Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[C:21]3[O:23][CH2:24][O:25][C:18]=2[C:19]([F:27])=[C:20]3[F:26])[C:13]([F:28])=[CH:12][N:11]=1>>[F:27][C:19]1[C:18]2[O:25][CH2:24][O:23][C:21]([C:20]=1[F:26])=[CH:22][C:17]=2[NH:16][C:14]1[C:13]([F:28])=[CH:12][N:11]=[C:10]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=2)[N:15]=1
Reactant: Fc1cnc(Cl)nc1Nc1cc2c(F)c(F)c1OCO2
Reactant: Nc1cccc(O)c1
Product: Oc1cccc(Nc2ncc(F)c(Nc3cc4c(F)c(F)c3OCO4)n2)c1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 3-hydroxyaniline with 2-chloro-N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine gave N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: purity: 85%; MS (m/e): 377 (MH+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[CH3:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[C:38]1[CH2:39][CH2:40][NH:41][CH2:42][CH:43]=1>CS(C)=O>[CH3:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[C:38]1[CH2:39][CH2:40][N:41]([CH2:12][CH:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)[CH2:42][CH:43]=1
Reactant: Cc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)ccc4c3O2)cc1
Solvent: CS(C)=O
Product: Cc1ccc2[nH]cc(C3=CCN(CC4COc5ccc6nc(C)ccc6c5O4)CC3)c2c1
Temperature: 75 °C

Procedure:
(2R)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl 4-methylbenzenesulfonate (0.55 g, 1.4 mmole) and 5-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.80 g, 3.8 mmole) were combined in 10 mL of DMSO. The mixture was heated at 70-80 ° C. under nitrogen for 6 hours. After cooling to room temperature, the mixture was partitioned between 400 mL each of ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was removed, washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was column chromatographed on silica gel using 0-2% methanol/chloroform as eluant. The product-containing fractions were concentrated in vacuum and the residue recrystallized from isopropanol with the addition of fumaric acid to give 0.32 g of the (S)-enantiomer of the title compound as a yellow solid monofumarate, three-quarter hydrate (m.p. 150-155° C.).
Reaction SMILES: C([O:3][C:4]([C@@H:6]([NH:15][C@H:16]1[CH2:22][S:21][CH2:20][C@@H:19]([CH3:23])[N:18]([CH2:24][C:25]([OH:27])=[O:26])[C:17]1=[O:28])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])C.[OH-].[Na+]>>[C:4]([C@@H:6]([NH:15][C@H:16]1[CH2:22][S:21][CH2:20][C@@H:19]([CH3:23])[N:18]([CH2:24][C:25]([OH:27])=[O:26])[C:17]1=[O:28])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSC[C@@H](C)N(CC(=O)O)C1=O
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H]1CSC[C@H](N[C@@H](CCc2ccccc2)C(=O)O)C(=O)N1CC(=O)O
Yield: 57.1 %

