Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[C:12]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)#[N:13].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.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>[C:12]([C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])[CH:17]=[CH:16][CH:15]=1)#[N:13]
Reactant: Cc1cc([N+](=O)[O-])ccc1Br
Reactant: N#Cc1cccc(B(O)O)c1
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: CCO
Product: Cc1cc([N+](=O)[O-])ccc1-c1cccc(C#N)c1
Reaction time: 0.17 h
Yield: 87.2 %

Procedure:
A solution of 2-bromo-5-nitrotoluene (8.82 gm, 40.83 mmol) in 1,2-dimethoxyethane (150 mL) was added to a solution of tetrakis(triphenylphosphine)palladium(0) (2.35 gm, 2.04 mmol) in 1,2-dimethoxyethane (100 mL) under nitrogen at room temperature. A solution of 3-cyanophenylboronic acid (J. Med.Chem., 1997, 40, 4208)(9.0 gm, 61.25 mmol) in ethanol (45 mL) was added and stirred for 10 mins. Finally, 2M aqueous sodium carbonate (234 mL) was added and the mixture was heated under reflux for 18 h. After being cooled, the mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was washed with water, dried (Na2SO4), concentrated under reduced pressure and triturated with diethyl ether to give 1-(3-cyanophenyl)-2-methyl-4-nitrobenzene (8.48 gm, 87%) as a brown solid.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[CH:4]=O.Cl.[NH2:16][OH:17].[OH-].[Na+].O>C(O)C>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[CH:4]=[N:16][OH:17]
Reactant: NO
Reactant: O=Cc1c(C(F)(F)F)ccc(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1c(C(F)(F)F)ccc(F)c1F
Yield: 44.8 %

Procedure:
To a solution of 0.5 g of 2,3-difluoro-6-trifluoromethylbenzaldehyde in 8 ml of ethanol was added 0.4 g of hydroxylamine hydrochloride and a solution prepared by dissolving 0.23 g of sodium hydroxide into 2 ml of water and the mixture was heated at reflux for 40 minutes. The reaction mixture was allowed to room temperature, then concentrated under reduced pressure and extracted with ethyl acetate. The extract obtained was washed with water and with saturated saline solution and dried over anhydrous magnesium sulfate. After concentrating the extract solution, the crude product obtained was washed with n-hexane to obtain 0.24 g of the title compound (mp. 111-112° C.).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][Br:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccccc2c1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2ccccc2c1Br

Procedure:
A solution of 100 parts of 1-bromo-2-methylnaphthalene, 80.5 parts of N-bromosuccinimide and 0.5 part of benzoyl peroxide in 1500 parts by volume of carbon tetrachloride is heated at reflux temperature for several hours. The solution is then cooled, washed twice with water and the organic layer separated. The organic layer is dried over calcium sulfate, filtered and concentrated to give 1-bromo-2-(bromomethyl)naphthalene, as an oil which solidifies on standing.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3)[CH:7]=[C:6]2[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH2:3][CH2:2]1.[F:26][B-](F)(F)F.F[N+]1C(C)=CC(C)=CC=1C>C(Cl)Cl>[CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3)[C:7]([F:26])=[C:6]2[C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)[CH2:3][CH2:2]1
Reactant: F[B-](F)(F)F
Reactant: CCOc1ccc2cc(-c3ccc([N+](=O)[O-])cc3)n(CC3CC3)c2c1
Agent: Cc1cc(C)[n+](F)c(C)c1
Solvent: ClCCl
Product: CCOc1ccc2c(F)c(-c3ccc([N+](=O)[O-])cc3)n(CC3CC3)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 25.4 %

