Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7]([CH2:10][CH2:11][C:12]3[CH:34]=[CH:33][N:15]4[C:16](=[O:32])[C:17](/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])=[C:18]([N:20]5[CH2:25][CH2:24]C[CH:22]([OH:26])[CH2:21]5)[N:19]=[C:14]4[CH:13]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C1(C2N=C(CCC3C=CN4C(=O)C(/C=C/C(OC(C)(C)C)=O)=C(N5CCOCC5)N=C4C=3)SC=2)CCC1>>[CH:1]1([C:5]2[N:6]=[C:7]([CH2:10][CH2:11][C:12]3[CH:34]=[CH:33][N:15]4[C:16](=[O:32])[C:17](/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])=[C:18]([N:20]5[CH2:21][CH2:22][O:26][CH2:24][CH2:25]5)[N:19]=[C:14]4[CH:13]=3)[S:8][CH:9]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)/C=C/c1c(N2CCCC(O)C2)nc2cc(CCc3nc(C4CCC4)cs3)ccn2c1=O
Agent: CC(C)(C)OC(=O)/C=C/c1c(N2CCOCC2)nc2cc(CCc3nc(C4CCC4)cs3)ccn2c1=O
Product: O=C(O)/C=C/c1c(N2CCOCC2)nc2cc(CCc3nc(C4CCC4)cs3)ccn2c1=O
Yield: 73 %

Procedure:
Reactions were performed in the same manner as in Example 1, (L) by using tert-butyl (E)-3-{8-[2-(4-cyclobutyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (127 mg, 0.2430 mmol) to obtain 82.7 mg (73%) of the title compound as yellow crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([CH3:19])[CH2:9][CH2:8][C:7]2[C:10]([CH3:18])=[C:11]([O:16][CH3:17])[C:12]([CH3:15])=[C:13]([CH3:14])[C:6]=2[O:5]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>N1C=CC=CC=1>[CH3:17][O:16][C:11]1[C:12]([CH3:15])=[C:13]([CH3:14])[C:6]2[O:5][C:4]([CH2:3][CH2:2][O:1][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=3)(=[O:28])=[O:27])([CH3:19])[CH2:9][CH2:8][C:7]=2[C:10]=1[CH3:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(CCO)O2
Agent: Cl
Solvent: c1ccncc1
Product: COc1c(C)c(C)c2c(c1C)CCC(C)(CCOS(=O)(=O)c1ccc(C)cc1)O2
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
Pyridine (150 ml) was added to 40 g (160 mmol) of 3,4-dihydro-2-(2-hydroxyethyl)-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran for dissolution of the latter. Then the solution was cooled to 0° C. and thereto was added with vigorous stirring 34.5 g of p-toluenesulfonyl chloride gradually. After stirring at 0° C. for 1 hour, the reaction mixture was poured into 1 liter of dilute hydrochloric acid and extracted with diethyl ether. The ether layer was washed with water, dried over anhydrous magnesium sulfate and filtered. After removal of low-boiling substances from the filtrate by distillation, the residue was purified by silica gel column chromatography to give 49.8 g (78.6% yield) of 3,4-dihydro-6-methoxy-2-[2-(p-toluenesulfonyloxy)ethyl]-2,5,7,8-tetramethyl-2H-benzopyran, which has the following FD mass spectrum.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[N+:12]([O-:14])=[O:13].[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.C(OCC)C.[Pd](Cl)Cl.[Cu]I>[N+:12]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:11]2)([O-:14])=[O:13]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1cccc2cc(Br)cnc12
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[Si](C)(C)C#Cc1cnc2c([N+](=O)[O-])cccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.5 %