Procedure:
175 mg of α-{6(R)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-3(R)-methyl-5-oxoperhydro-1,4-thiazepin-4-yl}acetic acid (prepared as described in Example 31 above) was hydrolyzed with aqueous sodium hydroxide in the same manner as described in Example 5, to give 93 mg of the title compound as a powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[CH2:18]([C:20]([OH:25])([CH2:23][CH3:24])[C:21]#[CH:22])[CH3:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.CN(C=O)C.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.[Cu]I>[CH2:18]([C:20]([OH:25])([CH2:23][CH3:24])[CH2:21][CH2:22][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1)[CH3:19]
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Reactant: C#CC(O)(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(O)(CC)CCc1cccc(CCCNC(=O)C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
To a degassed solution of N-(3-(3-bromophenyl)propyl)-2,2,2-trifluoroacetamide (3) (0.930 g, 3 mmol) and 3-ethylpent-1-yn-3-ol (4) (0.670 g, 6 mmol) in triethylamine (4 mL) and DMF (12 mL) was added PdCl2(PPh3)2 (0.053 g, 0.075 mmol), tri-o-tolylphosphine (0.046 g, 0.15 mmol), and CuI (0.014 g, 0.075 mmol). The resulting mixture was degassed and stirred under argon at 90° C. for 6 h. The mixture was cooled to room temperature then concentrated under reduced pressure and diluted with EtOAc (100 mL) and water (70 mL). After vigorous shaking, the layers were separated. The organic layer was treated with charcoal, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (7 to 60% EtOAc-hexanes gradient) gave N-(3-(3-(3-ethyl-3-hydroxypentyl)phenyl)propyl)-2,2,2-trifluoroacetamide (5) as a yellow oil. Yield (0.663 g, 65%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.17-7.28 (m, 4H), 5.11 (s, 1H), 3.16 (q, J=7.2 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 1.76 (quint, J=7.2 Hz, 2H), 1.53-1.67 (m, 4H), 0.97 (t, J=7.2 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16]>C(O)(=O)C>[C:14]([CH2:15][CH2:16][N:1]([CH2:5][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: C=CC(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)CCN(CCC(=O)OCC)c1ccc(CC(=O)OCC)cc1

Procedure:
The 2-pentenyleneimino starting material is prepared as follows: The mixture of 89.6 g ethyl 4-aminophenylacetate, 400 g ethyl acrylate and 100 ml acetic acid is refluxed for 19 hours and concentrated in vacuo. The concentrate is poured onto 500 ml ice water, the mixture made basic with aqueous sodium hydroxide and extracted with diethyl ether. The extract is dried, filtered, evaported, the residue distilled and the fraction boiling at 211°-213°/0.6 mm Hg collected, to yield the ethyl 4-(bis-carbethoxyethylamino)-phenylacetate.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][C:11](=[N:13][OH:14])[NH2:12].[CH2:16](OC(OCC)OCC)C.B(F)(F)F.CCOCC>>[CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][C:11]1[N:12]=[CH:16][O:14][N:13]=1
Reactant: CCOC(OCC)OCC
Reactant: CN(C)c1ccccc1SCC(N)=NO
Agent: FB(F)F
Solvent: CCOCC
Product: CN(C)c1ccccc1SCc1ncon1
Reaction time: 5 h

Procedure:
A mixture of 2-(2-dimethylaminophenylthio)acetamidoxime (1.0 g), triethylorthoformate (1.5 ml) and boron trifluoride etherate (0.015 ml) was warmed at 70° whence a solution soon formed. Heating at 70° was continued for 5 hours, the reaction mixture cooled and solvent removed by evaporation under reduced pressure. The residual oil was taken up in diethyl ether, washed with 5% aqueous sodium carbonate solution and water, dried and evaporated to dryness under reduced pressure. The residue was distilled under reduced pressure to give 3-(2-dimethylaminophenylthiomethyl)-1,2,4-oxadiazole as a colourless oil, b.p. 119° (0.07 mm Hg).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[CH2:7][N:6]([C:8]([OH:10])=[O:9])[C:5]2[CH:11]=[C:12]([O:19]CC3C=CC=CC=3)[C:13]3[NH:14][CH:15]=[C:16]([CH3:18])[C:17]=3[C:4]1=2.C1COCC1.C([O-])=O.[NH4+]>[Pd].CO>[Cl:1][CH2:2][CH:3]1[CH2:7][N:6]([C:8]([OH:10])=[O:9])[C:5]2[CH:11]=[C:12]([OH:19])[C:13]3[NH:14][CH:15]=[C:16]([CH3:18])[C:17]=3[C:4]1=2
Reactant: Cc1c[nH]c2c(OCc3ccccc3)cc3c(c12)C(CCl)CN3C(=O)O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c[nH]c2c(O)cc3c(c12)C(CCl)CN3C(=O)O

