothiophene, 0.75 g of 4-chlorophenylboric acid, 5 ml of a 2M-aqueous potassium carbonate solution and 2 ml of ethanol were added and stirred at room temperature for 30 minutes in a nitrogen atmosphere. Successively 0.28 g of Pd(PPh3)4 was added and heat-refluxed for 2 hours. The aqueous layer was separated from the reaction mixture and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue thus obtained was purified by silica gel column chromatography to obtain 1.1 g of the product as a yellow crystal. The yield was 98%. 1H-NMR(CDCl3, δ value):7.29(1H, d, J=5.9), 7.43(4H, s), 7.66(1H, d, J=5.9)
Reaction SMILES: C1(NC2C(C)=NC3C(N=2)=C(C2NC4[C@H]([C@H](O)C)NC(=O)C=4C=2)C(F)=CC=3)CC1.Br[CH2:30][C:31]([C:33]1[C:42]([F:43])=[CH:41][CH:40]=[C:39]2[C:34]=1[N:35]=[C:36]([NH:45][CH:46]1[CH2:48][CH2:47]1)[C:37]([CH3:44])=[N:38]2)=[O:32].[C:49]([O:53][C:54]([NH:56][C@H:57]([C@@H:66]([O:68][Si:69]([C:72]([CH3:75])([CH3:74])[CH3:73])([CH3:71])[CH3:70])[CH3:67])[C:58](=[O:65])[CH2:59][C:60]([O:62][CH2:63][CH3:64])=[O:61])=[O:55])([CH3:52])([CH3:51])[CH3:50].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCO.CC(O)=O>[C:49]([O:53][C:54]([NH:56][C@H:57]([C@@H:66]([O:68][Si:69]([C:72]([CH3:74])([CH3:73])[CH3:75])([CH3:70])[CH3:71])[CH3:67])[C:58](=[O:65])[CH:59]([CH2:30][C:31]([C:33]1[C:42]([F:43])=[CH:41][CH:40]=[C:39]2[C:34]=1[N:35]=[C:36]([NH:45][CH:46]1[CH2:48][CH2:47]1)[C:37]([CH3:44])=[N:38]2)=[O:32])[C:60]([O:62][CH2:63][CH3:64])=[O:61])=[O:55])([CH3:52])([CH3:50])[CH3:51]
Reactant: Cc1nc2ccc(F)c(C(=O)CBr)c2nc1NC1CC1
Reactant: CCOC(=O)CC(=O)[C@H](NC(=O)OC(C)(C)C)[C@H](C)O[Si](C)(C)C(C)(C)C
Agent: Cc1nc2ccc(F)c(-c3cc4c([nH]3)[C@H]([C@@H](C)O)NC4=O)c2nc1NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)C(CC(=O)c1c(F)ccc2nc(C)c(NC3CC3)nc12)C(=O)[C@H](NC(=O)OC(C)(C)C)[C@H](C)O[Si](C)(C)C(C)(C)C
Yield: 96 %