Procedure:
A mixture of 3-bromo-8-nitroquinoline (300 mg), trimethylsilylacetylene (140 mg), palladium (II) chloride (38 mg), catalytic amount of copper (I) iodide, triethylamine (3 ml) and triphenylphosphine (113 mg) in acetonitrile (3 ml) was stirred for 3 hours at ambient temperature. The mixture was diluted with diethyl ether, and insoluble material was filtered off. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (n-hexane-ethyl acetate) to give 8-nitro-3-(trimethylsilylethynyl)quinoline (210 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.ClCCCl.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:8][C:6]2[N:7]=[C:2]([NH2:1])[CH:3]=[CH:4][CH:5]=2)[CH2:13][CH2:12]1
Reactant: CN1CCNCC1
Reactant: Nc1cccc(C=O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCN(Cc2cccc(N)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 1-neck round-bottom flask, 6-Amino-pyridine-2-carbaldehyde (2.85 g, 23.3 mmol), 1-Methylpiperazine (5.00 mL, 45.1 mmol), 1,2-Dichloroethane (100 mL, 1000 mmol) and Acetic acid (2.50 mL, 44.0 mmol) were added and stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (14.8 g, 70.0 mmol) was added portion wise over 20 minutes. The reaction mixture was stirred at room temperature over night. The reaction was partitioned with Sat. NaHCO3. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and stripped to give a yellow solid. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 20% methano). The collected fractions afforded 6-(4-Methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine as a yellow solid (1.20, 25%)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([N:17]2[CH2:26][CH2:25][C:20]3(OCC[O:21]3)[CH2:19][CH2:18]2)[C:14]([CH2:27][N:28]([CH3:39])[C@@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][CH2:31][CH2:30]2)=[C:13]([CH3:40])[N:12]=1)[CH3:2].Cl.[OH-].[Na+]>CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([N:17]2[CH2:26][CH2:25][C:20](=[O:21])[CH2:19][CH2:18]2)[C:14]([CH2:27][N:28]([CH3:39])[C@@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][CH2:31][CH2:30]2)=[C:13]([CH3:40])[N:12]=1)[CH3:2]
Reactant: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(N2CCC3(CC2)OCCO3)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(N2CCC(=O)CC2)n1
Temperature: 60 °C

Procedure:
To a flask containing [2-(2,6-diethyl-phenyl)-4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-6-methyl-pyrimidin-5-ylmethyl]-methyl-(1S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine (80 mg, 0.148 mmol) is added HCl (3 M, 20 mL) and the reaction is heated at 60° C. for 4 h. Once cool, the reaction is basified with NaOH (1 N, 100 mL)) and EtOAc (100 mL) is added to extract the product. The organic layer is washed with water (100 mL), brine (100 mL) and dried over Na2SO4. Filtration, concentration and vacuum drying yields the title compound as a colorless gum. [mass expected (496.69); mass found (496.32)].
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26].B(O)O>>[CH3:23][O:24][C:25](=[O:26])[C:27]1[CH:32]=[CH:31][C:30]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Agent: OBO
Product: COC(=O)c1ccc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccnc2)cc1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 4-methoxycarbonylphenylboronic acid as a boronic acid, the desired compound was obtained.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1.C([O:24][B:25](OC(C)C)[O:26]C(C)C)(C)C>C1COCC1>[F:13][C:14]1[C:19]([B:25]([OH:26])[OH:24])=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1ccc(F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cnc(F)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
n-Butyllithium (2.5M solution in hexane, 9.6 mL, 24 mmol) was added to a mixture of diisopropylamine (3.4 mL, 24 mmol) in THF (5.00 mL, 61 mmol) at 0° C. and the resulting pale yellow solution was stirred at the same temperature for 30 min and then cooled down to −78° C. A suspension of 2-fluoro-5-methylpyridine (Aldrich, St. Louis, Mo.) (2.22 g, 20 mmol) in THF (5.00 mL, not complete dissolved) was slowly added. The resulting bright yellow solution was stirred at −78° C. for 1 h, treated with a solution of tri-i-propylborate (6.9 mL, 30 mmol) in THF (10.00 mL) and then allowed to warm up to room temperature. The yellow suspension was quenched with 1 N NaOH until basic (pH about 10) and the organic layer was separated. The aqueous layer was collected and carefully acidified with 6 N aqueous HCl until slightly acidic, and then extracted with EtOAc (×3). The combined organic layers were dried (Na2SO4), filtered and concentrated. The resulting white solid was washed with ether to give 2-fluoro-5-methylpyridin-3-ylboronic acid (2.9196 g, 94% yield) as a white solid. LCMS (API-ES) m/z 156 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8]C(=O)C)=[C:6]([O:12][CH3:13])[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1.[OH-].[Na+]>Cl>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([O:12][CH3:13])[C:5]([O:14][CH3:15])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)c(NC(C)=O)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Cl)c(N)c1OC
Yield: 99.4 %

