Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:23][CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)[C:11]1[CH:12]=[C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH:14]=[CH:15][CH:16]=1.O.[OH-].[K+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:23][CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)[C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH:14]=[CH:15][CH:16]=1
Reactant: CN1CCC(OC(c2cccc(C#CCCCN)c2)c2nc3ccccc3[nH]2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(OC(c2cccc(C=CCCCN)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To a solution of 5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)-methyl]phenyl}pent-4-ynylamine (200 mg) in N,N-dimethylformamide (1.8 mL) are added water (0.05 mL), potassium hydroxide (42 mg) and palladium(II) acetate. The tube is evacuated, filled with argon and sealed. After stirring at 120° C. for 24 h, the mixture is filtered on celite, and the solvent removed under reduced pressure.diluted with water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 90/10/0 to 90/10/1) to give 5-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-enylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5]Br.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>>[CH:13]1([NH:16][CH2:5][C:4]2[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=[C:2]([F:1])[CH:3]=2)[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1cc(F)cc(CBr)c1
Reactant: NC1CC1
Product: O=[N+]([O-])c1cc(F)cc(CNC2CC2)c1
Yield: 89 %

Procedure:
Using an analogous procedure to that described in the third paragraph of the portion of Example 12 above that is concerned with the preparation of starting materials, 3-fluoro-5-nitrobenzyl bromide was reacted with cyclopropylamine to give N-cyclopropyl N-(3-fluoro-5-nitrobenzyl)amine in 89% yield; 1H NMR: (DMSOd6) 0.25 (m, 2H), 0.35 (m, 2H), 2.03 (m, 1H), 3.02 (br s, 1H), 3.85 (s, 2H), 7.69 (m, 1H), 7.95 (m, 1H), 8.08 (s, 1H); Mass Spectrum: M+H+: 211.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[CH2:4][C:3]1([CH3:14])[CH3:13].C1C=CC(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:29]([CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[CH2:4][C:3]1([CH3:14])[CH3:13])=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC1(C)Cc2ccc(C#N)cc2C1O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)Cc2ccc(C#N)cc2C1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of Step B. 3-hydroxy-2,2-dimethyl-2,3-dihydro-1H-indene-5-carbonitrile (4.98 g, 0.027 mol) in toluene (60 mL) at 0° C. was added DPPA (8.6 mL, 0.040 mol) via syringe dropwise followed by DBU (6.0 mL, 0.040 mol) via syringe dropwise. After stirring at 0° C. for 10 min and rt for 30 min, the mixture was heated at 80° C. for 60 h, then cooled to rt and partitioned between EtOAc (400 mL)/water (100 mL). Resulting layers were separated and the organic layer was washed with water (100 mL), aq HCl (1N, 60 mL×2), water (100 mL), sat. aq. NaHCO3 (80 mL), brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give yellow oil as the crude product. Purification by flash chromatography on silica gel (120 g) eluting with EtOAc/hexane mixtures provided the title compound as a colorless oil (4.12 g, 73% yield). HPLC Ret. time: 3.37 min. LCMS MH+ (m/z) 213.3. 1H NMR: (DMSO-d6, 400 MHz): δ 7.86 (s, 1H), 7.76 (d, 1H), 7.49 (d, 1H), 4.74 (s, 1H), 2.80 (m, 2H), 1.13 (s, 3H), 1.06 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1>[Pt](=O)=O.CO>[F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([NH2:10])[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CO
Product: Nc1cc(F)c(F)cc1N
Reaction time: 5 h
Yield: 81.4 %

Procedure:
Into a Parr bottle were placed 4,5-difluoro-2-nitroaniline (5.00 g, 28.72 mmol), platinum (IV) oxide (0.31 g, 1.13 mmol) and methanol (60 mL). The bottle was flushed three times with hydrogen and was finally pressurized to 45 psig with hydrogen. The bottle was shaken for 5 h, after which time it was depressurized and the contents were poured into a separatory funnel containing ethyl acetate (300 mL) and water (300 mL). The organic layer was collected and washed with saturated aqueous brine solution (100 mL), dried over magnesium sulfate and the solvents were removed under reduced pressure using a rotary evaporator to leave 3.37 g (81%) of a brown solid. MS (Cl): m/z 145 (M+1).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][CH:13]=[N:14][C:15]=2[NH:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO[C:30](OC)([CH3:32])[CH3:31].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CC(C)=O>[OH:9][CH2:8][C@@H:5]1[C@H:6]2[O:7][C:30]([CH3:32])([CH3:31])[O:1][C@H:2]2[C@H:3]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[O:4]1
Reactant: COC(C)(C)OC
Reactant: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(NC(=O)c3ccccc3)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
N-{9-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-9H-purin-6-yl}benzamide (0.643 g, 1.73 mmol), 2,2-dimethoxypropane (1.06 mL, 8.66 mmol), and para-toluenesulfonic acid monohydrate (0.333 g, 1.73 mmol) were dissolved in acetone (43 mL). The solution was stirred at room temperature overnight and then heated to 40° C. for 3 hours. Once cooled to room temperature, saturated sodium bicarbonate solution was added to the reaction mixture and then approximately half the solvent was removed in vacuo. The resulting solution was diluted with water and extracted four times with CH2Cl2. Combined organics were washed with brine and dried over Na2SO4. The crude material was purified by silica gel chromatography (0 to 5% MeOH/CH2Cl2) to isolate the title compound (0.419 g, 59%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2C(OC(C)(C)C)=O)[CH:5]=[C:6]([OH:8])[CH:7]=1.[ClH:21].O1CCOCC1>C(Cl)Cl>[ClH:21].[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc(O)cc(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Oc1cc(F)cc([C@H]2CCCN2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.3 %

Procedure:
To a solution of (R)-tert-butyl 2-(3-fluoro-5-hydroxyphenyl)pyrrolidine-1-carboxylate (10.3 g, 36.5 mmol) in DCM (20 mL) was added 4N HCl in dioxane (36.5 mL, 146 mmol) and the mixture was stirred at ambient temperature for 15 hours. The resulting precipitate was filtered and washed with DCM to afford (R)-3-fluoro-5-(pyrrolidin-2-yl)phenol hydrochloride (5.81 g, 73.3% yield).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]2[C:11]([NH:12][C:13]([C:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([CH2:34][C:35]([F:38])([F:37])[F:36])C(=O)OC(C)(C)C)[CH:21]=4)[O:18][CH:19]=3)=[O:14])=[CH:10][N:9]([CH3:39])[N:8]=2)[C:4](=[O:40])[CH2:3]1.C(=O)([O-])O.[Na+].[CH2:46]([O:49][CH2:50][CH2:51]Br)[CH2:47]Br.O>C1(C)C=CC=CC=1>[CH3:39][N:9]1[CH:10]=[C:11]([NH:12][C:13]([C:15]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:34][C:35]([F:36])([F:37])[F:38])[CH:21]=3)[O:18][CH:19]=2)=[O:14])[C:7]([N:5]2[CH2:6][C@@H:2]([N:1]3[CH2:51][CH2:50][O:49][CH2:46][CH2:47]3)[CH2:3][C:4]2=[O:40])=[N:8]1
Reactant: BrCCOCCBr
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2C[C@@H](N)CC2=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1cc(NC(=O)c2coc(-c3ccnc(NCC(F)(F)F)c3)n2)c(N2C[C@@H](N3CCOCC3)CC2=O)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (4-(4-((3-((4S)-4-amino-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-1,3-oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (79 mg) and sodium hydrogen carbonate (70 mg) in toluene (0.70 mL) was added 2,2′-dibromodiethyl ether (0.035 mL), and the mixture was stirred overnight at 100° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in TFA (0.70 mL), and the solution was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and recrystallized from ethyl acetate/hexane to give the title compound (3.3 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:26])/[CH:13]=[CH:14]/[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]=1[Br:25])=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:26])/[CH:13]=[CH:14]/[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]=1[Br:25])([OH:4])=[O:2]