Procedure:
This compound (2.43 g, 73% yield) as a bright yellow crystalline solid was prepared according to the procedures described for Intermediate 352b, using 2-bromo-1-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanone (613) (1.82 g, 5.39 mmol) and (4R,5S)-ethyl 4-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-3-oxohexanoate (615) (2.61 g, 6.47 mmol) and K2CO3 (0.931 g, 6.73 mmol) in DMF (10 mL) as the strafing materials, followed by subsequent treatment of the resulting (4R,5S)-ethyl 4-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-2-(2-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxohexanoate (353a) (3.42 g, 96% yield, LC-MS m/z 661.1, [M+H]+) with NH4OAc (5.98 g, 78 mmol) in 10 mL of EtOH and 5 mL of AcOH. 19F NMR (DMSO-d6; 376 MHz): δ −110.91 (s, 1F). LC-MS m/z 642.2, [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]=C)[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].I([O-])(=O)(=O)=[O:18].[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]=[O:18])[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Agent: O=[Os](=O)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(Cl)nc(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 2-chloro-6-vinylisonicotinate (9.6 g, 40.1 mmol) in THF (100 mL) and water (100 mL) were added osmium tetroxide (4% in water; 6.3 mL, 0.80 mmol) and sodium periodate (25.7 g, 120.0 mmol). The mixture was stirred at ambient temperature. After 30 min, saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:31][CH2:32][CH3:33])=[C:15]([C:17]2[NH:18][C:19](=[O:30])[C:20]3[N:25]([CH3:26])[N:24]=[C:23]([CH2:27][CH2:28][CH3:29])[C:21]=3[N:22]=2)[CH:16]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:32]([O:31][C:14]1[CH:13]=[CH:12][C:11]([C:9](=[O:10])[CH2:8][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:16][C:15]=1[C:17]1[NH:18][C:19](=[O:30])[C:20]2[N:25]([CH3:26])[N:24]=[C:23]([CH2:27][CH2:28][CH3:29])[C:21]=2[N:22]=1)[CH3:33]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(C(=O)CBr)ccc3OCC)nc12
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(C(=O)CN4CCCCC4)ccc3OCC)nc12
Yield: 28 %

Procedure:
Piperidine (0.22 ml, 0.0022 mol) was added to a stirred suspension of 5-(5-bromoacetyl-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Preparation 8, 0.95 g, 0.0022 mol) and anhydrous potassium carbonate (0.6 g, 0.0044 mol) in acetonitrile (50 ml) at room temperature. After 18 hours the mixture was evaporated under vacuum, the residue dissolved in water (50 ml) and the solution extracted with ethyl acetate (3×30 ml). The organic extracts were combined, washed with brine (3×20 ml), dried (Na2SO4) and evaporated under vacuum. The resulting yellow solid was chromatographed on silica gel (12 g), using a methanol in dichloromethane elution gradient (0-2% methanol), to give an off-white solid. Crystallisation from ethyl acetate-hexane gave the title compound as an off-white powder (0.27 g, 28%), m.p. 149-151° C. Found: C,66.13; H,6.90; N, 15.95. C24H31N5O5 requires C,65.88; H,7.14; N,16.01%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([OH:31])=[C:6]([C:8]2[N:17]=[C:16]([NH:18][C@H:19]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CC(N(C)C)=O>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[CH:4][C:5]([OH:31])=[C:6]([C:8]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:23][CH2:22][NH:21][CH2:20]4)[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)[CH:7]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3cc(Br)ccc3O)nc3ccccc23)C1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Oc1ccc(-c2ccc(F)cc2)cc1-c1nc(N[C@H]2CCNC2)c2ccccc2n1
Reaction time: 16 h
Yield: 27 %

