Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:6]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:1][NH:7][CH2:13][C:9]1[S:8][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccco1
Reactant: O=Cc1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1coc(CNCc2cccs2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of furfurylamine (2.0 g, 0.0206 mol) and 2-thiophenecarboxaldehyde (2.31 g, 0.0206 mol) in dichloromethane (60 ml) was stirred at room temperature for 5 minutes before adding portionwise sodium triacetoxyborohydride (5.24 g, 0.0247 mol). After addition was complete (approx. 2 minutes), the reaction mixture was stirred at room temperature for 3 hours and washed with sat'd NaHCO3 (aq.), dried (MgSO4), filtered and concentrated. The product mixture was purified by flash chromatography (silica gel 60, 230-400 mesh, 4:1 hexanes:EtOAc to 1:1 hexanes:EtOAc) to obtain the amine as a light yellow oil, 1.65 g (41%). MS (APCI): (M+1)+=194; 1H-NMR is consistent with structure.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([O:42][CH3:43])[CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]4[S:17][CH:18]=[CH:19][N:20]=4)(=[O:13])=[O:14])=[CH:9][CH:10]=3)[CH:5]=[N:4][N:3]=2)=[C:35]([O:42][CH3:43])[CH:34]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nncc3c2)c(OC)c1
Reactant: COc1cc(Cl)ccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Cl)ccc1-c1nncc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
A vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)phthalazine-6-sulfonamide (Intermediate AAAA) (56.22 mg, 0.118 mmol), (4-chloro-2-methoxyphenyl)boronic acid (Combi-Blocks, San Diego, Calif., 26.4 mg, 0.141 mmol), Pd(AmPhos)2Cl2 (4.17 mg, 5.89 μmol), potassium phosphate (75 mg, 0.354 mmol), 1,4-dioxane (442 μl), and water (147 μl). The vial was flushed with Ar (g), then sealed and heated in a microwave reactor for 30 min h at 90° C. LC/MS showed fairly clean protected product. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 2 h, the mixture was diluted with MeOH and filtered through diatomaceous earth with the aid of MeOH. The filtrate was concentrated, and the crude product was purified by chromatography on silica gel (12-g column, 0 to 6% MeOH/DCM) to give 1-(4-chloro-2-methoxyphenyl)-N-(thiazol-2-yl)phthalazine-6-sulfonamide (26.3 mg, 0.061 mmol, 51.5% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.97 (br. s., 1H), 9.92 (s, 1H), 8.73 (d, J=1.8 Hz, 1H), 8.22 (dd, J=1.9, 8.7 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.37 (d, J=1.9 Hz, 1H), 7.32-7.22 (m, 2H), 6.91 (d, J=4.6 Hz, 1H), 3.70 (s, 3H); m/z (ESI) 433.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][NH:6]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][N:6]1[C:29]([O:30][CH3:31])=[O:32]
Reactant: COC(=O)C1CCNC(Cc2c(F)cccc2F)C1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2c(F)cccc2F)C1
Yield: 98.2 %

Procedure:
Methyl 2-(2,6-difluorobenzyl)piperidine-4-carboxylate (5.008 g, 18.60 mmol) was dissolved in DCM (121 mL) and DIPEA (3.89 mL, 22.32 mmol) followed by methyl carbonochloridate (2.050 mL, 26.04 mmol) were added. After 3.5 h at room temperature the solution was washed with 0.1 M HCl and satd NaHCO3. The organic phase was dried and concentrated to yield dimethyl 2-(2,6-difluorobenzyl)piperidine-1,4-dicarboxylate (5.98 g, 98%). MS m/z 328 (M+H)+
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]([OH:18])(=[O:17])[C:11]([CH2:13][C:14](O)=[O:15])=[CH2:12].N(CCO)(CCO)CCO>>[CH2:1]([N:9]1[C:14](=[O:15])[CH2:13][CH:11]([C:10]([OH:18])=[O:17])[CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: OCCN(CCO)CCO
Product: CCCCCCCCN1CC(C(=O)O)CC1=O
Yield: 162.3 %

