Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.[O:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1.[C:22]([O:26][C:27]([NH:29][C@@H:30]([CH3:34])[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:22]([O:26][C:27](=[O:28])[NH:29][C@H:30]([C:31](=[O:32])[NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][CH:11]1[CH2:10][CH2:9][O:8][CH2:13][CH2:12]1)[CH3:34])([CH3:23])([CH3:24])[CH3:25]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccccc1NC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.5 %

Procedure:
Et3N (2.6 mL, 18.9 mmol) was added to a stirred mixture of N-(tetrahydropyran-4-yl)benzene-1,2-diamine (1.21 g, 6.29 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (1.31 g, 6.92 mmol), HOAt (0.94 g, 6.92 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.33 g, 6.92 mmol) in anhydrous DCM (30 mL) at 0° C. under a nitrogen atmosphere. Stirring was continued for 10 min at 0° C. then the mixture was slowly warmed to RT and stirred at RT for 4 h. The reaction mixture was partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was further extracted with DCM and the combined organic layers were then washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-4% 2M NH3/MeOH in DCM) affording {(S)-1-[2-(Tetrahydropyran-4-ylamino)phenylcarbamoyl]ethyl}carbamic acid tertbutyl ester as a white solid (1.91 g, 83%). LCMS: RT 2.78 min [M+H-tBu]+ 308.1.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][CH:6]=2.[CH3:14][O-:15].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[C:3]([O:15][CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][CH:6]=2
Reactant: Nc1nc2cc(Cl)ccc2nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc2ccc(Cl)cc2nc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
To 3-amino-2,6-dichloroquinoxaline (1.30 g, 6.07 mmol) dissolved in tetrahydrofuran (60 ml), 25 wt % sodium methoxide (13.1 g, 60.7 mmol) in methanol was added at room temperature and stirred further at room temperature for 90 minutes. The resulting mixture was concentrated under the reduced pressure to remove the solvent. The product was extracted with dichloromethane and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 1.22 g of the titled compound (yield, 96%).
Reaction SMILES: [C:1]([N:8]1[C@H:12]([C:13]#[CH:14])[C@@H:11]([CH3:15])[O:10]C1(C)C)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([NH:8][C@H:12]([C:13]#[CH:14])[C@H:11]([OH:10])[CH3:15])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: C#C[C@@H]1[C@@H](C)OC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: C#C[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O
Reaction time: 8 h
Yield: 82.5 %

Procedure:
A solution of (4R,5R)-N-boc-4-ethynyl-2,2,5-trimethyl-oxazolidine (1.60 g 6.69 mmol) (Example 102B) and p-toluenesulfonic acid monohydrate (130 mg 0.67 mmol) in MeOH (70 mL) was heated at refluxed. After stirring overnight the solvent was concentrated and the residue was chromatographed directly on a silica gel column with a 0-40% EtOAc in hexanes gradient. This afforded the product (Yield 1.10 g, 83%) as well as recovered starting material (220 mg, 14%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](O)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1cncc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Reactant: CC(C)(C)C(=O)O
Product: C[C@H](Nc1cncc(-n2cnc3cc(NC(=O)C(C)(C)C)ccc32)n1)c1ccccc1
Yield: 29 %

Procedure:
In a procedure analogous to example 44, reaction of 1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-amine (33 mg, 0.10 mmol) and pivalic acid (12 mg, 0.11 mmol) furnished the product (12 mg, 29%) after chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](I)[C:3]=1[CH:10]([OH:28])[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH:19]2[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)=[CH2:12].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]2[C:3]=1[C:10](=[O:28])[CH:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH:19]3[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]3)[CH2:15][CH2:14]1)[CH2:12]2
Reactant: C=C(C1CCC(C2CCC(CCC)CC2)CC1)C(O)c1c(F)cc(C)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCC1CCC(C2CCC(C3Cc4cc(C)cc(F)c4C3=O)CC2)CC1
Temperature: 25 °C