Procedure:
(S)-tert-Butyl 3-(2-(5-bromo-2-hydroxyphenyl)quinazolin-4-ylamino)pyrrolidine-1-carboxylate (0.051 g, 0.105 mmol, prepared in a method analogous to that described in Synthesis 2-A), 4-fluorobenzene boronic acid (0.016 g, 0.114 mmol), palladium tetrakistriphenyl phosphine (0.028 g, 0.024 mmol) and potassium phosphate (0.051 g, 0.243 mmol) were dissolved in dimethyl acetamide (0.7 mL) and water (0.3 mL) and the mixture was heated in a microwave for 10 mins at 150° C. The mixture was filtered through a short plug of silica using ethyl acetate as eluent and the filtrate concentrated in vacuo. The residue was dissolved in methanol (1.2 mL) and 4M HCl in dioxane (1.2 mL) was added and the mixture stirred for 16 h. The mixture was concentrated and purified by ion exchange chromatography on SCX-2 Isolute acidic resin (2 g), eluting with methanol and then 1 M ammonia in methanol. The basic fractions were combined and purified by silica column chromatography, eluting with dichloromethane then 10% methanol in dichloromethane, to give the title compound as a yellow solid (0.013 g, 27%).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:21]([C:29]1([CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[C:41]2[CH:40]=[C:39]([B:42]3[O:46][C:45]([CH3:48])([CH3:47])[C:44]([CH3:50])([CH3:49])[O:43]3)[CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][C:32](B1OC(C)(C)C(C)(C)O1)=[CH:33][CH:34]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].CC(C)=O.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.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.CCCCCC.O>[CH2:60]([C:29]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:30]2[CH:31]=[C:32]([C:2]3[CH:20]=[CH:19][C:5]([N:6]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[CH:4][CH:3]=3)[CH:33]=[CH:34][C:35]=2[C:36]2[C:41]1=[CH:40][C:39]([B:42]1[O:43][C:44]([CH3:49])([CH3:50])[C:45]([CH3:47])([CH3:48])[O:46]1)=[CH:38][CH:37]=2)[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67]
Reactant: CCCCCCCCC1(CCCCCCCC)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2-c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Solvent: CC(C)=O
Solvent: O
Solvent: CCCCCC
Product: CCCCCCCCC1(CCCCCCCC)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2-c2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Bromo-N,N-diphenylaniline (19.44 g, 60 mmole, 1 equiv), 2-[9,9-dioctyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (76.9 g, 120 mmole, 2 equiv), Aliquat™ 336 (tricaprylylmethylammonium chloride) (6 g, 15 mmole, 0.25 equiv) and 2M sodium carbonate solution (75 mL, 150 mmole, 2.5 equiv) were added to 600 mL of toluene. This was purged with a stream of nitrogen for about 30 min. Under a nitrogen purge, tetrakis(triphenylphosphine palladium (0) (348 mg, 0.30 mmole, 0.005 equiv) was added. The reaction mixture was then refluxed for 16 hrs. The reaction was cooled to room temperature and water added. The organic layer was separated and washed with water followed by brine. Drying of the organic layer over Na2SO4 and evaporation of the solvent gave a light yellow solid. This was suspended in acetone and the mixture brought to reflux and then allowed to stand at room temperature overnight. Filtration of the solid and concentration of the filtrate gave a solid that was subjected to column chromatography (toluene:hexane 3:7) to give 4-[9,9-dioctyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl]-N,N-diphenylaniline.
Reaction SMILES: C[O:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([CH3:17])[CH:10]=2)=[CH:5][C:4]=1[C:18]1[NH:19][C:20]2[C:25]([C:26]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:24][CH:23]=[C:22]([CH2:33][N:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1)[CH:21]=2.C[Si](Cl)(C)C.[I-].[K+]>C(#N)C>[OH:16][C:12]1[C:11]([CH3:17])=[CH:10][C:9]([C:6]2[CH:5]=[C:4]([C:18]3[NH:19][C:20]4[C:25]([C:26]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][CH:23]=[C:22]([CH2:33][N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH:21]=4)[C:3](=[O:2])[NH:8][N:7]=2)=[CH:14][C:13]=1[CH3:15]
Reactant: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1[nH]c2cc(CN3CCN(C)CC3)ccc2c1-c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(-c2cc(-c3[nH]c4cc(CN5CCN(C)CC5)ccc4c3-c3ccccc3)c(=O)[nH]n2)cc(C)c1O
Reaction time: 2 h
Yield: 34.2 %

Procedure:
48 mg 4-{6-Methoxy-5-[6-(4-methyl-piperazin-1-ylmethyl)-3-phenyl-1H-indol-2-yl]-pyridazin-3-yl}-2,6-dimethyl-phenol are dissolved in 1.2 mL acetonitrile. 34 □L TMSCl and 45 mg potassium iodide are added. The reaction mixture is heated to reflux for 3 hours. Again 34 □L TMSCl and 45 mg potassium iodide are added and the reaction mixture stirred for an additional 2 hours. Purification by HPLC affords 16 mg (34%) 6-(4-hydroxy-3,5-dimethyl-phenyl)-4-[6-(4-methyl-piperazin-1-yl-methyl)-3-phenyl-1H-indol-2-yl]-2H-pyridazin-3-one as its trifluoroacetate salt.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:18]=[O:19].[NH2:20]C1C=CC=CC=1>O1CCOCC1.C(OCC)C>[O:19]1[C:18]2[CH:2]=[CH:3][CH:4]=[CH:5][C:8]=2[CH2:11][CH2:16][NH:20]1.[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: C=O
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: c1ccc2c(c1)CCNO2
Temperature: 25 °C