Procedure:
129 g of octylamine, 130 g of itaconic acid and 149 g of triethanolamine were used to obtain 391 g of N-octyl-5-oxopyrrolidine-3-carboxylic acid triethanolammonium salt with
Reaction SMILES: Br[CH2:2][C:3]([N:5]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:4].[CH2:22]([OH:33])[CH2:23][C:24]1[CH:32]=[CH:31][C:29]([OH:30])=[C:26]([O:27][CH3:28])[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH2:13][N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3](=[O:4])[CH2:2][O:30][C:29]1[CH:31]=[CH:32][C:24]([CH2:23][CH2:22][OH:33])=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)CBr
Reactant: COc1cc(CCO)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(CCO)cc1OC
Yield: 79 %

Procedure:
2-Bromo-N-(2,4-difluorobenzyl)-N-heptylacetamide (135 mg, 0.373 mmol), homovanillyl alcohol (63 mg, 0.373 mmol) and potassium carbonate anhydrous (77 mg, 0.559 mmol) were mixed in acetonitrile (10 ml). The mixture was heated to reflux for 4 hours and then evaporated to dryness. The residue (with additional DCM, 1 ml×2) was loaded onto a column (ISOLUTE® SI, 1 g/6 ml). It was eluted with DCM and then MeOH/DCM (0.5:99.5, then 1:99). The product fractions were combined and evaporated Oil product 132 mg was obtained yield 79%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.S(Cl)(Cl)=O.[CH3:19]O>C(=O)(O)[O-].[Na+]>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][C:12]([O:14][CH3:19])=[O:13])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CO
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3,5-dimethoxyphenyl)acetic acid (5) (600 mg, 3.06 mmol) in MeOH (30 mL) was added dropwise thionyl chloride (3 mL) at 0° C., and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by liquid chromatography-mass spectrometry (LCMS). The mixture was diluted with saturated sodium bicarbonate (aq., 20 mL) and extracted by EtOAc (3×20 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated to give methyl 2-(3,5-dimethoxyphenyl)acetate (crude, 700 mg) as a yellow oil. MS (ES+) C11H14O4 requires: 210. Found: 211 [M+H]+.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]([C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[S+:11]=1)([CH3:9])([CH3:8])[CH3:7].[CH3:21][N:22]([CH3:31])[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C(OCC)C>C(OC(=O)C)(=O)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]([C:10]1[CH:15]=[C:14]([CH:16]=[CH:27][C:26]2[CH:29]=[CH:30][C:23]([N:22]([CH3:31])[CH3:21])=[CH:24][CH:25]=2)[CH:13]=[C:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[S+:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Cc1cc(C(C)(C)C)[s+]c(C(C)(C)C)c1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C=Cc2cc(C(C)(C)C)[s+]c(C(C)(C)C)c2)cc1
Temperature: 100 °C

Procedure:
319 mg of 2,6-di-tert-butyl-4-methylthiopyrylium perchlorate and 150 mg of 4-dimethylaminobenzaldehyde were heated in 5 ml of acetic anhydride for 40 minutes on an oil bath maintained at 100° C. After allowing to cool, diethyl ether was added to precipitate crystals and then the crystals were recrystallized from ethanol. Yield: 210 mg; m.p.: 240° C.
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[N+:18]([O-:20])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.[Br:21]C1C=CC(/C=C/[N+]([O-])=O)=CC=1>>[Br:21][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[N+:18]([O-:20])=[O:19])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(Br)cc1
Reactant: O=[N+]([O-])[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Product: O=[N+]([O-])[C@@H]1C[C@H]1c1ccc(Br)cc1
Yield: 27 %

Procedure:
This compound was synthesized using the same methodology described in Intermediate C, using the commercially available 1-bromo-4-[(trans)-2-nitrovinyl]benzene as starting material. 27% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[C:8]2[OH:18].C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:26][CH3:27].CN(C=O)C>CCOC(C)=O>[CH2:26]([O:18][C:8]1[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[CH:11]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=1)[CH3:27]
Reactant: CCI
Reactant: CCOC(=O)c1cc(O)c2cccc(OC)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OCC)c2cccc(OC)c2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a 25 mL round bottom flask were added ethyl 8-methoxy-4-hydroxynaphthalene-2-carboxylate (0.25 g, 1.02 mmol), Cs2CO3 (0.33 g, 1.02 mmol), iodoethane (0.79 g, 5.1 mmol) and DMF (4 mL). The resulting reaction mixture was stirred at 70° C. overnight. After cooling to room temperature, the reaction was diluted with EtOAc (30 mL), washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified on a silica gel column eluting with a gradient of 10-20% EtOAc/hexanes to give the title intermediate (0.19 g) as a light yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([O:31]CC)=[O:30])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([C:28](=[O:34])[C:29]([OH:31])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2cccc(-c3ccc(OC(F)(F)F)cc3)c12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2cccc(-c3ccc(OC(F)(F)F)cc3)c12
Yield: 83.5 %

