Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:13]1([NH:19][C:20](=[O:28])[CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[NH2:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[C:3]([N:25]2[CH2:26][CH2:27][N:22]([CH2:21][C:20]([NH:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:28])[CH2:23][CH2:24]2)[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: O=C(CN1CCNCC1)Nc1ccccc1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3ccccc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (10 ml) was added N-phenyl-2-piperazin-1-yl-acetamide×2HCl salt (0.160 g, 0.55 mmol) followed by diisopropylethylamine (0.32 ml, 1.76 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 30% ethyl acetate in dichloromethane. The title compound was obtained as a pale yellow solid (0.134 g, 62%); 1H-NMR (500 MHz, DMSO-d6) 2.67 (br s, 4H, piperazine N(CH2)2), 3.12 (br s, 4H, piperazine N(CH2)2), 3.19 (s, 2H, NCH2CO), 7.06 (m, 3H, 2-NH2, p-ArH), 7.31 (t, J=7.44 Hz, 2H, m-ArH), 7.62 (d, J=8.29 Hz, 2H, o-ArH), 8.16 (s, 1H, 6-H), 9.76 (s, 1H, CONH);
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.[C:10]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[C:10]([N:20]1[CH2:21][CH2:22][N:23]([C:7]([CH:2]2[NH:1][C:5](=[O:6])[CH2:4][CH2:3]2)=[O:9])[CH2:24][CH2:25]1)([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: O=C1CCC(C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)N1
Yield: 85.5 %

Procedure:
Pyroglutamic acid (112.4 g), 147.7 g of N-carbobenzoxypiperazine, 179.7 g of dicyclohexylcarbodiimide and 6.7 liters of acetonitrile were heated to reflux for 6 hours with stirring. The insoluble matters were removed by filtering the reaction mixture and the solvent was evaporated from the filtrate in vacuo. The residue was subjected to a silica gel column chromatography to give 190 g of oily N-carbobenzoxy-N'-(2-pyrrolidon-5-carbonyl)piperazine. Thirty grams of this was dissolved in 450 ml of methanol and the solution was subjected to a catalytic reduction using 3.0 g of 5% palladium-carbon with stirring at room temperature. The catalyst was removed by filtering the reaction solution and the solvent was evaporated in vacuo from the filtrate to give 20 g of the product. This was recrystallized from a mixture of methanol and ethyl acetate to give 17.5 g of desired compound, m.p. 162°-163° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].[H-].[Na+].[Br:8][C:9]1[CH:10]=[CH:11][C:12](F)=[N:13][CH:14]=1>CN(C=O)C.O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:4][CH2:3][CH:2]([CH3:5])[CH3:1])=[N:13][CH:14]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(Br)cn1
Yield: 86.3 %

Procedure:
To 2-methyl-propan-1-ol (10 g, 0.41 mol) was added NaH (60%, 8.2 g, 0.204 mol) portionwise under a nitrogen atmosphere at room temperature over 10 minutes. The mixture was refluxed for 30 minutes. A solution of 5-bromo-2-fluoro-pyridine (24 g, 0.136 mol) in DMF (400 mL) was added dropwise and the mixture refluxed for 18 hours. The reaction mixture was then diluted with water (1 L) and extracted with EtOAc (3×500 mL). The combined organics were washed with brine (3×300 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue obtained was purified by flash column chromatography eluting with petroleum ether to yield the title compound as a colourless oil (27 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[C:9]1=[O:26].[ClH:27].O1CCOCC1>C(OCC)(=O)C>[ClH:27].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]([CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[C:9]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccn(-c3ccccc3F)c2=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=c1n(-c2ccccc2F)ccn1C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
tert-Butyl 4-(3-(2-fluorophenyl)-2-oxo-2,3-dihydroimidazol-1-yl)piperidine-1-carboxylate (215 mg, 594.9 μmol) was dissolved in ethyl acetate (4.0 mL). 4N Hydrogen chloride in 1,4-dioxane (5.0 mL, 20.0 mmol) was added to the mixture. Reaction stirred at room temperature for 18 hours. The material was concentrated by roto-vap. Residue was triturated in diethyl ether. Solids were filtered off and washed with diethyl ether. Solids were collected and dried in vacuo. Title compound was obtained as tan solid in 46% yield. MS (M+H)+=262.0.
Reaction SMILES: C(OC([N:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[C:28]([F:29])=[CH:27][C:26]([F:30])=[C:25]([NH:31][CH2:32][CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36])[C:21]=3[C:22](=[O:24])[CH:23]=2)=[CH:14][C:13]=1[F:38])COC)=O)(C)(C)C.S(=O)(=O)(O)O.O>C(O)C>[NH2:8][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[C:28]([F:29])=[CH:27][C:26]([F:30])=[C:25]([NH:31][CH2:32][CH2:33][CH:34]=[C:35]([CH3:36])[CH3:37])[C:21]=3[C:22](=[O:24])[CH:23]=2)=[CH:14][C:13]=1[F:38]
Reactant: COCN(C(=O)OC(C)(C)C)c1ccc(-c2cc(=O)c3c(NCCC=C(C)C)c(F)cc(F)c3o2)cc1F
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CC(C)=CCCNc1c(F)cc(F)c2oc(-c3ccc(N)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
1.03 g (1.94 mmol) of the above 2-[4-[N-(tert-butoxycarbonyl)-N-methoxymethylamino]-3-fluorophenyl]-6,8-difluoro-5-(4-methyl-3-pentenylamino)-4H-1-benzopyran-4-one was dissolved in 80 mL of ethanol, 20 mL of 50% sulfuric acid was added and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with an aqueous saturated solution of sodium bicarbonate, once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:2-2:1) to give 520 mg of Compound 137 (yield: 69%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[O:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C(O)(=O)C.Cl>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:19]2[CH2:20][CH2:21][O:16][CH2:17][CH:18]=2)[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: O=C1CCOCC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C2=CCOCC2)c(O)c(C(C)(C)C)c1
Reaction time: 60 h
Yield: 47.1 %