Procedure:
75 g (0.15 mol) of 1-(2-fluoro-6-iodo-4-methylphenyl)-2-(4′-propyl-bicyclohexyl-4-yl)-prop-2-en-1-ol, 50 ml of triethylamine, 400 mg of palladium(II) acetate (1.8 mmol) and 960 mg (3.7 mmol) of triphenylphosphine are dissolved in 200 ml of acetonitrile and refluxed overnight. The mixture is cooled down to room temperature and subjected to conventional workup.
Reaction SMILES: [ClH:1].N[C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH:9]([CH3:20])[N:10]3[C:15]=2[C:14]=1[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11]3.N([O-])=O.[Na+]>O>[Cl:1][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH:9]([CH3:20])[N:10]3[C:15]=2[C:14]=1[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11]3
Reactant: Cl
Reactant: CC1CCc2ccc(N)c3c(=O)c(C(=O)O)cn1c23
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC1CCc2ccc(Cl)c3c(=O)c(C(=O)O)cn1c23
Reaction time: 1 h

Procedure:
A mixture of 75 ml. of 6N hydrochloric acid and 10-amino-6,7-dihydro-5-methyl-1-oxo-benzo[ij]quinolizine-2-carboxylic acid (12.9 g., 0.05 mole) is diazotized at 5 to 10° C. with sodium nitrite (4.14 g., 0.06 mole) dissolved in about 10 ml. of water. The cold mixture is filtered, then it is added to a mixture of cuprous chloride (19.7 g., 0.1 mole) and concentrated hydrochloric acid (150 ml.) while maintaining the temperature below 20° C. After stirring 1 hour the mixture is diluted with water to provide a creamy-white solid which is collected by filtration. Two recrystallizations from N,N-dimethyl formamide provide 10-chloro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 219.5°-222° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[CH:20]([N:23]([CH3:32])[C:24](N1C=C[N+](C)=C1)=[O:25])([CH3:22])[CH3:21]>C(OCC)(=O)C.CCCCCCC>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:24](=[O:25])[N:23]([CH:20]([CH3:22])[CH3:21])[CH3:32])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: CC(C)N(C)C(=O)n1cc[n+](C)c1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [I-]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)N(C)C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(isopropyl-methyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (ethyl acetate/heptane 1:5) (77%, white crystals). HPLC-MS m/z=355.1 (M+1), Rt: 4.80 min.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[OH:11][CH:12]([CH2:23][O:24][CH3:25])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=1)=[O:14].Cl[C:27]1[N:32]=[CH:31][N:30]=[C:29]2[N:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])[N:34]=[CH:35][C:28]=12.O>C1COCC1.CCOC(C)=O>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[N:33]1[C:29]2=[N:30][CH:31]=[N:32][C:27]([O:11][CH:12]([CH2:23][O:24][CH3:25])[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)=[O:14])=[C:28]2[CH:35]=[N:34]1
Reactant: COCC(O)C(=O)Nc1ccc(C)cn1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COCC(Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1ccc(C)cn1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
LHMDS (1.40 mL, 1.0 M in THF, 1.40 mmol) was added slowly to a stirred solution of 2-hydroxy-3-methoxy-N-(5-methylpyridin-2-yl)propanamide (200 mg, 0.951 mmol) in anhydrous THF (5 mL). The reaction mixture was kept at ambient temperature for 10 minutes, and a solution of 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (265 mg, 1.00 mmol) in anhydrous THF (3 mL) was added. The reaction mixture was heated at 50° C. for ½ hrs (another 3 equivalents of LHMDS were added and the reaction heated for 18 hrs at 50° C. in example 49). Water and EtOAc were added, and the two phases were separated. The organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with DCM/EtOAc:2/1) to give the title compound as a colourless solid (323 mg), 1H NMR (500 MHz, CDCl3) δ 8.67 (br s, 1H), 8.62 (s, 1H), 8.48 (s, 1H), 8.18 (d, 1H), 8.12 (s, 1H), 7.65 (d, 1H), 7.52 (m, 4H), 6.13 (t, 1H), 4.14 (m, 2H), 4.06 (m, 1H), 3.49 (s, 3H), 2.32 (s, 3H), HRMS: calcd for (M+H+) C21H2035ClN6O3: 439.1285. Found: 439.1287.
Reaction SMILES: [Li+].[Br-].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([OH:23])[C:11]([N:13]2[C@H:17]([C:18]([O:20]CC)=[O:19])[CH2:16][CH:15]=[N:14]2)=[O:12])=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl>CCOC(C)=O.O.C(#N)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([OH:23])[C:11]([N:13]2[C@H:17]([C:18]([OH:20])=[O:19])[CH2:16][CH:15]=[N:14]2)=[O:12])=[CH:6][CH:5]=1
Reactant: CCOC(=O)[C@@H]1CC=NN1C(=O)[C@H](O)c1ccc(F)cc1
Agent: Cl
Agent: [Br-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)[C@@H]1CC=NN1C(=O)[C@H](O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 5.4 %