Procedure:
A solution of intermediate (2-a) (0.59 mol) in hydrochloric acid (20%) (1500 ml) was stirred and refluxed for 2 hours. The mixture was cooled, alkalized with NaOH 50% and extracted twice with DCM. The combined organic layers were washed with water, dried, filtered, and the solvent was evaporated. The product was used in the next reaction step without further purification, yielding 110 g (100%) of 6-chloro-2,3-di-methoxybenzenamine (intern. 2-b)
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[F:8][C:9]([F:21])([F:20])[C:10]1[CH:11]=[C:12]([N:17]=[C:18]=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]>C1C=CC=CC=1>[Cl:16][C:15]1[CH:14]=[CH:13][C:12]([NH:17][C:18]([N:1]=[C:2]2[CH2:6][CH2:5][CH2:4][N:3]2[CH3:7])=[O:19])=[CH:11][C:10]=1[C:9]([F:8])([F:20])[F:21]
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
The hydrochloride salt of 2-imino-1-methylpyrrolidine (6.73 g.; 0.05 mole) is converted to free base by adding 5 ml. of 50% NaOH and extracting into benzene. After drying over K2CO3, the benzene solution is stirred at room temperature and 11.08 g. (0.05 mole) of 3-trifluoromethyl-4-chlorophenylisocyanate [prepared according to the method of K. Inukai and Y. Maki, Kogyo Kagaku Zasski, 70 (4), 491-4 (1967)] dissolved in about 50 ml. of anhydrous benzene is added dropwise to this solution. After one-half of the amount is added cloudiness occurs and then solid precipitates. The mixture is stirred at room temperature overnight. The solid is collected, 1-(4-chloro-3-trifluoromethylphenyl)-3-(1-methyl-2-pyrrolidylidene)urea, and recrystallizations from ethyl acetate yields the pure product, m.p. = 175° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[C:5]([CH3:13])[CH:4]=1.[Se](=O)=[O:15]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:15])[C:10](=[O:12])[CH3:11])=[C:5]([CH3:13])[CH:4]=1
Reactant: COc1ccc(CC(C)=O)c(C)c1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: COc1ccc(C(=O)C(C)=O)c(C)c1
Temperature: 100 °C

Procedure:
C8 (6.00 g, 33.7 mmol) and selenium dioxide (7.47 g, 67.3 mmol) were suspended in 1,4-dioxane (50 mL) and heated at 100° C. for 18 hours. The reaction mixture was cooled to room temperature and filtered through Celite; the filtrate was concentrated in vacuo. Silica gel chromatography (Eluent: 10% ethyl acetate in heptane) afforded the product as a bright yellow oil. Yield: 2.55 g, 13.3 mmol, 39%. LCMS m/z 193.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.6 Hz, 1H), 6.81 (br d, half of AB quartet, J=2.5 Hz, 1H), 6.78 (br dd, half of ABX pattern, J=8.7, 2.6 Hz, 1H), 3.87 (s, 3H), 2.60 (br s, 3H), 2.51 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20](F)(F)F)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.BrC1C=CC2[C:31]3[N:32]=[C:33]([C:39](N)=[O:40])S[C:35]=3CCOC=2C=1.N1(CCNN)CCOCC1>>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][CH2:20][N:32]5[CH2:33][CH2:39][O:40][CH2:35][CH2:31]5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: NNCCN1CCOCC1
Product: Brc1ccc2c(c1)OCCc1sc(-c3ncnn3CCN3CCOCC3)nc1-2

Procedure:
Following the procedure for 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide 25 was reacted with (2-morpholin-4-yl-ethyl)-hydrazine to give 8-bromo-2-[2-(2-morpholin-4-yl-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene. MS (ESI+) 462.1/464.1.
Reaction SMILES: [CH3:1][S:2]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38](O)=[O:39])=[CH:32][CH:31]=1)(=[N:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[O:25][CH:26]=[CH:27][C:28]=3[CH3:29])=[O:23])[CH:16]=2)[CH:12]=1)=[O:6])=[O:3].[NH:41]1[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42]1>>[OH:46][CH:43]1[CH2:44][CH2:45][N:41]([C:38](=[O:39])[CH2:37][CH2:36][C:33]2[CH:34]=[CH:35][C:30]([S:2]([CH3:1])(=[O:3])=[N:4][C:5](=[O:6])[C:7]3[CH:12]=[C:11]([C:13]#[C:14][C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]5[O:25][CH:26]=[CH:27][C:28]=5[CH3:29])=[O:23])[CH:16]=4)[CH:10]=[N:9][CH:8]=3)=[CH:31][CH:32]=2)[CH2:42]1
Reactant: OC1CCNC1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)O)cc3)c2)c1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)N4CCC(O)C4)cc3)c2)c1
Yield: 26.7 %