Procedure:
A mixture consisting of 21.9 g (0.106 mol) of 2,4-di-tert-butylphenol, 5.3 g (0.053 mol) of tetrahydro-4H-pyran-4-one and 5 ml of acetic acid is melted melted together and is then saturated, with stirring, with hydrochloric acid gas at 40-45° C. After standing for 60 hours at room temperature, the reaction mixture is diluted with toluene and washed with water, sodium chloride solution and sodium hydrogencarbonate solution. The organic phase is dried over magnesium sulfate and concentrated on a rotary evaporator. The residue is crystallised from methanol, giving 7.2 g (47%) of 2,4-di-tert-butyl-6-(3,6-dihydro-2H-pyran-4-yl)phenol, m.p. 135-139° C. (compound (103), Table 1).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([C:17]1[CH:18]=[C:19]([C:25]#[N:26])[C:20](=[CH:23][CH:24]=1)[C:21]#[N:22])([O-])=O.C(=O)([O-])[O-].[K+].[K+]>Cl>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:17]3[CH:18]=[C:19]([C:25]#[N:26])[C:20](=[CH:23][CH:24]=3)[C:21]#[N:22])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1ccc(Oc2ccc(-c3ccccc3)cc2)cc1C#N
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 88.7 %

Procedure:
A 1 L round 3-necked round-bottomed flask was charged with 4-phenylphenol (45.7 g, 0.27 mole), 4-nitrophthalonitrile (50 g, 0.29 mole), potassium carbonate (51.9 g, 0.38 mole), and dimethylformide (470 mL). The resulting solution was heated under nitrogen with stirring to 90° C. for 1.5 hour (progress of reaction can be monitored by TLC). The dark brown reaction mixture was then poured into 2M aqueous HCl solution (300 mL) with stirring. The product precipitated out as a pale brown powder. The powder was collected by filtration and dried in a vacuum oven at 150° C. to give the desired product (71 g, 94% yield).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:6][CH:7]1[CH2:8][CH2:9][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12]1)(=[O:4])=[O:3]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCC(OS(C)(=O)=O)CC1
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (2.4 mL, 31 mmol) was slowly added to a dichloromethane solution (75 mL) of ethyl 4-hydroxycyclohexanecarboxylate (4.63 mL, 28.7 mmol) and triethylamine (8.2 mL, 59 mmol) at 0° C. The reaction mixture was stirred for 30 minutes, concentrated in vacuo and diluted in diethyl ether (100 mL). The solution was washed with 10% hydrochloric acid (25 mL), water (25 mL), and saturated sodium bicarbonate (15 mL). The organics were dried (magnesium sulfate) and concentrated in vacuo to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 1.23 (t, J=7.1 Hz, 3H), 1.54-1.82 (m, 4H), 1.87-1.97 (m, 2H), 2.00-2.08 (m, 2H), 2.34-2.41 (m, 1H), 3.00 (s, 3H), 4.13 (q, J=7.1 Hz, 2H), 4.88-4.92 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=1)#[CH:2].[F:11][C:12]1[CH:17]=[C:16](I)[CH:15]=[C:14]([F:19])[CH:13]=1>C(N(CC)CC)C.C(Cl)Cl.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:11][C:12]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=2)[CH:15]=[C:14]([F:19])[CH:13]=1
Reactant: C#Cc1nc(C)ccc1N
Reactant: Fc1cc(F)cc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N)c(C#Cc2cc(F)cc(F)c2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.8 %