Procedure:
To a solution of acetonitrile (70 mL), water (1.5 mL) and LiBr (12.69 g, 146.12 mmol) was added ethyl (5S)-1-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxylate (8.6 g, 29.22 mmol) followed by triethylamine (10.13 mL, 73.06 mmol). The homogenous clear solution was then stirred at room temperature over night. EtOAc (200 mL) and 1M HCl (aq., 150 mL) were added. The aqueous phase was extracted with EtOAc (100 mL). The pooled organic layers were then concentrated. This furnished 7.2 g of the desired acid as a solid. The pooled aqueous layers was extracted with EtOAc (2×50 mL), followed by washing of the combined organic layers with water (50 mL), an additional 0.42 g product was isolated. Total yield 98%. 1H NMR [400 MHz, (CD3)2SO] δ 2.86 (ddd, 1H), 3.23 (ddd, 1H), 4.53 (dd, 1H), 5.71-5.77 (m, 2H), 7.07-7.15 (m, 3H), 7.36-7.42 (m, 2H), 12.97 (s, br, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[O:6][C@H:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([N+:18]([O-])=O)=[C:14]([F:17])[CH:15]=3)[CH:10]=[C:9]2[C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])[CH2:4][O:3]1>C(O)C>[NH2:18][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][C:14]=1[F:17])[N:8]([CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:1])([CH3:26])[O:6]1)[C:9]([C:21]([CH3:25])([CH3:24])[CH2:22][OH:23])=[CH:10]2
Reactant: CC1(C)OC[C@@H](Cn2c(C(C)(C)CO)cc3cc([N+](=O)[O-])c(F)cc32)O1
Solvent: CCO
Product: CC1(C)OC[C@@H](Cn2c(C(C)(C)CO)cc3cc(N)c(F)cc32)O1
Reaction time: 2.5 h
Yield: 79.3 %