Procedure:
{1-Benzyl-4-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl {1-benzyl-4-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetate (0.167 g, 0.357 mmol), and potassium hydroxide (0.103 g, 1.84 mmol) in THF (5 mL) and water (5 mL), according to the procedure described in Step 4 of Example 5. Drying for 12 hours at 90° C. furnished the title compound as a light yellow solid (0.131 g, 83%), mp: 167-169° C. (dec.). Mass spectrum (+ESI, [M+H]+) m/z 440; 1HNMR (500 MHz, DMSO-d6): δ 13.5-14.0 (br s, 1H), 8.65 (s, 1H), 7.65 (d, 1H, J=8.2 Hz), 7.25-7.4 (m, 10H), 7.15 (d, 2H, J=7.3 Hz), and 5.6 ppm (s, 2H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]([O:19][CH2:20][CH:21]1[O:25][C:22]1([CH3:24])[CH3:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][CH:21]([CH2:20][O:19][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:22]([CH3:24])([OH:25])[CH3:23]
Reactant: CCCCCCCCCCCCCCOCC1OC1(C)C
Reactant: NCCO
Solvent: CCO
Product: CCCCCCCCCCCCCCOCC(NCCO)C(C)(C)O
Temperature: 80 °C
Yield: 57.8 %

Procedure:
A 100-ml two-necked flask equipped with a stirrer and a dropping funnel was charged with 15.3 g (16.7 mmol) of ethanolamine and 5.0 g of ethanol. While heating and stirring the mixture at 80° C. in a nitrogen atmosphere, an ethanol solution of 5.00 g (16.7 mmol) of 1-tetradecyloxy-3-methyl-2-butene oxide was added dropwise over 3 hours. After heating and stirring the mixture further for 16 hours, the resultant reaction mixture was concentrated under reduced pressure, and the resultant residue was purified by column chromatography on silica gel, thereby obtaining 3.47 g (yield: 58%) of the title compound (IIc-4).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:22][O:21][C:20]3[CH:23]=[C:24]4[C:28](=[CH:29][C:19]1=3)[CH2:27][CH2:26][O:25]4)[C:5](=O)[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2CCCCC.[N:57]1[CH:62]=[C:61](B(O)O)[CH:60]=[N:59][CH:58]=1.CN(C)C1N=CC(B(O)O)=CC=1>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:6]1[C:7]2[C:3](=[C:2]([C:61]3[CH:62]=[N:57][CH:58]=[N:59][CH:60]=3)[CH:10]=[CH:9][CH:8]=2)[C:4]2([CH2:22][O:21][C:20]3[CH:23]=[C:24]4[C:28](=[CH:29][C:19]2=3)[CH2:27][CH2:26][O:25]4)[CH2:5]1
Reactant: O=C1N(Cc2ccccn2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Reactant: OB(O)c1cncnc1
Agent: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: CN(C)c1ccc(B(O)O)cn1
Product: c1ccc(CN2CC3(COc4cc5c(cc43)CCO5)c3c(-c4cncnc4)cccc32)nc1