Procedure:
To a solution of Cul (4.3 mg, 23 μmol) in triethylamine (5 ml) were added (2-ethynyl-6-methyl-pyridin-3-yl)amine (60 mg, 0.45 mmol), (PPh3)2PdCl2 (16 mg, 23 μmol), and 1,3-difluoro-5-iodobenzene (109 mg, 0.45 mmol). The reaction mixture was stirred at room temperature for 20 h. The solvent was evaporated to afford a brown oil which was taken up in DCM and the solution was washed with water. The aqueous phase was extracted twice with DCM. The organic phases were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography (hexane/ethyl acetate 7:3) to yield 64 mg (0.26 mmol, 58%) of (2-(3,5-difluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18](S(C)=O)=[N:19][CH:20]=2)[N:15]([CH2:26][CH3:27])[C:14]1=[O:28].[CH2:29]([N:31]([CH2:37][CH3:38])[CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])[CH3:30]>>[CH2:29]([N:31]([CH2:37][CH3:38])[CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:18]1[N:17]=[C:16]2[N:15]([CH2:26][CH3:27])[C:14](=[O:28])[N:13]([C:3]3[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[F:12])[CH2:22][C:21]2=[CH:20][N:19]=1)[CH3:30]
Reactant: CCN(CC)CCCCN
Reactant: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(S(C)=O)nc21
Product: CCN(CC)CCCCNc1ncc2c(n1)N(CC)C(=O)N(c1c(F)c(OC)cc(OC)c1F)C2
Yield: 88.4 %

Procedure:
7-(4-Diethylamino-butylamino)-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-1-ethyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as described in Example 3 using 0.46 g (1.11 mmol) of 3-(2,6-difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-methylsulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.32 g (2.22 mmol) of 4-diethylamino-butylamine. The crude product was purified using a gradient of 9:1 ethyl acetate/methanol to 9:0.25:0.25 to 9:0.5:0.25 ethyl acetate/methanol/triethylamine to give 0.4833 g (83%) of the title compound: mp 140° C.–141° C. MS (APCI) (m+1)/z 493.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=[C:16](Br)[CH:17]=2)=[CH:7][CH:6]=1)[CH3:2].[C:22]([C:26]1[CH:50]=[CH:49][C:29]([C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[C:34]=2[CH3:48])=[O:31])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=[C:16]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([NH:32][C:30](=[O:31])[C:29]4[CH:28]=[CH:27][C:26]([C:22]([CH3:23])([CH3:24])[CH3:25])=[CH:50][CH:49]=4)[C:34]=3[CH3:48])[CH:17]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2cc(Br)cn(C)c2=O)cc1
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1ccc(Nc2cc(-c3cccc(NC(=O)c4ccc(C(C)(C)C)cc4)c3C)cn(C)c2=O)cc1
Temperature: 100 °C
Yield: 77.8 %

Procedure:
A mixture of 4-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-benzoic acid ethyl ester (2) (380 mg; 1.1 mmol), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (5) (510 mg; 1.3 mmol), tetrakis(triphenylphosphine)palladium (130 mg; 0.1 mmol), 1N sodium carbonate (1.6 mL; 3.2 mmol), and 1,2-dimethoxyethane (8 mL) was heated at 100° C. in a sealed pressure vessel for 16 h. The mixture was cooled to room temperature, treated with water (70 mL) and extracted with ethyl acetate (3×60 mL). The combined organic extracts were washed with water (1×40 mL) and brine (1×40 mL), dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by flash chromatography (3:1-1:3, hexane/EtOAc, gradient) to give 4-{5-[3-(4-tert-butyl-benzoylamino)-2-methylphenyl]-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino}-benzoic acid ethyl ester (6) as a brown solid (460 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=1)=[C:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:7]([CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:6]2.[OH-].[Na+]>C1COCC1.CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:18][CH:19]=1)=[C:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:7]([CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:6]2
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(CC(C)C)cc3cc(OC)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccccc3)c(CC(C)C)cc2c1
Yield: 100.1 %

