Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]([O:14]C)=[O:13])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+].Cl>C1COCC1.O>[CH3:1][C:2]1([CH3:16])[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: COC(=O)c1cccc2c1NC(C)(C)C=C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C=Cc2cccc(C(=O)O)c2N1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2,2-dimethyl-1,2-dihydroquinoline-8-carboxylate (0.188 g, 0.865 mmol) in THF (5 mL) and H2O (5 mL) was added a 1N aqueous solution of sodium hydroxide (3.46 mL, 3.46 mmol). After stirring at 60° C. overnight the reaction mixture was acidified to pH 2 using 1N aqueous HCl, extracted with ethyl acetate (three times), dried over MgSO4 and concentrated under vacuum to afford the desired compound that was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:11][CH:10]=3)=[CH:5][CH:4]=2)=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(CN)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(CNCc3ccc(C(F)(F)F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 43 %

Procedure:
To a solution of tert-butyl 4′-(aminomethyl)-1,1′-biphenyl-4-carboxylate (2.0 g) and 4-(trifluormethyl)-benzaldehyde (0.88 mL) in DCE (40 mL) was added at once sodium triacetoxyborohydride (1.904 g). The resulting mixture was stirred for 14 h at rt. Water (50 mL) was added and the mixture extracted with DCM (3×). The combined organic layers were washed with water (50 mL), then dried over MgSO4, evaporated off to give a yellow oil. This crude was purified by flash chromatography (c-Hex/AcOEt 4/1) to give the title compound as a white powder (1.30 g, 43%). M+(LC/MS(ESI)): 442.02
Reaction SMILES: [OH-].[Na+].C([O:6][C:7](=[O:20])[C:8]1[CH:13]=[C:12]([F:14])[C:11]([O:15][CH2:16][C:17]#[CH:18])=[CH:10][C:9]=1[F:19])C#C.Cl>CO>[F:19][C:9]1[CH:10]=[C:11]([O:15][CH2:16][C:17]#[CH:18])[C:12]([F:14])=[CH:13][C:8]=1[C:7]([OH:20])=[O:6]
Reactant: C#CCOC(=O)c1cc(F)c(OCC#C)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CCOc1cc(F)c(C(=O)O)cc1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
To a mixed solution of 20 ml of methanol and 20 ml of an aqueous 15% sodium hydroxide solution, 7.3 g of 2,5-difluoro-4-(2-propynyloxy)benzoic acid 2-propynyl ester was added, followed by stirring at 50° C. for 2 hours. The reaction mixture was added to hydrochloric acid and the obtained solid was collected by filtration. The solid was dried and washed with hexane, and 3.8 g of 2,5-difluoro-4-(2-propynyloxy)benzoic acid was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:9]1[S:13](=[O:15])(=[O:14])[O:12][CH2:11][CH2:10]1>C(O)C>[S:13]([CH2:9][CH2:10][CH2:11][NH:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1)([OH:15])(=[O:14])=[O:12]
Reactant: O=S1(=O)CCCO1
Reactant: Nc1cccc(O)c1
Solvent: CCO
Product: O=S(=O)(O)CCCNc1cccc(O)c1

Procedure:
In 3 liters of ethanol were dissolved 330 g of m-amino-phenol and the resulting solution was boiled under reflux and to this solution were added 360 g of propanesultone all together. Continuation of the reflux yielded gradually white powdery crystal. After refluxing for 5 hours, the reaction solution was cooled with ice and the yielded white powdery crystal was collected by filtration and washed several times with ethanol. The yield was 146 g and the melting point was above 250° C.
Reaction SMILES: [C:1]12([O:11][CH2:12][C:13]3[NH:17][N:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[C:15](=[O:24])[C:14]=3[Br:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH3:28]I>>[C:1]12([O:11][CH2:12][C:13]3[N:17]([CH3:28])[N:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[C:15](=[O:24])[C:14]=3[Br:25])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=c1c(Br)c(COC23CC4CC(CC(C4)C2)C3)[nH]n1C1CCCCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: Cn1c(COC23CC4CC(CC(C4)C2)C3)c(Br)c(=O)n1C1CCCCC1