Procedure:
(R)-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan-1-ol (2.5 g, 6.82 mmol) was dissolved ethanol (70 mL) and the reaction was flushed with N2. Then Pd—C (250 mg, 5% wt) was added. The reaction was flushed with nitrogen again and then stirred under H2 (atm). After 2.5 hours only partial conversion to the product was observed by LCMS. The reaction was filtered through Celite and concentrated. The residue was re-subjected to the conditions above. After 2 hours LCMS indicated complete conversion to product. The reaction mixture was filtered through Celite. The filtrate was concentrated to yield the product as a black solid (1.82 g, 79%). ESI-MS m/z calc. 336.2, found 337.5 (M+1)+. Retention time 0.86 minutes. 1H NMR (400 MHz, DMSO-d6) δ 7.17 (d, J=12.6 Hz, 1H), 6.76 (d, J=9.0 Hz, 1H), 6.03 (s, 1H), 4.79-4.76 (m, 1H), 4.46 (s, 2H), 4.37-4.31 (m, 3H), 4.06 (dd, J=6.1, 8.3 Hz, 1H), 3.70-3.67 (m, 1H), 3.55-3.52 (m, 2H), 1.41 (s, 3H), 1.32 (s, 6H) and 1.21 (s, 3H) ppm.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][CH2:7][CH:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH:24]([CH3:26])[CH3:25])[C:18](=[O:27])[CH2:17]3)[CH2:9]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:5][O:4][C:2](=[O:3])[NH:6][CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([F:23])[CH:22]=2)[N:19]([CH:24]([CH3:25])[CH3:26])[C:18](=[O:27])[CH2:17]3)[CH2:9]1
Reactant: CC(C)N1C(=O)Cc2cc(N3CC(CN)OC3=O)cc(F)c21
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC[C@H]1CN(c2cc(F)c3c(c2)CC(=O)N3C(C)C)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (0.097 ml, 1.26 mmol) is added dropwise to 5-(5-aminomethyl-2-oxo-oxazolidin-3-yl)-7-fluoro-1-isopropyl-1,3-dihydro-indol-2-one (21, 0.355 g, 0.842 mmol) and diisopropylethylamine (0.616 ml, 3.37 mmol) in dichloromethane (4 ml) at 0° C. The reaction is stirred at 0° C. for 30 minutes and then allowed to warm at room temperature. The reaction mixture is diluted with dichloromethane, washed with water, citric acid and brine, dried (Na2SO4) and evaporated. The residue is purified to give the title compound as a solid. HPLC r.t. 4.42 min; 1H NMR (300 MHz, CDCl3) δ7.33 (d, J=1.2 Hz, 1H), 7.24 (dd, J=2.1, 14 Hz, 1H), 5.14 (br s, 1H), 4.80-4.92 (m, 1H), 4.75-4.84 (m, 1H), 4.05 (t, J=8.7 Hz, 1H), 3.81 (dd, J=6.6, 9 Hz, 1H), 3.71 (s, 3H), 3.57 (s, 2H), 3.52-3.65 (m, 2H), 1.44 (d, J=6.9 Hz, 6H); MS for C17H20FN3O5 m/z 366 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C:8]2[CH:17]=[C:16](B(O)O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.[Cl:22][C:23]1[CH:28]=[N:27][CH:26]=[C:25](Cl)[N:24]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C:8]2[CH:17]=[C:16]([C:25]3[CH:26]=[N:27][CH:28]=[C:23]([Cl:22])[N:24]=3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1
Reactant: OB(O)c1cc(-c2cc(Cl)ccc2F)nc2ncccc12
Reactant: Clc1cncc(Cl)n1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Cl)cc1-c1cc(-c2cncc(Cl)n2)c2cccnc2n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A solution of 302 mg (1.00 mmol) 2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine-4-boronic acid, 194 mg (1.30 mmol) 2,6-dichloropyrazine and 101 mg (1.2 mmol) sodium bicarbonate in 4 ml DMF and 1 ml water was heated to 80° C. under nitrogen. Then 14.0 mg (0.02 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added and the reaction mixture was stirred for 16 hours at 80° C. Water was added to the reaction mixture and the resulting precipitate was filtered off. The residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent yielding 2-(5-chloro-2-fluoro-phenyl)-4-(6-chloro-pyrazin-2-yl)-[1,8]naphthyridine as colourless crystals; HPLC-MS: 2.35 min, [M+H] 371.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]([CH3:13])[CH3:12])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][C:15]=1[O:22]C.B(Br)(Br)Br.C1CCCCC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:11]([CH3:13])[CH3:12])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[OH:22]
Reactant: COc1ccc(-c2nn(C(C)C)c3c(Cl)cccc23)c(OC)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CC(C)n1nc(-c2ccc(O)cc2O)c2cccc(Cl)c21
Yield: 74.3 %

Procedure:
Prepared according to Method D step C from 7-chloro-3-(2,4-dimethoxyphenyl)-1-isopropyl-1H-indazole (0.132 g, 0.4 mmol), boron tribromide (0.377 mL, 4.0 mmol) and 1.0 mL of cyclohexene to give the product (0.090 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([O:11][CH3:12])=[C:4](I)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:13]([C:15]1[CH:16]=[N:17][N:18]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH:19]=1)#[CH:14]>CC#N.CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([C:14]#[C:13][C:15]2[CH:16]=[N:17][N:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(I)c(OC)c1F
Reactant: C#Cc1cnn(Cc2ccc(OC)cc2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(Cn2cc(C#Cc3ccc(OC)c(F)c3OC)cn2)cc1
Reaction time: 3 h