Procedure:
34.2 g (0.15 mole) of bisphenol-A and 48.6 g (0.6 mole) of aqueous formaldehyde (37%) were added into a 4-neck reactor equipped with a stirrer, temperature controller, and condenser, and then 100 ml of 1,4-dioxane was added as a solvent. The mixture was stirred at room temperature, and to the resulting solution 27.9 g aniline in 30 ml 1,4-dioxane was dripped at a rate of one drop per second while stirring. Upon completion of the dripping the solution was heated and reacted under refluxing for 10 hours. The reaction mixture was dried in a rotary evaporator under vacuum to obtain a yellowish solid. The yellowish solid was dissolved in ethyl ether and washed with 3N aqueous NaOH three times, followed by 1 N aqueous HCl solution several times and pure water several times, before removing the solvent in vacuo. The dried solid was ground to obtain bisphenol-A dihydrobenzoxazine powder, which is yellowish white. m.p. 110° C. EA: Calcd.: C: 80.50%; H: 6.49%; N: 6.00%. Found: C: 80.00%; H: 6.56%; N: 6.08%.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:21]COC)=[C:6]([O:19][CH3:20])[CH:7]=[C:8]2/[C:13](/[CH3:18])=[CH:14]/[C:15]([OH:17])=[O:16])[CH3:2].O>CC(C)=O.Cl>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:21])=[C:6]([O:19][CH3:20])[CH:7]=[C:8]2/[C:13](/[CH3:18])=[CH:14]/[C:15]([OH:17])=[O:16])[CH3:2]
Reactant: CCc1cccc2c(/C(C)=C/C(=O)O)cc(OC)c(OCOC)c12
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCc1cccc2c(/C(C)=C/C(=O)O)cc(OC)c(O)c12
Reaction time: 1 h
Yield: 72.9 %

Procedure:
280 mg of (E)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-butenoic acid was dissolved in 8 ml of acetone, to which 1 ml of concentrated hydrochloric acid was added at room temperature. After stirring for 1 hour, 30 ml of water was added, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and evaporated to obtain 177 mg of the titled compound as pale yellow crystals.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[C:16]1([CH2:15][CH2:14][CH2:13][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: BrCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(CCCn2cnc3ccccc32)cc1

Procedure:
To a flask were added 5 g benzimidazole and 75 ml tetrahydrofuran under nitrogen and the solution was cooled to 10 C with stirring. 2.2 g Sodium hydride were added in small portions and the reaction was stirred for 10 minutes. 1-Bromo-3-phenylpropane was added and the reaction mixture was heated to 40 C for 5 hrs. After cooling to 5 C, the reaction was quenched with slow addition of 100 ml water. After the tetrahydrofuran was removed of by rotovap, the mixture was extracted with 100 ml ethyl acetate and washed with 25 ml water and the solvent was removed on the rotovap. The product was purified by column chromatography using 40% ethyl acetate in hexane resulting in a light yellow oil which crystallized in the freezer.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[C:35]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH3:46])=[CH:40][CH:39]=3)[C:34]([Cl:47])=[C:33]([O:48]CC=C)[C:32]=2[O:52]CC=C)[O:11][C@@H:10]1[CH2:56][O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[NH4+].[Cl-]>C1COCC1.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>[Cl:47][C:34]1[C:35]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH3:46])=[CH:40][CH:39]=2)=[CH:36][C:31]([C@H:12]2[C@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@H:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:10]([CH2:56][O:57][CH2:58][C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)[O:11]2)=[C:32]([OH:52])[C:33]=1[OH:48]
Reactant: C=CCOc1c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc(Cc2ccc(OCC)cc2)c(Cl)c1OCC=C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)c(O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
To a solution of compound 203 (2.82 g, 2.06 mmol) in THF (20 mL) were added NaBH4 (0.23 g, 6.00 mmol) and Pd(PPh3)4 (0.23 g, 0.20 mmol) at 0° C. The mixture was warmed up to r.t. slowly and stirred at r.t. for 12 h. The mixture was cooled to 0° C. and aq. sat'd NH4Cl solution (50 mL) was added to the mixture slowly. The mixture was extracted with EtOAc (50 mL). The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 204 (1.42 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=3)[O:15][C:16]=2[CH3:17])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(F)cc3)c(C)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(F)cc1
Yield: 74.8 %