Procedure:
A 110 mg quantity (0.26 mM) of the product of Step 4A, 1,1-dimethylethyl ester of 1-(chloromethyl)-1,6-dihydro-8-methyl-5-(phenylmethoxy)-benzo[1,2-b:4,3-b']dipyrrole-3(2H)-carboxylic acid, is stirred at room temperature under nitrogen in 2 ml freshly distilled THF and 2 ml methanol. 120 mg 10% Pd/C (palladium on charcoal) and 130 mg ammonium formate is added. After TLC shows the reaction mixture to be complete, the reaction mixture is filtered, and the solid washed with freshly distilled THF. The combined filtrate and wash is partitioned between ethyl acetate and brine (saturated aqueous sodium chloride solution), the layers separated and the aqueous layer reextracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate and evaporated yield (BOC)CPI hydrochloride, 1,1-dimethylethyl ester of 1-(chloromethyl)-1,6-dihydro-5-hydroxy-8-methyl-benzo[1,2-b:4,3-b']dipyrrole-3(2H)-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]2O.O=P(Cl)(Cl)[Cl:20]>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]2[Cl:20]
Reactant: CCOC(=O)c1cnc2c(Br)cccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(Br)cccc2c1Cl

Procedure:
A solution of ethyl 8-bromo-4-hydroxyquinoline-3-carboxylate (2.0 g, 6.75 mmol) in POCl3 (10 mL) was heated at 80° C. for 3 h. Then the volatiles were removed and ice-water was added to the residue. The precipitated solid was filtered and dried to afford 1.8 g of the title product. 1H NMR (300 MHz, DMSO d6): δ 9.26 (s, 1H), 8.44-8.37 (m, 2H), 7.79-7.64 (t, J=7.8 Hz, 1H), 4.48-4.43 (q, J=7.2, 14.1 Hz, 2H), 1.41-1.36 (t, J=6.9 Hz, 3H); MS (m/z): 314.01 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.[CH3:21][N:22]1[CH:26]=[C:25]([CH:27]=[O:28])[C:24]([CH3:29])=[N:23]1>>[Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:27]([C:25]4[C:24]([CH3:29])=[N:23][N:22]([CH3:21])[CH:26]=4)[OH:28])=[C:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: Cc1nn(C)cc1C=O
Product: COC(=O)c1nc2n(c1C(O)c1cn(C)nc1C)CCOc1cc(F)c(Br)cc1-2

Procedure:
Methyl 10-bromo-3-((1,3-dimethyl-1H-pyrazol-4-yl)(hydroxy)methyl)-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate was prepared similarly according to the procedure in Example 9. methyl 10-bromo-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxylate was reacted with 1,3-dimethyl-1 h-pyrazole-4-carbaldehyde to afford the crude title compound which was carried forward without further purification.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:45][CH3:46])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:18]=2)[C:12]1=[O:44])[C:4]([O:6]C(C)(C)C)=[O:5].ClCCl>FC(F)(F)C(O)=O>[CH3:1][C@@H:2]([CH2:45][CH3:46])[C@H:3]([N:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:18]=2)[C:12]1=[O:44])[C:4]([OH:6])=[O:5]
Reactant: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CCN(Cc2cccc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1=O