Procedure:
The compound was prepared by treating 5-(adamantan-1-yloxymethyl)-4-bromo-2-cyclohexyl-1,2-dihydro-pyrazol-3-one with sodium hydride and methyl iodide as outlined in Reaction Scheme 5.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[C:7]([CH:9]=1)[OH:8])[OH:4].[O:12]=[C:13]([N:27]1[CH2:32][CH2:31][N:30]2[C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=[C:29]2[CH2:28]1)[CH2:14][C@H:15]([NH2:26])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25]>C(O)(C)C.C(#N)C>[C:1]([O-:11])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[C:7]([CH:9]=1)[OH:8])[OH:4].[O:12]=[C:13]([N:27]1[CH2:32][CH2:31][N:30]2[C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=[C:29]2[CH2:28]1)[CH2:14][C@H:15]([NH2:26])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25]
Reactant: O=C(O)c1cc(O)ccc1O
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CC(C)O
Solvent: CC#N
Product: O=C([O-])c1cc(O)ccc1O

Procedure:
The gentisic acid salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine was formed by mixing gentisic acid (0.113 g), (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (0.300 g) in a mixture of isopropylalcohol (0.6 mL) and acetonitrile (1.5 mL), followed by stirring at reflux temperature for 2 h. The solvent was distilled out at reduced pressure to obtain solid gentisate salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine as an amorphous solid. [Wt.: 0.410 g, % purity: 98.9%, XRD=amorphous FIG. (2)].
Reaction SMILES: [CH3:1][C:2]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)(=[O:6])=[O:5])[CH3:3].[CH3:23][S:24]([C:27]1[CH:35]=[C:34]([O:36][C:37]([F:40])([F:39])[F:38])[CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30])(=[O:26])=[O:25].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CS(C)=O.O.FC(F)(F)C(O)=O.CN(C)C=O>[CH3:23][S:24]([C:27]1[CH:35]=[C:34]([O:36][C:37]([F:38])([F:39])[F:40])[CH:33]=[CH:32][C:28]=1[C:29]([N:20]1[CH2:21][CH2:22][CH:17]([C:2]([CH3:1])([S:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)(=[O:5])=[O:6])[CH3:3])[CH2:18][CH2:19]1)=[O:30])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)c1cc(OC(F)(F)F)ccc1C(=O)O
Reactant: CC(C)(C1CCNCC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C1CCN(C(=O)c2ccc(OC(F)(F)F)cc2S(C)(=O)=O)CC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 10 ml vial was added 4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine (70.8 mg, 0.211 mmol), 2-(methylsulfonyl)-4-(trifluoromethoxy)benzoic acid (50 mg, 0.176 mmol), Bop reagent (93 mg, 0.211 mmol), diisopropylethyl amine (0.062 ml, 0.352 mmol) and 2 ml dimethylformamide. The resulting solution was stirred at room temperature for 10 minutes. The reaction mixture was diluted with 1 ml dimethyl sulfoxide, 1 ml water and 0.03 ml of trifluoroacetic acid. This mixture was loaded on a reverse phase column and purified with HPLC eluted with water/acetonitrile gradient solvent. Desired fraction was collected and lyophilized to give to give title compound as fluffy white solid.
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[N:12]([C@H:15]1[C@@H:21]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:20][CH:18]([OH:19])[C@H:17]([OH:31])[C@H:16]1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[N+:13]=[N-:14].N1C=CN=C1>CN(C)C1C=CN=CC=1.CN(C)C=O>[N:12]([C@H:15]1[C@@H:21]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:20][C@@H:18]([O:19][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[C@H:17]([OH:31])[C@H:16]1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=N[C@@H]1[C@H](OCc2ccccc2)[C@@H](O)C(O)O[C@@H]1COCc1ccccc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](O[C@@H]1O[C@H](COCc2ccccc2)[C@H](N=[N+]=[N-])[C@H](OCc2ccccc2)[C@H]1O)(C(C)C)C(C)C
Reaction time: 19 h
Yield: 59.4 %