Procedure:
To 1-cyclopropylmethyl-6-ethoxy-2-(4-nitro-phenyl)-1H-indole (600 mg, 1.79 mmol) in CH2Cl2 (4 mL) was added 1-fluoro-2,4,6-trimethyl pyridinium tetrafluoroborate (418 mg, 1.85 mmol). The reaction mixture was stirred at room temperature for 3 days and then diluted in CH2Cl2 and washed with aq. NaHCO3. The organic layer was dried, concentrated and purified by silica gel chromatography (1:1 CH2Cl2/hexane) to provide 1-cyclopropylmethyl-6-ethoxy-3-fluoro-2-(4-nitro-phenyl)-1H-indole (161 mg, 25%) as a yellow solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[NH2:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:25](OC)(OC)(OC)[CH2:26][CH2:27][CH2:28][CH3:29]>C1(C)C=CC=CC=1>[CH2:26]([C:25]1[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OCCCCNc1c(N)cnc2ccccc12
Reactant: CCCCC(OC)(OC)OC
Solvent: Cc1ccccc1
Product: CCCCc1nc2cnc3ccccc3c2n1CCCCO[Si](C)(C)C(C)(C)C

Procedure:
A solution of N4-[4-(tert-butyldimethylsilanyloxy)butyl]quinoline-3,4-diamine (62.9 g, 182 mmol) and trimethyl orthovalerate (45.2 g, 278 mmol) in toluene (200 mL) was heated at reflux for 2 hours and then concentrated under reduced pressure to provide 2-butyl-1-[4-(tert-butyldimethylsilanyloxy)butyl]-1H-imidazo[4,5-c]quinoline as an oil that was used directly in the next step without further purification.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:38]=[C:37]([CH3:39])[C:29]3[NH:30][C:31]([C:33]([F:36])([F:35])[F:34])=[N:32][C:28]=3[CH:27]=2)[CH:20]=1.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN(C=O)C>[CH3:39][C:37]1[C:29]2[NH:30][C:31]([C:33]([F:34])([F:36])[F:35])=[N:32][C:28]=2[CH:27]=[C:26]([O:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:20]=2)[CH:38]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2nc(C(F)(F)F)[nH]c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2nc(C(F)(F)F)[nH]c12

Procedure:
21 mg (0.08 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 22 mg (0.07 mmol) 5-(6-chloropyrimidin-4-yloxy)-7-methyl-2-(trifluoromethyl)-1H-benzo[d]-imidazole and 40 μL (0.24 mmol) DIPEA in 2.0 mL DMF were stirred at 50° C. over the weekend. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with a 1M aqueous NaOH solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([CH2:10]O)=[N:5]2.S(Cl)([Cl:14])=O>>[Cl:14][CH2:10][C:6]1[CH:7]=[CH:8][C:9]2[N:4]([CH:3]=[CH:2][N:1]=2)[N:5]=1
Reactant: OCc1ccc2nccn2n1
Reactant: O=S(Cl)Cl
Product: ClCc1ccc2nccn2n1
Yield: 69 %

Procedure:
Thionyl chloride (10 ml) was added to imidazo[1,2-b]pyridazin-6-ylmethanol (1.5 g, 9.0 mmol) at 20° C. under an atmosphere of nitrogen at RT. The reaction mixture was stirred at reflux for 3 h (the reaction was monitored by TLC) upon which the volatiles were removed under reduced pressure. The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 15% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 6-(chloromethyl) imidazo[1,2-b]pyridazine (1.2 g, 69%) as an off-white solid. 1H NMR, 200 MHz, DMSO-d6: δ 8.35 (s, 1H), 8.3 (d, 1H), 7.85 (s, 1H), 7.35 (d, 1H), 4.95 (s, 2H). MS: [M+H]+: m/z=149.9.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:24]2[CH2:23][S:22][CH2:21][C@@H:20]([C:25]([O:27][CH3:28])=[O:26])[NH:19][C:18](=[O:29])[C@@H:17]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:16][O:15][C:14](=[O:38])[C:13]=2[C:12]([CH3:39])=[C:11]([O:40][CH3:41])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:42](O)C>C(OCC)(=O)C.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[Si:1]([O:8][C:9]1[C:24]2[CH2:23][S:22][CH2:21][C@@H:20]([C:25]([O:27][CH2:28][CH3:42])=[O:26])[NH:19][C:18](=[O:29])[C@@H:17]([NH:30][C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:16][O:15][C:14](=[O:38])[C:13]=2[C:12]([CH3:39])=[C:11]([O:40][CH3:41])[CH:10]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(OC)c(C)c2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(OC)c(C)c2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1