Reactant: COC(=O)c1ccccc1NC(=O)/C=C/c1ccc2ccccc2c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(/C=C/c1ccc2ccccc2c1Br)Nc1ccccc1C(=O)O

Procedure:
Prepared analogously to Example 2 from trans-3-(1-bromo-naphth-2-yl)-acrylic acid-N-(2-methoxycarbonyl-phenyl)-amide and sodium hydroxide solution in methanol.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH2:15])[N:9]=2)=[CH:5][C:4]([C:16]([F:19])([F:18])[F:17])=[N:3]1.C(N(C(C)C)CC)(C)C.[C:29](Cl)(=[O:33])[CH:30]=[CH:31][CH3:32]>C(Cl)Cl>[CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:29](=[O:33])[CH:30]=[CH:31][CH3:32])[NH2:15])[N:9]=2)=[CH:5][C:4]([C:16]([F:19])([F:17])[F:18])=[N:3]1
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cccc(CN)n1
Reactant: CC=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC=CC(=O)C(N)c1cccc(Oc2cc(C(F)(F)F)nn2C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.100 g (0.368 mmol) of 2-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-6-(aminomethyl)-pyridine was introduced in 5 ml of methylene chloride together with 71.1 mg (0.55 mmol) of diisopropylethylamine, at room temperature 46.1 mg (0.44 mmol) of but-2-enoyl chloride were added and the mixture was stirred at room temperature for 3 h. The crude product was concentrated, subjected to extraction with 1 N HCl and ethyl acetate and then filtered over a silica gel bed. The filtrate was concentrated. The residue was crystalline.
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:45])[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C:18]([O:31][CH2:32][CH2:33][OH:34])=[C:17]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C[N+]1([O-])CC[O:50]CC1.OS([O-])=O.[Na+].Cl>CC#N.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH2:1]([NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:42])([F:43])[F:44])[CH:36]=2)[C:18]([O:31][CH2:32][C:33]([OH:50])=[O:34])=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=2)[CH:20]=1)=[O:45])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C[N+]1([O-])CCOCC1
Reactant: CCCCCCCCCCCCNC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: Cl
Solvent: CC#N
Product: CCCCCCCCCCCCNC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCC(=O)O)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
To a solution of N-dodecyl-3,5-bis(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)benzamide (0.254 g, 0.40 mmol) in CH3CN was added NMO (0.145 g, 0.89 mmol) and TPAP (0.014 g, 0.04 mmol). The reaction was stirred at rt overnight. Additional NMO (0.045 g, 0.38 mmol) and TPAP (0.013 g, 0.04 mmol) were required as indicated by TLC. After stirring 48 h, 10% NaHSO3 solution was added and the resulting biphasic mixture was stirred vigorously for 30 min. Conc. HCl (2 mL) was added and stirring was continued for 10 min. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc:Hexane+1% Formic acid) followed by preparatory plate chromatography (30% EtOAc:Hexane+1% Formic acid) to afford the title compound (0.089 g, 34%) as a white solid. mp 154.3-158.2 ° C.; 1H NMR (DMSO-d6) δ 8.55 (t, 1H); 7.98-7.88 (m, 6H); 7.78-7.67 (m, 4H); 3.57 (s, 2H); 3.25 (m, 2H); 1.50 (m, 2H), 1.23 (m, 18H); 0.82 (t, 3H); IR (KBr) 3275, 2900, 1725, 1600, 1575, 1460, 1325, 1190, 1125, 1075, 775, 725, 700, 625 cm−1; mass spectrum [(−)ESI], m/z 650 (M−H)−; Anal. Calcd. for C35H39F6NO4: C, 64.51; H. 6.03; N, 2.15, Found: C, 62.50; H, 5.99; N, 2.01.