Procedure:
Triisopropylsilyl chloride (0.63 mL, 3.0 mmol, 1.2 equiv) was added to a solution of hemiacetal 223 (0.959 g, 2.49 mmol, 1.00 equiv), imidazole (0.409 g, 6.01 mmol, 2.41 equiv), and 4-dimethylaminopyridine (29 mg, 0.24 mmol, 0.096 equiv) in dimethylformamide (2.5 mL). After 19 h, the yellow solution was concentrated and purified by silica gel chromatography (hexane/ethyl acetate 19:1 to 9:1) to afford 224 (0.800 g, 1.48 mmol, 59% yield) as a colorless oil. Rf=0.49 (hexane/ethyl acetate 4:1); 1H NMR (500 MHz, CDCl3) δ 7.43-7.24 (m, 10H), 4.78 (d, J=11.8, 1H), 4.75 (d, J=11.8, 1H), 4.55 (d, J=11.6, 1H), 4.52 (d, J=12.0, 1H), 4.51 (d, J=7.3, 1H), 3.98 (d, J=3.6, 1H), 3.72 (ddd, J=9.5, 7.3, 2.1, 1H), 3.69-3.58 (m, 3H), 3.56 (dd, J=9.6, 3.7, 1H), 2.26 (d, J=2.2, 1H), 1.19-0.99 (m, 21H); 13C NMR (126 MHz, CDCl3) δ 137.86, 137.84, 128.70, 128.63, 128.08, 128.05, 127.97, 127.93, 98.09, 80.69, 73.81, 73.78, 72.80, 72.01, 68.83, 59.83, 17.96, 17.90, 12.33; FTIR (neat film) 3463.8, 2943.4, 2866.2, 2108.6, 1455.3, 1366.1, 1280.0, 1185.4, 1099.0, 1028.7, 1014.6, 997.6, 883.5, 805.4, 736.3, 695.5, 669.0 cm−1; HRMS (ESI) m/z: Calcd for C29H43N3O5SiNa (M+Na+) 564.2870. found 564.2870.
Reaction SMILES: O.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7](B(O)O)[CH:8]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=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(OCC)(=O)C.C(COC)OC>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[CH:8]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1B(O)O
Reactant: Fc1ccc(I)cc1
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: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(Cl)cc1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To water (2 mL) and dimethoxyethane (20 mL), 5-chloro-2-nitrophenylboronic acid (3.27 g, 16.4 mmol), 1-fluoro-4-iodobenzene (3.65 g, 16.4 mmol), tetrakis(triphenylphosphine)palladium (0.95 g, 0.82 mmol) and potassium carbonate (6.81 g, 49.3 mmol) were added, and the mixture was stirred under a nitrogen atmosphere at 60° C. for 2 hours. After the reaction, the reaction mixture was cooled to room temperature and ethyl acetate (30 mL) was added. After the organic phase was washed with water (30 mL) and saturated brine (20 mL), it was dried with sodium sulfate. The solvent was distilled off under reduced pressure to give 5-chloro-4′-fluoro-2-nitrobiphenyl as a crude product. The obtained compound was used for the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23].CO[N:26](CCCCN1C2C3C=CC=CC=3N=CC=2N=C1CCC)C(=O)C>>[CH3:1][O:2][N:3]=[CH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:26])[C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC=NOC
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCN(OC)C(C)=O
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCC=NOC

Procedure:
The general method of Part G of Example 6 was followed using 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde O-methyloxime (17.5 g, 56.5 mmol), prepared as described in Parts A-D of Example 6, in lieu of N-methoxy-N-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]acetamide. Purification by flash column chromatography on silica gel afforded 11.4 g of 4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde O-methyloxime.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:26])[C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:27])[N:3]=1.CCO.[ClH:31]>[Fe].O>[ClH:31].[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[CH:5]=[C:4]([CH3:27])[N:3]=[C:2]([NH2:1])[N:7]=3)=[CH:14][CH:13]=2)=[O:26])=[CH:18][CH:19]=1
Reactant: Cc1cc(Nc2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cc2)nc(N)n1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc(N)cc3)cc2)nc(N)n1
Yield: 90 %

Procedure:
To a refluxing suspension of amide E4 (2.10 g, 5.77 mmol) in 2:1 EtOH:H2O (100 mL) were sequentially added Fe dust (1.29 g, 23.09 mol) and c.HCl (1-2 mL), and the resulting mixture was refluxed for 24 h. After this time, the hot reaction mixture was filtered through a pad of Celite, and solvent was removed under reduced pressure. The resulting residue was crystallized from MeOH:EtOAc to afford amine E5 (in two batches) as a cream-coloured amorphous solid (1.94 g, 90%). 1H NMR [(CD3)2SO]): 2.27 [s, 3H, ArCH3], 6.16 [br s, 2H, ArNH2], 6.75 [d, J=8.36 Hz, 2H, ArNH2], 7.74 [m, 8H, ArH], 9.90 [br s, 1H ArH], 10.55 [br s, 1H, ArNHAr], 12.58 [br s, 1H, ArC(O)NH]. LCMS (APCl+): 335 (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[CH:10]=[CH2:11].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[N:3]=[CH:4][C:5](/[CH:11]=[CH:10]/[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C=CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(/C=C/C(=O)OCc2ccccc2)cn1
Yield: 39.3 %