Procedure:
A solution of 61 mg of tert-butyl (4R, 7S)-14-(tert-butyldimethylsilyloxy)-1,3,4,5,6,7,8,10-octahydro-12-methoxy-4-methoxycarbonyl-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate and 11.4 mg of tetraisopropyl orthotitanate in 2 ml of ethanol was heated at reflux for 40 hours. The solution was diluted with ethyl acetate and washed successively with 1N hydrochloric acid and with brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using ethyl acetate/hexane (1:2, v/v) as eluent to yield tert-butyl (4R, 7S)-14-(tert-butyldimethylsilyloxy)-4-ethoxycarbonyl-1,3,4,5,6,7,8,10-octahydro-12-methoxy-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate. This material was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 13 to yield, after crystallization from ethyl acetate/hexane, tert-butyl (4R, 7S)-4-ethoxycarbonyl-1,3,4,5,6,7,8,10-octahydro-14-hydroxy-12-methoxy-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21](O)=[O:22])[C:15](=[O:24])[C@@H:14]2[CH3:25])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH2:27]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][C@H:30]2[OH:35])[CH2:28]1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]([N:32]3[CH2:33][CH2:34][C:29]4([CH2:27][CH2:28]4)[C@H:30]([OH:35])[CH2:31]3)=[O:22])[C:15](=[O:24])[C@@H:14]2[CH3:25])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[C@H]1C(=O)N(CCC(=O)O)CCN1C(=O)/C=C/c1ccc(F)c(Cl)c1
Reactant: O[C@@H]1CNCCC12CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H]1C(=O)N(CCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)/C=C/c1ccc(F)c(Cl)c1
Yield: 55.3 %

Procedure:
To a solution of 3-{(S)-4-[(E)-3-(3-chloro-4-fluoro-phenyl)-acryloyl]-3-methyl-2-oxo-piperazin-1-yl}-propionic acid (50 mg, 0.14 mmol), (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2; 24 mg, 0.15 mmol) and 4-methylmorpholine (41 mg, 0.41 mmol) in N,N-dimethylformamide (1 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (77 mg, 0.20 mmol) at room temperature, then after 16 h the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; dichloromethane→dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (37 mg, 54%). White solid, MS: 478.2 (M+H, Cl)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N:15]([CH2:20][CH3:21])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:22]=[C:23]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:24]([C:25]([O:27]CC)=[O:26])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>C(O)C>[CH2:1]([O:8][C:9]1[C:14]([N:15]([CH2:20][CH3:21])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:22]=[C:23]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[C:24]([C:25]([OH:27])=[O:26])=[C:11]2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(CC)S(C)(=O)=O)c(OCc3ccccc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)O)c2cc1OCc1ccccc1)S(C)(=O)=O
Temperature: 45 °C

Procedure:
Ethyl 5-(benzyloxy)-6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carboxylate (0.15 g, 0.29 mmol, 1 eq) was dissolved in ethanol. Then sodium hydroxide (0.035 g, 1.17 mmol, 3 eq) was added, followed by the addition of water (1 ml). The reaction was warmed to 45° C. for 14 h. The solution was concentrated and diluted with water and the pH of the reaction was brought to 3 using Conc.HCl. The solid precipitated was filtered and dried under vacuum. Yield: 0.12 g (86%). 1HNMR (400 MHz, DMSO-d6): δ 1.06-1.10 (t, J=7.14 Hz, 3H), 3.01 (s, 3H), 3.62 (m, 2H), 5.34 (s, 2H), 7.27 (t, J=8.9 Hz, 2H), 7.32-7.46 (m, 4H), 7.56 (d, J=7.0 Hz, 2H), 7.63 (s, 1H), 7.80 (t, J=4.77 Hz, 2H), 8.98 (s, 1H). LCMS: (ES+) m/z=484.0 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[N:22]3[C:17]([C:18]([NH2:23])=[N:19][CH:20]=[N:21]3)=[C:16](Br)[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([N:32]1[CH:40]=[C:39]2[C:34]([CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=[CH:38]2)=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[N:22]3[C:17]([C:18]([NH2:23])=[N:19][CH:20]=[N:21]3)=[C:16]([C:36]3[CH:37]=[CH:38][C:39]4[C:34]([CH:35]=3)=[N:33][N:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:40]=4)[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cc(Br)c3c(N)ncnn23)C1
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 110 °C
Yield: 46.2 %