Procedure:
To a stirred solution of 3-fluoro-2,4-dimethoxy-iodobenzene (200 mg, 0.71 mmol) and 4-ethynyl-1-(4-methoxy-benzyl)-1H-pyrazole (180 mg, 0.85 mmol) in dry MeCN (4 ml) and NEt3 (2 ml) was added Pd(Ph3P)2Cl2 (15 mg, 3 mol %) and the reaction vessel was evacuated and backfilled with N2 (g) three times. Copper (I) iodide (6 mol %) was added and the reaction rapidly became dark. Stirring was continued at room temperature for 3 hours, then the crude mixture was concentrated directly onto silica-gel and purified by flash chromatography (silica-gel, eluted sequentially with hexanes:EtOAc, 3:1, 2:1) to give the product as a resin that crystallised slowly upon standing in the freezer (230 mg, 89%). 1H-NMR (300 MHz, CDCl3) δ 7.66 (s, 1H), 7.50 (s, 1H), 7.19 (d, J=8.6 Hz, 2H), 7.10 (dd, J=8.7, 2.1 Hz, 1H), 6.87 (d, J=8.6 Hz, 2H), 6.61 (t, J=8.2 Hz, 1H), 5.24 (s, 2H), 4.01 (s, 3H), 3.87 (s, 3H), 3.79 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21].O>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([O:6][CH2:21][CH:20]=[CH2:19])=[O:5]
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of 2,4,6-trimethylbenzoic acid (10 g, 61 mmol) in DMF (100 mL) were sequentially added potassium carbonate (17 g, 122 mmol) and allyl bromide (11 g, 91.5 mmol). The mixture was stirred at rt overnight before it was poured into water (˜1 L). The resulted precipitate was filtered and washed with water, then dried in vacuo to give allyl 2,4,6-trimethylbenzoate as a solid (10.2 g, 82%) which was nitrated and then reduced as shown for Example 14 (procedure B and C) to give allyl 3-amino-2,4,6-trimethylbenzoate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([C:14](=[O:21])[CH2:15][N:16]([CH2:17][CH2:18][O:19][CH3:20])[C:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)=[O:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCCNCC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: COCCN(CC(=O)N1CC(=O)N(c2cccc(Cl)c2C)C1)C(=O)Nc1ccc(Cl)cc1

Procedure:
A mixture of 3-(3-Chloro-2-methyl-phenyl)-1-[2-(2-methoxy-ethylamino)-acetyl]-imidazolidin-4-one (100 mg, 0.3 mmol, 1 eq), 1-Chloro-4-isocyanato-benzene (56 mg, 0.36 mmol, 1.2 eq), in THF (2 ml) was stirred at room temperature overnight. It was concentrated, dissolved in acetonitrile and purified with HPLC to give the desired product. LCMS observed for (M+H)+: 479.1
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[CH2:20]([O:22][C:23]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])[CH3:21].O>C(OCC)C.O1CCCC1>[CH2:20]([O:22][C:23]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:24]=1[CH:25]([C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)[OH:26])[CH3:21]
Reactant: Cc1ccnc(Br)c1
Reactant: CCOc1cc([N+](=O)[O-])ccc1C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc([N+](=O)[O-])ccc1C(O)c1cc(C)ccn1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
2-bromo-4-methylpyridine (1.5 ml) was dissolved in diethylether (50 ml), and the mixture was cooled to −78° C. under argon atmosphere. 1.6M n-butyllithium hexane solution (8.3 ml) was added dropwise to the solution, and the mixture was stirred for 40 minutes. The reaction solution was added dropwise to a solution of 2-ethoxy-4-nitrobenzaldehyde (2.2 g) in tetrahydrofuran (200 ml) under argon atmosphere at −78° C. The mixture was allowed to be at room temperature and stirred overnight, and water was added to the mixture. The mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was evaporated. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give (2-ethoxy-4-nitrophenyl)(4-methylpyridin-2-yl)methanol (1.9 g) as brown crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:13]=[CH:14][N:15](C)C)=[C:4]([N+]([O-])=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[H][H]>C(OCC)(=O)C.[Ni]>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[NH:15][CH:14]=[CH:13][C:3]=12
Reactant: [H][H]
Reactant: COc1ncc(Cl)c(C=CN(C)C)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: COc1ncc(Cl)c2cc[nH]c12
Yield: 117.5 %

Procedure:
To a solution of Example 108C (12 g, 46.6 mmol) in ethyl acetate (150 mL) was added Raney-Ni (20.0 g, 4.66 mmol), and the reaction mixture was stirred for 20 hours at room temperature under 30 atm. hydrogen. The reaction mixture was filtered and rinsed with ethyl acetate. The filtrate was concentrated to a small volume, and the precipitates were collected by filtration and dried to provide the title compound (10 g, 93% yield).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([Cl:15])[C:9]([F:16])=[CH:8][C:4]=1[C:5](Cl)=[O:6]>C1COCC1>[Cl:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([Cl:15])[C:9]([F:16])=[CH:8][C:4]=1[C:5]([NH2:1])=[O:6]
Reactant: O=C(Cl)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Reaction time: 0.33 h

Procedure:
32%-aq. NH3-solution (250 mL) is dropped to 2,4-dichloro-5-fluoro-3 nitro-benzoic acid chloride (16.0 g, 59 mmol) in 100 mL THF and it is stirred for 20 min. Then the mixture is concentrated and the resulting precipitate is collected and dried.