Procedure:
A solution of 2-amino-5-bromopyridine (2.25 g, 13.0 mmole), benzyl acrylate (3.2 g, 19.7 mmole), Pd(OAc)2 (0.31 g, 1.4 mmole), tri-ortho-tolylphosphine (0.73 g, 2.4 mmole), and diisopropylethylamine (3.5 mL, 20.0 mmole) in propionitrile (50 mL) was heated at reflux overnight. The dark mixture was filtered through celite®, and the filtrate was concentrated. Flash chromatography on silica gel (3% MeOH/CH2Cl2) gave the title compound (1.3 g, 39%): MS (ES) m/e 255 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[N:24]1([C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)[CH:28]=[CH:27][CH:26]=[N:25]1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[CH:30][C:29]([N:24]6[CH:28]=[CH:27][CH:26]=[N:25]6)=[CH:34][CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: OB(O)c1ccc(-n2cccn2)cc1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(-n5cccn5)cc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 4-(1H-pyrazol-1-yl)phenylboronic acid (Combi-Blocks, San Diego, USA, 24 mg, 0.126 mmol) to give the title compound as a white solid. (HPLC: tR 2.79 min (Method A); M+H=436 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.60-8.56 (m, 1H), 8.19-8.15 (m, 1H), 8.13-8.07 (m, 1H), 7.99-7.93 (m, 3H), 7.80-7.75 (m, 1H), 7.63-7.56 (m, 3H), 6.59-6.53 (m, 1H), 3.95 (s, 31-1), 3.57 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [OH:1][S:2]([OH:5])(=[O:4])=[O:3].[Br:6][C:7]1[N:8]=[C:9]2[C:15]([CH2:16][OH:17])=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1.[CH3:18][C:19]([CH3:21])=[O:20].OS(O)(=O)=O.[O:27]=[Cr:28](=[O:30])=[O:29]>O.CC(C)=O>[CH3:18][C:19]([CH3:21])=[O:20].[OH:4][S:2]([OH:5])(=[O:3])=[O:1].[O:27]=[Cr:28](=[O:30])=[O:29].[Br:6][C:7]1[N:8]=[C:9]2[C:15]([CH:16]=[O:17])=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1
Reactant: OCc1c[nH]c2ncc(Br)nc12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: O=Cc1c[nH]c2ncc(Br)nc12
Reaction time: 0.25 h