Procedure:
A solution of the product of Example 286B (0.35 g) in trifluoroacetic acid:dichloromethane (3 mL, 2:1) was stirred at 25° C. for 2 hrs. The solvents were evaporated and the residue was directly used for the next step.
Reaction SMILES: Cl.Cl.Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[C:17]([CH3:29])[CH:16]=1.[O:30]1[CH:34]=[CH:33][C:32](B(OC(C)C)OC(C)C)=[CH:31]1>>[O:30]1[CH:34]=[CH:33][C:32]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][N:8]=[C:7]3[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([CH3:29])[CH:16]=2)=[CH:31]1
Reactant: CC(C)OB(OC(C)C)c1ccoc1
Reactant: Cc1cc(Nc2ncnc3ccc(Br)cc23)ccc1OCc1ccccn1
Agent: Cl
Product: Cc1cc(Nc2ncnc3ccc(-c4ccoc4)cc23)ccc1OCc1ccccn1
Yield: 55 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-bromo-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazoline dihydrochloride salt was reacted with di-isopropyl 3-furylboronate to give 6-(3-furyl)-4-[3-methyl-4-(2-pyridylmethoxy)anilino]-quinazoline in 55% yield, m.p. 206-208° C.;
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:32]=[C:31]([F:33])[C:7]([CH2:8][N:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[C:11]([C:17]3[N:22]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:20]([OH:30])=[CH:19][N:18]=3)=[N:10]2)=[C:6]([F:34])[CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:42][CH2:43][N:44]([CH3:46])[CH3:45]>CN(C=O)C>[CH3:45][N:44]([CH3:46])[CH2:43][CH2:42][O:30][C:20]1[C:21]([NH:23][C:24]2[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=2)=[N:22][C:17]([C:11]2[C:12]3[CH2:16][CH2:15][CH2:14][C:13]=3[N:9]([CH2:8][C:7]3[C:6]([F:34])=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:32][C:31]=3[F:33])[N:10]=2)=[N:18][CH:19]=1
Reactant: CN(C)CCCl
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(O)c(Nc4ccncc4)n3)c3c2CCC3)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OCCN(C)C)c(Nc4ccncc4)n3)c3c2CCC3)c(F)c1
Temperature: 50 °C

Procedure:
100 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]-pyrazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-ol 2-2-1 (0.215 mmol, 1.00 eq.) were dissolved in 8 mL of dry DMF and 149 mg potassium carbonate (1.08 mmol, 5.00 eq.) and 47 mg 2-chloro-N,N-dimethylethanamine (0.323 mmol, 1.50 eq.) were added. The reaction mixture was stirred over night at 50° C. The reaction mixture was partitioned between aqueous half saturated sodium chloride solution and DCM/isopropanol (4:1). The separated aqueous layer was extracted with DCM/isopropanol (4:1). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The purification of the residue by flash chromatography provided 51 mg (0.09 mmol, 42%) of analytically pure target compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([CH:6]=[C:7]([C:14]([OH:16])=O)[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[NH:22][C:23]([C:25]1[C:33]2[NH:32][C:31]([NH2:34])=[N:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)=[O:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:19]1[CH:20]=[CH:21][N:17]=[C:18]1[NH:22][C:23]([C:25]1[C:33]2[N:32]=[C:31]([NH:34][C:14]([C:7]3[N:8]=[CH:9][C:10]4[C:5]([CH:6]=3)=[CH:4][CH:3]=[C:2]([Cl:1])[C:11]=4[O:12][CH3:13])=[O:16])[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)=[O:24]
Reactant: COc1c(Cl)ccc2cc(C(=O)O)ncc12
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(Cl)ccc2cc(C(=O)Nc3nc4c(C(=O)Nc5ncc[nH]5)cccc4[nH]3)ncc12
Yield: 13 %

Procedure:
10 mg (13%) of 7-chloro-8-methoxy-isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide was synthesized according to the general procedure A using 7-chloro-8-methoxy-isoquinoline-3-carboxylic acid (from previous step), 36.3 mg (0.15 mmol) of intermediate B (2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide), 69 mg (0.18 mmol) of HBTU, 0.106 mL (0.6 mmol) of DIEA in 2 mL of DMF stirring at 80° C. for 2 h. LCMS: 462 (M+1)+.
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[N:14]=[C:15]([NH:18][CH:19]([CH3:21])[CH3:20])[O:16][CH:17]=2)=O)=[C:8]([Cl:22])[C:7]([O:23][CH3:24])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].C1COCC1.Cl>C1(C)C=CC=CC=1.CCOCC.O.CC#N>[Cl:22][C:8]1[C:7]([O:23][CH3:24])=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([C:13]1[N:14]=[C:15]([NH:18][CH:19]([CH3:21])[CH3:20])[O:16][CH:17]=1)[CH:2]=[C:1]2[OH:3]
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2coc(NC(C)C)n2)c1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc2c(O)cc(-c3coc(NC(C)C)n3)nc2c1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 102.7 %