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bronno-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and pyrimidin-5-ylboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (16%) as a colorless solid: mp>200° C.; 1H NMR (300 MHz, CDCl3) δ 9.09 (s, 1H), 8.59 (d, 1H), 8.14 (s, 2H), 7.74 (t, 1H), 7.67 (d, 1H), 7.63 (d, 1H), 7.52 (d, 1H), 7.47-7.42 (m, 1H), 7.37 (d, 1H), 7.30 (d, 1H), 7.09 (d, 1H), 6.82 (d, 1H), 6.62 (s, 1H), 6.07 (s, 1H), 5.18 (ABq, 2H), 4.62 (ABq, 2H), 4.62-4.48 (m, 2H), 3.02 (t, 2H); MS (ES+) m/z 449.5 (M+1).
Reaction SMILES: C1(=O)[NH:5]C(=O)C2=CC=CC=C12.[K].[CH2:13]([O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[O:25][CH2:24][C:23]([CH2:29]Br)=[CH:22]2)[CH2:14][CH2:15][CH2:16][CH3:17]>CN(C=O)C.O>[CH2:13]([O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[O:25][CH2:24][C:23]([CH2:29][NH2:5])=[CH:22]2)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCCOc1ccc2c(c1)C=C(CBr)CO2
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCOc1ccc2c(c1)C=C(CN)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.25 g (6.75 mmol) of potassium phthalimide are added to a solution of 1.4 g (4.5 mmol) of the brominated compound obtained in Step D in 15 ml of DMF; the medium is then stirred overnight at ambient temperature and under argon. After evaporation of the solvent in vacuo, the residue obtained is taken up in water; the aqueous phase is then extracted with dichloromethane. The organic phase, dried over magnesium sulphate and then filtered, is concentrated in vacuo. Chromatography on a silica column (eluant: ethyl acetate/petroleum ether 10/90) allows access to the title phthalimide in the form of a white solid.
Reaction SMILES: C[C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])(C)N1.C(=O)=O.[Li]CCCC.[Cl:19][C:20]1[C:21]([Cl:29])=[N:22][CH:23]=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26].C(=O)C1C=CC=CC=1>C1COCC1>[Cl:29][C:21]1[N:22]=[CH:23][C:24]2[C:25](=[O:27])[O:26][CH:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:2][CH:10]=3)[C:28]=2[C:20]=1[Cl:19]
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: O=Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1OC(c2ccccc2)c2c1cnc(Cl)c2Cl
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A solution of 2,2,6,6-tetramethyl-piperidine (7.5 ml, 44 mmol) in a 250 ml round bottomed flask equipped with a magnetic stirrer, is put under argon atmosphere and 30 ml of dry THF is added. The reaction mixture is cooled to −50° C. by adding a controlled amount of dry ice to an acetone bath. The cooled reaction mixture is treated dropwise with nBuLi solution (16.3 mL of a 2.5 M solution in hexanes, 40 mmol) and the reaction is let stir at that −50° C. for 0.5 h. A solution of 5,6-dichloro-nicotinic acid, (3.7 g, 18.5 mmol) in THF (15 mL) is added dropwise to the reaction at −50° C. The reaction is stirred at −50° C. for 0.5 h. The reaction mixture is treated with benzaldehyde (2.5 ml, 24 mmol) dropwise at −50° C. The reaction is stirred at −50° C. for 2 h and warmed to room temperature overnight. The reaction mixture is concentrated to remove solvent and water and ether are added. The aqueous layer is extracted with ether (6×50 ml). The aqueous phase is treated with 1N HCl, until the pH of aqueous layer is ˜6 and is then extracted with ether (3×40 mL.) The aqueous solution is treated with 1N HCl solution until the pH ˜2 and solution is heated at 100° C. overnight. On cooling a white precipitate appeared. The precipitate is filtered off and washed with bicarbonate and air-dried to give the title compound (4.6 g, 89%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[CH2:21][C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:18]=[C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:19])[N:9]1[C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH3:8])[CH:5]=1)[O:1][CH2:21][C:22]#[N:23]
Reactant: Cc1cc(O)cc(N2C(=O)c3ccccc3C2=O)c1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCC#N)cc(N2C(=O)c3ccccc3C2=O)c1
Yield: 88.8 %