Reaction SMILES: Cl.C(OCC)(=O)C.[CH2:8]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][C@H:20]1[O:32][CH3:33])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC1[CH:36]=[CH:37][C:38]([N+:45]([O-:47])=[O:46])=[C:39]([CH:44]=1)[C:40]([O:42][CH3:43])=[O:41].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CO>[CH2:8]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:36]=[CH:37][C:38]([N+:45]([O-:47])=[O:46])=[C:39]([CH:44]=2)[C:40]([O:42][CH3:43])=[O:41])[CH2:21][C@H:20]1[O:32][CH3:33])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanol (15 ml) and a 4 N hydrochloric acid/ethyl acetate solution (30 mL) were added to tert-butyl cis(±)-4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained in Example (40a) (1.5 g, 4.12 mmol), and the mixture was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure, azeotropically dehydrated by adding toluene, and dissolved in DMF (10 ml). Methyl 5-chloro-2-nitrobenzoate (900 mg, 4.17 mmol) and potassium carbonate (2.1 g, 15.2 mmol) were added, and the mixture was stirred at 175° C. for 24 hours. The reaction solution was diluted with ethyl acetate, washed with water, and concentrated under reduced pressure. Thereafter, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane) to obtain the title compound. The total resulting compound was used for the next reaction.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=O)=[CH:12][CH:11]=1.[CH3:20][O:21][C:22](=[O:27])[C@H:23](CO)[NH2:24]>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:19]=[CH:18][C:13]([C:14]2[O:16][CH:17]=[C:23]([C:22]([O:21][CH3:20])=[O:27])[N:24]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: COC(=O)[C@@H](N)CO
Product: COC(=O)c1coc(-c2ccc(-c3nc4ccccc4[nH]3)cc2)n1

Procedure:
Using essentially the same procedures described in Examples 23 and 24 and employing methyl 4-(1-H-benzimidazol-2-yl)benzoate and serine methyl ester as starting materials the title compound was obtained and identified by NMR and mass spectral analyses. 1HNMR (400 MHz, DMSO-d6): 3.86 (s, 3H), 7.22-7.24 (m, 2H), 7.62 (d, J=3.2 Hz, 2H), 8.19 (d, J=7.6 Hz, 2H), 8.36 (d, J=8 Hz, 2H), 9.02 (s, 1H), 13.1 (s, 1H). LCMS (ESI+) 319 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.Cl.C1C[O:33][CH2:32]C1>O.C(OC)(C)(C)C.C(O)(=O)C.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:32]=[O:33]
Reactant: Fc1cccc(Br)c1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: COC(C)(C)C
Product: O=Cc1c(F)cccc1Br
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
1-Bromo-3-fluorobenzene (17.3 g, 0.1 M) was added over 5 minutes to a solution of lithium diisopropylamide (prepared from the addition of 40 mL of 2.5 N butyllithium in hexanes to 11.5 g of 0.1 M diisopropylamine) in THF at a temperature between −70 and −75° C. The mixture was stirred cold for 1 hour after which DMF (8 mL) was added over 10 minutes. The mixture was stirred cold for an additional 40 minutes followed by the addition of acetic acid (26 g). The mixture was allowed to warm to ambient temperature, transferred into a mixture of 200 mL methyl tert-butyl ether, 200 mL water and 150 mL hydrochloric acid (˜4 N). The organic layer was separated and concentrated under reduced pressure to provide the title compound. 1H-NMR (CDCl3) δ 10.36 (s, 1H), 7.49 (dt, 1H), 7.40(dt, 1H), 7.15 (tdd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C(Cl)(Cl)Cl>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][CH:18]=1)=[O:33]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)cc3)c2cc1OC