Procedure:
2-Isopropylamino-oxazole-4-carboxylic acid (6-acetyl-2-chloro-3-methoxyphenyl)amide (863 mg, 2.45 mmol) was suspended in toluene (20 ml). NaH (147.3 mg, 3.7 mmol) was added to the vigorously stirred mixture while monitoring H2 evolution. The reaction was refluxed (110° C.) for 3 h. After cooling, additional NaH (approx 80 mg) was carefully added, followed by 20 mL of THF to aid solubility. The mixture was heated for an additional 2 h. After cooling to room temperature, the reaction mixture was acidified to pH 2 with conc. HCl. The slurry was stirred for 1 h at rt, then 10 mL of CH3CN was added, followed by 5 mL H2O and 20 mL of ether. The mixture was stirred for another 30 min, and then the solids were collected by filtration and washed with ether and hexane. The wet cake was dried under high vacuum to a constant weight to provide 8-chloro-2-(2-isopropylaminooxazol-4-yl)-7-methoxy-quinolin-4-ol (840 mg, 100% yield) that was used without further purification. LCMS found 334 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]4[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[C:26]([N:33](C)[C:34]1[N:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=1)(OC(C)(C)C)=O>>[CH:20]([N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:37]5[CH:38]=[N:39][C:34]([NH:33][CH3:26])=[CH:35][CH:36]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:25])[C:13]2=[O:24])[C:16]([CH3:23])=[N:17]1)([CH3:21])[CH3:22]
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CNc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(C(C)C)nc2C)c(=O)n4C)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 58.8 mg, 0.147 mmol) and 6-(N-boc-methylamino)pyridine-3-boronic acid pinacol ester (Alfa Aesar, Heysham, UK, 58.8 mg, 0.176 mmol) to give crude boc-protected title compound that is treated for 25 min at rt with trifluoroacetic acid (1.5 ml) and then purified by prep. HPLC to give the title compound as a light yellow solid. (HPLC: tR 2.21 min (Method A); M+H=428 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.90 (s, 1H), 8.23-8.14 (m, 2H), 8.05-7.98 (m, 1H), 7.87-7.79 (m, 1H), 7.48-7.37 (m, 2H), 6.78-6.70 (m, 1H), 6.49-6.42 (m, 1H), 4.61-4.50 (m, 1H), 3.56 (s, 3H), 2.77 (d, 3H), 1.95 (d, 3H), 1.51-1.45 (m, 6H))
Reaction SMILES: [CH:1]1(O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]3=2)[C:3](O)=[C:2]1O.CC(C)=O.C([O-])([O-])=O.[K+].[K+].ClC[C:29]#[N:30]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CO.C(Cl)Cl>[CH:1]1([C:29]#[N:30])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]3=2)[CH:3]=[CH:2]1
Reactant: OC1=C(O)C(O)c2c1ccc1ccccc21
Reactant: N#CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Solvent: CO
Solvent: ClCCl
Product: N#CC1C=Cc2ccc3ccccc3c21
Temperature: 23 °C
Reaction time: 44 h