Procedure:
59 g (233 mmol) 2-(3-hydroxy-5-methyl-phenyl)-isoindole-1,3-dione, 44 ml (700 mmol) chloroacetonitrile and 96.7 g (700 mmol) potassium carbonate were heated for 4 h to 80° C. in 300 ml dry dimethyl-formamide. It was poured onto 2 l water, filtered and 60.5 g (89%) [3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-5-methyl-phenoxy]-acetonitrile of Fp 156°-157° C. was obtained.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[C:25]([O:29][C:30](=[O:47])[NH:31][CH2:32][CH2:33][NH:34][S:35]([C:38]1[CH:43]=[C:42](Br)[C:41]([F:45])=[CH:40][C:39]=1[F:46])(=[O:37])=[O:36])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:47])[NH:31][CH2:32][CH2:33][NH:34][S:35]([C:38]1[CH:43]=[C:42]([C:13]#[C:12][C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:6][C:7]=23)[C:41]([F:45])=[CH:40][C:39]=1[F:46])(=[O:36])=[O:37])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (675 mg, 2 mmol) and [2-(5-bromo-2,4-difluoro-benzenesulfonylamino)-ethyl]-carbamic acid tert-butyl ester (1080 mg, 2.6 mmol) according to general procedure II. Obtained as a yellow solid (670 mg, 50%). MS (ISP) 572.0 [(M+H)+]; mp 203-204° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:23](OCC)(OCC)(OCC)[CH2:24][CH3:25]>Cl.N1C=CC=CC=1>[CH2:24]([C:25]1[N:12]([CH2:13][C:14]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15]2)[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:23]
Reactant: CCOC(CC)(OCC)OCC
Reactant: CCOC(=O)C1(CNc2c(N)cnc3ccccc23)CCC1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1(Cn2c(CC)nc3cnc4ccccc4c32)CCC1
Yield: 91.8 %

Procedure:
The method described in Part E of Example 65 was used to treat ethyl 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclobutanecarboxylate (6 mmol) with triethyl orthopropionate (1.6 mL, 7.9 mmol) and pyridine hydrochloride (35 mg) and isolate the final product, ethyl 1-[(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanecarboxylate (1.86 g, 5.51 mmol), as a white solid, which was treated with sodium hydroxide (1.8 mL of 6 M) according to the method of Part F of Example 65. The product, 1-[(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanecarboxylic acid, was isolated as a tan solid (1.49 g) according to the methods of Part F of Example 65.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22](O)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C[N:31]1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[NH4+].[OH-]>O.O1CCCC1>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22]([NH2:31])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(C(=O)O)ccc1F
Reactant: CN1CCOCC1
Agent: COc1nc(Cl)nc(OC)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(C(N)=O)ccc1F
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A 250 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoic acid (3.65 g, 7.8 mmol), 4-methylmorpholine (2.6 mL, 23.4 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.64 g, 9.36 mmol) and tetrahydrofuran (40 mL). After stirring the mixture for 30 min at 250 C, NH4OH (20.0 mL) was added. The mixture was stirred for 30 min and diluted with water. The product precipitated from solution. The precipitated was filtered and washed with water and diethyl ether to give the title compound (2.37 g, 65%) as a white solid. 1H NMR (400 MHz, (CD3)2SO) δ 7.9 (d, J=7.3 Hz, 1H), 7.61 (q, J=8.6 and 6.7 Hz, 1H), 7.5 (m, 2H), 7.3 (t, J=9.6 Hz, 1H), 7.15 (t, J=8.7 Hz, 1H), 6.7 (s, 1H), 5.36 (s, 2H), 2 (s, 3H) ppm. ES-HRMS m/z 469.0172 (M+H calcd for C20H15BrF3N2O3 requires 469.0195).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:5]2=[N:6][C:7]=1[Cl:8].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[N:3]=[C:4]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]2=[N:6][C:7]=1[Cl:8]
Reactant: O=C1CCc2nc(Br)c(Cl)nc2N1
Reactant: CCOC(=O)CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCN1C(=O)CCc2nc(Br)c(Cl)nc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of 2-bromo-3-chloro-7,8-dihydro-5H-pyrido[2,3-b]pyrazin-6-one (prepared according to the preparation procedures disclosed in PCT patent application PCT/EP2011/062028, Intermediate J) (3.9 g, 14.86 mmol) and ethyl 7-bromoheptanoate (7.05 g, 29.7 mmol) in DMF (75 ml) under a nitrogen atmosphere was treated with potassium carbonate (10.27 g, 74.3 mmol) and the resulting solution was stirred at room temperature for 4 days. The mixture was diluted with water and extracted with EtOAc (×2). The extracts were washed with water and brine, dried (MgSO4) and evaporated under vacuum. The crude product was purified by chromatography on silica eluting with 0-60% EtOAc in iso-hexane to afford the titled compound;