Yield: 72 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (3 ml), and 2,4-difluorophenyl isocyanate (24 μl) was then added to the solution. The mixture was heated under reflux overnight. The precipitated crystal was collected by filtration and was washed to give 55 mg (yield 72%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=O)[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH2:28])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[NH:28][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)Nc3ccccc3N)c2)CC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3nc4ccccc4[nH]3)c2)CC1
Yield: 78.5 %

Procedure:
A solution of 4-[3-(2-amino-phenylcarbamoyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (1.20 g, 3.03 mmol) in acetic acid (12 mL) was heated overnight at 55° C., then the solvent was removed under reduced pressure. The solid obtained was triturated with Et2O to afford the title compound as a white solid (0.90 g, 79%) without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>>[CH3:21][S:18]([CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:32]4[CH:31]=[N:30][C:29]([NH2:28])=[N:34][CH:33]=4)[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]=3[CH:10]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: Nc1ncc(B(O)O)cn1
Reactant: CS(=O)(=O)C1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CS(=O)(=O)C1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica gave 283. NMR (400 MHz, CDCl3): 1.88-2.00 (2H, m), 2.04-2.20 (4H, m), 2.83-2.86 (4H, m), 3.13-3.20 (2H, m), 3.81 (2H, s), 3.88-3.90 (4H, m), 3.92-3.96 (4H, m), 5.25 (2H, br, s), 7.18 (1H, s), 9.37 (1H, s). (M+H)+ 490
Reaction SMILES: [ClH:1].Cl.O[NH:4][C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[N:19]=[C:18]1[NH2:29])=[NH:6]>[Ni].CO.O>[ClH:1].[ClH:1].[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[N:16][N:17]1[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[N:19]=[C:18]1[NH2:29])(=[NH:4])[NH2:6]
Reactant: N=C(NO)c1cccc2c1CCC2=Nn1cc(-c2ccc(F)cc2)nc1N
Agent: [Ni]
Agent: Cl
Solvent: O
Solvent: CO
Product: N=C(N)c1cccc2c1CCC2=Nn1cc(-c2ccc(F)cc2)nc1N

Procedure:
Analogously to Example 2, 0.25 g of Raney nickel is added to a solution of 1.0 g (2.105 mmol) of 1-[4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-ylideneamino]-2-amino-4-(4-fluorophenyl)-imidazole dihydrochloride in 70 ml of methanol/water (1:1), and hydrogenation is carried out at room temperature and under normal pressure until the absorption of hydrogen has ceased. The reaction mixture is then filtered, the filtrate is acidified to pH 3 with 3N methanolic hydrochloric acid, and concentration is carried out by evaporation in vacuo. The crystalline residue is recrystallized from methanol/diethyl ether, yielding the title compound with a water content of 4.88%, m.p. 245°-250° C. (decomp.), 1H-NMR (D2O): δ=8.09 (d, 1H); 7.81 (d, 1H); 7.44-7.61 (m, 3H); 7.42 (s, 1H); 7.03-7.15 (m, 2H); 3.27-3.33 (m, 2H); 3.11-3.17 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[CH:23][C:24]3[O:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][C:25]=3[C:34]=2[CH3:35])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:32]([O:31][C:29]([C:27]1[O:28][C:24]2[CH:23]=[CH:22][C:21]([N:18]3[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]3)=[C:34]([CH3:35])[C:25]=2[CH:26]=1)=[O:30])[CH3:33]
Reactant: CCOC(=O)c1cc2c(C)c(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2c(C)c(N3CCNCC3)ccc2o1
Reaction time: 2 h
Yield: 86.2 %

Procedure:
Trifluoroacetic acid (3 ml) was added to a stirred solution of 4-(2-Ethoxycarbonyl-4-methyl-benzofuran-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.4 g, 0.003 mol) in dichloromethane (10 ml) at room temperature. The reaction mixture was stirred for 2 hours. Solvent was concentrated under reduced pressure, the residue was triturated with diethyl ether (20 ml) to isolate 4-Methyl-5-piperazin-1-yl-benzofuran-2-carboxylic acid ethyl ester trifluoroacetic acid salt (1.25 g, 86.2%).