Procedure:
In a manner similar to that described in Example 485, 3-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)-phenyl]propanoic acid (0.050 g, 0.090 mmol) and pyrrolidin-3-ol (0.016 g, 0.180 mmol) were reacted to give the title compound (0.015 g, 27%).
Reaction SMILES: Cl.[C:2]1([CH:8]([OH:19])[CH:9]([NH:11]C(OC(C)(C)C)=O)[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[C:2]1([CH:8]([OH:19])[CH:9]([NH2:11])[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(NC(=O)OC(C)(C)C)C(O)c1ccccc1
Agent: Cl
Solvent: CO
Product: CC(N)C(O)c1ccccc1
Temperature: 25 °C
Yield: 77 %

Procedure:
20 ml of 3N-hydrochloric acid solution and 10 ml of methanol were added into the above-described 1-phenyl-2-(t-butoxycarbonylamino)propanol in an amount of 1.05 g (4.00 mmol), and the resulting solution was stirred for an hour at an ambient temperature. Then, the methanol in the solution was distilled out, and the aqueous layer of the solution was separated by extraction with ethyl acetate. The aqueous layer was adjusted to alkaline state by adding aqueous solution of sodium hydroxide and was then extracted with chloroform. The obtained chloroform solution was dried with anhydrous magnesium sulfate and distilled under reduced pressure to obtain 1-phenyl-2-aminopropanol in an amount of 465 mg (2.48 mmol) at a yield of 77%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([F:22])=[C:16]([F:21])[CH:17]=2)[CH:12]1[C:23]1[CH:28]=[C:27](Br)[CH:26]=[CH:25][C:24]=1[O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][N:38](C)C(=O)C>CCOC(C)=O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([F:22])=[C:16]([F:21])[CH:17]=2)[CH:12]1[C:23]1[CH:28]=[C:27]([C:37]#[N:38])[CH:26]=[CH:25][C:24]=1[O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1C1c2cc(F)c(F)cc2CCN1C(=O)OCc1ccccc1
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(C#N)cc1C1c2cc(F)c(F)cc2CCN1C(=O)OCc1ccccc1
Temperature: 120 °C
Reaction time: 0.42 h

Procedure:
To a solution of (±)-1-(5-bromo-2-ethoxycarbonylmethoxy-phenyl)-6,7-difluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (126 mg, 0.23 mmol, 1.00 eq.) in N,N-dimethylacetamide (0.45 mL) was added poly(methylhydrosiloxane) (5 μL) at r.t. The reaction mixture was heated to 120° C. and tris(dibenzylideneacetone) dipalladium(0) (4.5 mg, 0.005 mmol, 0.002 eq) then 1,1′-bis-(diphenylphosphino)-ferrocene (3.4 mg, 0.006 mmol, 0.027 eq.) were added. Afterwards, zinc cyanide (6.6 mg, 0.056 mmol, 0.25 eq.) was added. The resulting mixture was stirred at 150° C. during 25 min in a microwave. Zinc cyanide (3.3 mg, 0.028 mmol, 0.13 eq.), tris(dibenzylideneacetone) dipalladium(0) (2.3 mg, 0.002 mmol, 0.001 eq.) and 1,1′-bis-(diphenylphosphino)-ferrocene (1.7 mg, 0.003 mmol, 0.014 eq.) were added again. The resulting mixture was stirred at 150° C. during 25 min in a microwave. The reaction mixture was diluted with AcOEt and filtered over celite. The filtrate was washed with water, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by CC (SiO2, eluent:Hept/AcOEt) to yield the nitrile derivative as a pale yellow oil.
Reaction SMILES: NC1C=CC(C[N:9]2[C:19](=[O:20])[C:18]3[N:21]4[C:11](=[CH:12][N:13]=[C:14]4[CH:15]=[CH:16][CH:17]=3)[C:10]2=[O:22])=CC=1.C(N(CC)CC)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[N:13]1[CH:12]=[C:11]2[N:21]3[C:18](=[CH:17][CH:16]=[CH:15][C:14]=13)[C:19](=[O:20])[NH:9][C:10]2=[O:22]
Reactant: Nc1ccc(Cn2c(=O)c3cccc4ncc(c2=O)n43)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]c(=O)c2cnc3cccc1n32