Procedure:
A stock solution of Jones reagent (2.67 M) was prepared by carefully adding concentrated H2SO4 (2.3 mL) to CrO3 (2.67 g) then diluting to 10 mL with H2O. To a partial suspension of (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-methanol (4.6 g, 20.1 mmol) in acetone (300 mL) was slowly added Jones reagent (9 mL, 24.0 mmol). During the addition the starting material gradually dissolved and a thick green precipitate was formed. The reaction mixture was stirred for 15 min then quenched with i-PrOH (2 mL) and filtered over Celite, rinsing with acetone. The filtrate was concentrated to provide 4.76 g of 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a yellow-orange solid that was used without further purification. To a solution of this solid in DMF (50 mL) at 0° C. was added NaH (60% in mineral oil, 1.2 g, 30.1 mmol). The reaction mixture was stirred at room temperature for 30 min then cooled back to 0° C. and 2-(trimethylsilyl)ethoxymethyl chloride (4.3 mL, 24.1 mmol) was slowly added. The reaction mixture was warmed to room temperature and stirred for 1 h then quenched with H2O and extracted with EtOAc (3×). The combined organics were washed with H2O (3×) and brine then dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (20% to 30% EtOAc/hexanes) to isolate 3.82 g (53%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]3[CH:9]=[N:10][CH:11]=[CH:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:19])[CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][CH2:20][CH:18]([C:4]2[CH:3]=[C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[C:7]3[C:8]4[CH:9]=[N:10][CH:11]=[CH:12][C:13]=4[C:14]([CH3:17])([CH3:16])[O:15][C:6]=3[CH:5]=2)[CH3:19])=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(CCCc1ccc(F)cc1)c1cc(N)c2c(c1)OC(C)(C)c1ccncc1-2
Product: CC(CCCc1ccc(F)cc1)c1cc(NS(C)(=O)=O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
The titled compound was prepared by reacting 10-amino-8-[5-(4-fluorophenyl)-2-pentyl]-5,5-dimethyl-5H-[1]benzopyrano[4,3-c]pyridine with methanesulfonyl chloride according to the method of Example 3. The crude product was filtered and recrystallized from acetonitrile; m.p. 208°-209°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:22])=[C:10]2[C:23]([O:25]CCC#N)=[O:24])=[C:5]([O:30][CH3:31])[CH:4]=1)#[N:2].[OH-].[Na+].C(OCC)C.O>COCCOC.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:22])=[C:10]2[C:23]([OH:25])=[O:24])=[C:5]([O:30][CH3:31])[CH:4]=1)#[N:2]
Reactant: CCOc1nccc2c1C(c1ccc(C#N)cc1OC)C(C(=O)OCCC#N)=C(C)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: COCCOC
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC)C(C(=O)O)=C(C)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.20 g (17.21 mmol) of the compound from Example 21A are dissolved in 200 ml of 1,2-dimethoxyethane/water (3:1 v/v), mixed with 34.42 ml (34.42 mmol) of 1 N sodium hydroxide solution and stirred at room temperature overnight. The mixture is then mixed with 100 ml of diethyl ether and 100 ml of water, the organic phase is separated off, and the aqueous phase is adjusted to pH 4-5 with 1N hydrochloric acid. The resulting suspension is stirred for 1 h and the precipitated solid is then removed by filtration. The precipitate is washed with water and a little diethyl ether. Drying in vacuo at 40° C. results in 3.57 g (57% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[C:7]([N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:18]=O)[CH:15]=3)[CH2:10]2)[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].CCN(CC)CC.[BH4-].[Na+]>CO>[F:26][C:2]([F:1])([F:27])[C:3]1[CH:8]=[C:7]([N:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:18][NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:15]=3)[CH2:10]2)[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccc2c(c1)CN(c1ccc(-c3ccccc3)c(C(F)(F)F)c1)C2
Reactant: NCCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)CCNCc1ccc2c(c1)CN(c1ccc(-c3ccccc3)c(C(F)(F)F)c1)C2
Temperature: 50 °C
Yield: 36.3 %

Procedure:
To a solution of 2-(2-trifluoromethyl-biphenyl-4-yl)-2,3-dihydro-1H-isoindole-5-carbaldehyde (19 mg, 0.05 mmol) in 3 mL MeOH, β-alanine (8.7 mg, 0.1 mmol) and catalytic amount Et3N are added. The suspension is heated to 50° C. for 0.5 hours, followed by adding 2 mg of NaBH4. After pre-LC-MS, 8 mg of 3-{[2-(2-trifluoromethyl-biphenyl-4-yl)-2,3-dihydro-1H-isoindol-5-ylmethyl]-amino}-propionic acid is obtained as a white solid. MS m/z 441[M+1]+. 1H NMR (DMSO-d6): δ 7.08-7.26 (m, 9H), 6.80 (brs, 2H), 4.53 (s, 4H), 3.68 (s, 2H), 2.62 (t, 2H), 2.16 (t, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[N+:27]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(OC(F)(F)F)cc2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(OC(F)(F)F)cc2)cc1N
Yield: 68.2 %

Procedure:
Prepared from [2-nitro-4-(4-trifluoromethoxy-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example F12) (1.09 g, 2.58 mmol) by reduction with SnCl2.2H2O (2.91 g, 12.9 mmol) according to the general procedure G (method b). Obtained as a light brown solid (690 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH2:23])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH:23][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=2[N+:8]([O-:10])=[O:9])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(Nc2ccc(Br)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Yield: 103 %

Procedure:
Dissolve 5-bromo-2-fluoronitrobenzene (28.8 mmol, 3.55 mL), 3-amino-azetidine-1-carboxylic acid tert-butyl ester (28.8 mmol, 4.96 g), and triethylamine (35.9 mmol, 5.00 mL) in ethyl acetate (100 mL) and reflux under nitrogen for 48 h. Cool to room temperature. Wash with 0.5 M hydrochloric acid twice, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo to obtain a bright orange solid (11.04 g, >100%). LC-MS m/z (79Br/81Br) 394.0/396.0 [M+H]+.