Procedure:
Reaction of benzoate 46 (491 mg, 1.26 mmol) and 1 M NaOH (10 mL) in dioxane (10 mL) gave acid 47 (354 mg, 75%) as a white solid: mp (H2O) 269-272° C.; 1H NMR δ 13.20 (br s, 1H, CO2H), 8.05 (d, J=8.5 Hz, 2H, H-2, H-6), 7.91 (d, J=8.5 Hz, 2H, H-3, H-5), 7.84-7.89 (m, 2H, H-2′, H-6′), 7.47 (br t, J=8.8 Hz, 2H, H-3′, H-5′), 4.74 (s, 2H, CH2SO2), 2.06 (s, 3H, CH3); MS m/z 376.5 (MH+, 100%). Anal. calcd for C18H14FNO5S.¼H2O: C, 56.91; H, 3.85; N, 3.69. Found: C, 57.15; H, 3.63; N, 3.59%.
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]([C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]=3)=[O:13])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C.CS(C)=O>O>[CH3:19][N:18]1[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]=[C:14]1[C:12]([N:10]1[CH2:11][CH:8]([C:3]2[C:2]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9]1)=[O:13]
Reactant: Cn1c(C(=O)N2CC(c3nccnc3Cl)C2)nc2ccccc21
Reactant: C1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cn1c(C(=O)N2CC(c3nccnc3N3CCCCC3)C2)nc2ccccc21
Temperature: 120 °C
Yield: 63.3 %

Procedure:
To a mixture of [3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-(1-methyl-1H-benzoimidazol-2-yl)-methanone (0.10 g, 0.30 mmol), piperidine (0.052 g, 0.60 mmol) and triethylamine (0.091 g, 0.90 mmol) was added DMSO (4 mL). The solution was heated to 120° C. for 5 h. Then the mixture was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (10 mL), brine (10 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 50% EtOAc in petroleum ether) to give (1-methyl-1H-benzoimidazol-2-yl)-[3-(3-piperidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-methanone (0.072 g, 0.19 mmol, 63% yield) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:15]([O-])=O)=[C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:15])=[C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N)c(N2CCCCC2)c1
Yield: 98 %

Procedure:
1-(5-methoxy-2-nitro-phenyl)-piperidine (80 mg, 0.33 mmol, as prepared in the previous step) was stirred with 55 mg of 5% Pd—C in MeOH (4 mL) under H2 balloon pressure for 2 h. The reaction was filtered through Celite and concentrated in vacuo to afford 67 mg (98%) of the title compound as a reddish solid, which was used immediately without further purification. Mass spectrum (ESI, m/z): Calcd. for C12H18N2O, 207.1 (M+H), found 207.2.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1/[CH:19]=[CH:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])C1C=CC=CC=1>[Pd].C(O)C>[OH:8][C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][C:10]=1[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(F)(F)F)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1ccc(C(F)(F)F)cc1O
Yield: 89 %

Procedure:
A mixture of the product from step (iv) (3.25 g) and 10% palladium on carbon (0.325 g) in ethanol (40 ml) was hydrogenated at a pressure of 3.0 bar overnight. The mixture was filtered through celite and the filtrate concentrated under reduced pressure to give a white solid (2.22 g).