Procedure:
Ethyl ester (107) (0.82 g, 1.70 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.77 g (˜100%) of the title compound (108) as an off-white foam. 1H NMR (400 MHz, CDCl3): δ 0.75 (d, J=6.4 Hz, 6H), 1.60-1.70 (m, 1H), 2.46 (d, J=7.1 Hz, 2H), 3.93 (s, 3H), 6.22 (d, J=15.9 Hz, 1H), 6.57 (d, J=8.6 Hz, 2H), 7.04 (dd, J1=9.2 Hz, J2=2.2 Hz, 1H), 7.06-7.14 (m, 2H), 7.16 (d, J=2.2 Hz, 1H), 7.18-7.25 (m, 5H), 7.54 (s, 1H), 7.63 (d, J=16.0 Hz, 1H), 7.70 (d, J=9.2 Hz, 1H). LCMS (ESI): m/z 453 (M+H)+, m/z 451 (M−H)−.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]4[CH:42]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]4[CH:42]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-4-methyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: C[Si](C)(C)[O-].[K+].[C:7]([N:11]1[CH2:15][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[C@H:13]([C:24]([N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[CH2:39][C:40]([O:42]C)=[O:41])[CH2:28][CH2:27]2)=[O:25])[CH2:12]1)([CH3:10])([CH3:9])[CH3:8]>O1CCCC1>[C:7]([N:11]1[CH2:15][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[C@H:13]([C:24]([N:26]2[CH2:27][CH2:28][CH:29]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[CH2:39][C:40]([OH:42])=[O:41])[CH2:30][CH2:31]2)=[O:25])[CH2:12]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: COC(=O)Cc1cc(Cl)ccc1C1CCN(C(=O)[C@@H]2CN(C(C)(C)C)C[C@H]2c2ccc(F)cc2F)CC1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)N1C[C@@H](C(=O)N2CCC(c3ccc(Cl)cc3CC(=O)O)CC2)[C@H](c2ccc(F)cc2F)C1
Reaction time: 15 h

Procedure:
Potassium trimethylsilanolate (0.900 g, 7.05 mmol) was added to a stirred solution of methyl [2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-piperidin-4-yl)-5-chlorophenyl]acetate (1-9) (1.25 g, 2.35 mmol) in tetrahydrofuran (24 mL) at room temperature. After approximately 15 h, the volatiles were evaporated in vacuo and the crude residue was treated with a saturated solution of hydrogen chloride in ethyl acetate. After approximately 5 min, the reaction mixture was concentrated under reduced pressure and the crude residue triturated twice with dry diethyl ether to give 1-10 as an amorphous white solid (m/z (ES) 519 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[C:25]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])=[C:24]([CH3:34])[NH:23][C:22]=1[CH:35]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:22]4[NH:23][C:24]([CH3:34])=[C:25]([C:26]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[O:27])[C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCOCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)c(C)c1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 79.3 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3,5-dimethyl-4-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (70.9 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 98.5 mg (79%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.28 (br s, 1H, NH), 11.68 (br s, 1H, NH), 9.12 (br s, 1H), 8.29 (s, 1H), 7.71 (m, 1H), 7.40 (m, 1H), 7.31-7.36 (m, 2H), 3.56 (m, 4H, 2×CH2), 3.45 (m, 4H,2×CH2), 2.31 (s, 3H, CH3), 2.14 (s, 3H, CH3). MS 497 [M++1].
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([CH3:15])[C:9]([F:14])=[C:10]([F:13])[CH:11]=2)[C:6](=[O:16])[C:5]([C:17]([O:19]CC)=[O:18])=[CH:4]1)[CH3:2].Cl>C(O)(=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([CH3:15])[C:9]([F:14])=[C:10]([F:13])[CH:11]=2)[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2cc(F)c(F)c(C)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2c(C)c(F)c(F)cc21
Yield: 80.4 %

Procedure:
Employing ethyl 1-ethyl-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.55 g), conc. hydrochloric acid (1.5 ml) and 90 % acetic acid (6 ml), the procedure of Reference Example 10 is repeated to give 1-ethyl-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.40 g), as white crystals, m.p. >300° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:5]=[C:4]([NH:18][C:19]2[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=2)[CH:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][S:8][C:6]2[N:5]=[C:4]([NH:18][C:19]3[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=3)[CH:3]=[C:2]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[N:7]=2)=[CH:11][CH:12]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(CSc2nc(Cl)cc(Nc3cc(C)n[nH]3)n2)cc1
Product: COc1ccc(CSc2nc(Nc3cc(C)n[nH]3)cc(N3CCN(C)CC3)n2)cc1

Procedure:
The above-prepared [6-chloro-2-(4-methoxy-benzylsulfanyl)-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (500 mg, 1.38 mmol) in 1-methylpiperazine (10 mL) is heated at 130° C. for 15 hours. The solvent is then removed in vacuo and the residue is purified by flash chromatography (SiO2, dichloromethane/MeOH gradient) to give the desired product [2-(4-methoxy-benzylsulfanyl)-6-(4-methylpiperazin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.