Procedure:
A 50-L, three-neck, round-bottom flask equipped with a mechanical stirrer and a thermocouple was charged with benzindene triol (1250 g), acetone (19 L) and K2CO3 (powdered) (1296 g), chloroacetonitrile (567 g), tetrabutylammonium bromide (36 g). The reaction mixture was stirred vigorously at room temperature (23±2° C.) for 16-72 h. The progress of the reaction was monitored by TLC. (methanol/CH2Cl2; 1:9 and developed by 10% ethanolic solution of PMA). After completion of reaction, the reaction mixture was filtered with/without Celite pad. The filter cake was washed with acetone (10 L). The filtrate was concentrated in vacuo at 50-55° C. to give a light-brown, viscous liquid benzindene nitrile. The crude benzindene nitrile was used as such in the next step without further purification.
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6](=[O:42])[CH2:7][CH2:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[N:13]([C:21]2[N:26]=[C:25]([N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][CH2:28]3)[N:24]=[C:23]([N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[N:22]=2)[CH:12]=1)=[O:10].FC(F)(F)C(O)=O>ClCCl>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:21]1[N:26]=[C:25]([N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][CH2:28]3)[N:24]=[C:23]([N:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)[N:22]=1)[CH:12]=[C:11]2[C:9](=[O:10])[CH2:8][CH2:7][C:6]([OH:42])=[O:5]
Reactant: C[Si](C)(C)CCOC(=O)CCC(=O)c1cn(-c2nc(N3CCCCC3)nc(N3CCc4ccccc43)n2)c2ccc(Cl)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1cn(-c2nc(N3CCCCC3)nc(N3CCc4ccccc43)n2)c2ccc(Cl)cc12

Procedure:
To a stirred solution of 4-{5-chloro-1-[4-(2,3-dihydro-indol-1-yl)-6-piperidin-1-yl-[1,3,5]-triazin-2-yl]-1H-indol-3-yl}-4-oxo-butyric acid 2-trimethylsilanyl-ethyl ester (0.198 g, 0.314 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.25 mL, 3.25 mmol). Upon completion (TLC 5% methanol in dichloromethane), the solution was concentrated in vacuo to yield the titled compound as a white solid. Rf 0.21 (5% methanol in dichloromethane); 1H NMR (THF-d8, 300 MHz) δ 9.04 (1H, s, ArH), 8.73 (1H, d, J=9 Hz, ArH), 8.39 (1H, d, J=2 Hz, ArH), 8.34 (1H, d, J=7 Hz, ArH), 7.32 (1H, dd, J=9, 2 Hz, ArH), 7.23-7.16 (2H, m, ArH), 6.95 (1H, t, J=7 Hz, ArH), 4.40 (2H, m, CH2), 3.97 (4H, m, CH2), 3.28-3.18 (4H, m, CH2, CH2), 2.71 (2H, t, J=6 Hz, CH2), 1.75-1.65 (6H, m, NCH2); ESI-LCMS e/z calculated for C28H27ClN6O3 530.183, found 531 (M+H)+, 553 (M+Na)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1B(O)O>CN(C=O)C>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: OB(O)c1ccc(F)cc1F
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1F

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2,4-difluorophenylboronic acid (CAS RN 144025-03-6) and using DMF as reaction solvent. Off-white solid (60%). MS (ESI): m/z=461.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[C:9]1(=O)[O:14][CH:12]([CH3:13])[CH2:11][CH2:10]1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]2[C:3]=1[CH:12]([CH3:13])[CH2:11][CH2:10][C:9]2=[O:14]
Reactant: Fc1ccc(F)cc1
Reactant: CC1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC1CCC(=O)c2c(F)ccc(F)c21
Temperature: 110 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
1,4-Difluorobenzene (22 ml, 210 mmol) was mixed with gamma-valerolactone (4 ml, 42 mmol) and AlCl3 (28 g, 210 mmol) was added by portions to the stirred reaction mixture. The reaction mixture was then refluxed at stirring for 16 h (oil bath 110° C.). The reaction mixture was cooled down (ice/brine bath) and ice/conc. HCl was added and stirred until homogeneous mixture was obtained. The reaction mixture was then extracted into methylene chloride, washed with water (4×10 ml) and sodium bicarbonate solution (3×100 ml). The organic extract was dried over Na2SO4. Concentration by rotary evaporation gave 6.7 g of product as yellow powder. Yield 81%.