Procedure:
To a suspension of 1.46 g (5.0 mmol) of 4-[4-(amino)phenylmethyl]-4,5-dihydro-3H-1,4,8b-triazaacenaphthylene-3,5-dione and 1.05 ml (7.5 mmol) of triethylamine in methylene chloride (100 ml) was added dropwise, while stirring under ice-cooling, 1.01 ml (6.0 mmol) of trifluoromethanesulfonic acid anhydride. The mixture was stirred for one hour at room temperature. The reaction mixture was washed with 1N-HCl, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was eluted by column chromatography (eluent:chloroform/ethyl acetate=1:1) to afford 502 mg of 4,5-dihydro-4-[4-bis(trifluoromethane sulfonyl)imido)phenylmethyl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione (18.1%, a pale reddish brown solid).
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][C:41]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=O)=O.[H-].[Na+]>CN(C)C=O>[C:42]1([C:41]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[O:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CS(=O)(=O)OCCOCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COCCOCCOCCOCCOCCOCCOCCOCCOCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 73.8 %

Procedure:
To 17-phenylmethyloxy-3,6,9,12,15-pentaoxaheptadecan-1-ol (15) (16.38 g, 43.9 mmol) in dry dimethylformamide (250 ml) was added 8-triphenylmethyloxy-3,6-dioxaoctyl methanesulfonate (13) (28.23 g, 60 mmol, 1.35 eq.) and sodium hydride (4.0 g, 100 mmol, 2.3 eq., 60% w/w in mineral oil). The reaction was left to stir for four days at room temperature after which time it was concentrated in vacuo. The reaction mixture was re-dissolved in diethyl ether (400 ml) and cooled in an ice bath to 0° C. Water was then slowly added until hydrogen was no longer evolved. The organic phase was ten partitioned twice with aq. sat. NaCl with a little NaHCO3 (2×300 ml), dried over anhydrous sodium sulphate and concentrated in vacuo to give a viscous dark brown oil. The product was isolated by N.P.S.G. chromatography, eluting with ethyl acetate only to yield (16) as a yellow oil (24.2 g, 75.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[ClH:13].[NH:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)[NH2:15]>>[ClH:13].[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:15][NH:14][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:23])=[O:24])=[CH:18][CH:17]=1
Reactant: Nc1ccc2c(c1)C(=O)C(=O)N2
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: Nc1ccc2c(c1)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2

Procedure:
The title compound was prepared from 5-amino-1H-indole-2,3-dione and 4-hydrazinobenzenesulfonamide hydrochloride according to Procedure G: 1H NMR (DMSO-d6): δ 6.95 (d, J=8 Hz, 1H), 7.2 (d, J=8 Hz, 1H), 7.26 (s, 2H), 7.46 (s, 1H), 7.5 (d, J=8 Hz, 2H), 7.8 (d, J=8 Hz, 2H), 9.7 (br s, 3H), 11.2 (s, 1H), 12.8 (s, 1H); APCI−MS m/z 330.2 (M−H)−.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[C:19]([CH3:25])=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH2:26][CH3:27])[N:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[F:28].[Li+].[OH-]>O.C1COCC1>[NH2:24][C:21]1[N:20]=[C:19]([CH3:25])[C:18]([C:17]#[C:16][C:15]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[C:5]([F:28])[CH:6]=3)=[N:11][CH:12]=[N:13][C:14]=2[CH2:26][CH3:27])=[CH:23][CH:22]=1
Reactant: CCc1ncnc(-c2ccc(C(=O)OC)c(F)c2)c1C#Cc1ccc(N)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ncnc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1C
Temperature: 50 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 4.0 g (10.3 mmol) 4-[5-(6-Amino-2-methyl-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro-benzoic acid methyl ester using 1.29 g (30.7 mmoL) LiOH in 40 mL water and 200 mL THF. The reaction mixture is stirred over night at 50° C. The solvent is removed under reduced pressure and the residue is taken up in water. Aqueous 1 M HCl is added until pH 5 is reached. The precipitated product is filtered off and washed with ACN. After drying 1.3 g (32%) of the desired product are obtained a solid material.