Procedure:
To a stirred solution 3-(4-Amino-5-bromo-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.49 g, 1.24 mmol), Intermediate C (0.62 g, 1.86 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.37 g, 0.32 mmol) in degassed DMF (8 mL) was added aqueous Na2CO3 (2M, 2.00 mL). The resulting mixture was heated at 110° C. for 3 h and then cooled to rt. The reaction mixture was diluted with EtOAc and filtered through a Celite® pad. The organic layer was separated and concentrated in vacuo. The residue was purified by silica-gel column using a gradient of 50% to 100% EtOAc in hexanes to afford 0.30 g (46%) of the product. LC-MS [M+H]+=524.1, RT=3.19 min.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=O)=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][CH:34]([CH2:37][OH:38])[CH2:35][OH:36]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:33][CH:34]([CH2:37][OH:38])[CH2:35][OH:36])=[O:15])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: NC(CO)CO
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NC(CO)CO)c(Nc2ccc(I)cc2F)cc1=O
Yield: 34 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and CDI were dissolved in anhydrous THF/DMF (5:1) and treated with 2-amino-1,3-propandiol as for example 34. After workup, the residue was further purified by flash chromatography on silica gel (5% MeOH/CH2Cl2—10% MeOH/CH2Cl2 gradient elution) to give 4-(2-fluoro-4-iodoanilino)-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (34%) as a white solid; m.p. (EtOAc/Hexane) 93-98° C. (glue-liquid). 1H NMR [400 MHz, CH3OD] δ 8.22 (s, 1H), 7.61 (dd, J=9.9, 1.8 Hz, 1H), 7.58-7.54 (m, 1H), 7.21 (t, J=8.4, 1H), 5.78 (d, J=1.1 Hz, 1H), 4.12 (p, J=5.6 Hz, 1H), 3.72 (ddd, J=15.1, 11.2, 5.6 Hz, 4H), 3.51 (s, 3H). HRMS (FAB+) calcd for C16H18FIN3O4 462.0326 (M+), found 462.0323. HPLC 89.9% (254 nm).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[C:16]1([C:2]2[C:3]3[C:8]([CH:9]=[C:10]4[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Yield: 91.2 %

Procedure:
An amount of 15.14 g (58.9 mmol) of 9-bromoanthracene, 7.2 g (59 mmol) of phenylboronic acid, and 1 g of tetrakis triphenylphosphine palladium as catalysis were dissolved in a mixed solvent of 100 ml of toluene and 25 ml of ethanol. Then, 50 ml of 2M sodium carbonate solution was added to the mixed solvent and allowed to react at 90° C. for 12 hours. After the reaction was completed, the organic layer was separated and purified by column chromatography to obtain 13.65 g (53.7 mmol) of 9-phenylanthracene. The yield was 91.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C[Si]([C:14]#[N:15])(C)C.C(N(CC)CC)C>C(#N)C>[C:14]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)#[N:15]
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1cc(Cl)cc(Cl)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ncc(Cl)cc1Cl
Yield: 94.8 %

Procedure:
3,5-Dichloropyridine-N-oxide (10.0 g, 61 mmol), trimethysilylcyanide (25 mL, 183 mmol) and triethylamine (17 mL, 122 mmol) combined in acetonitrile (60 mL) and heated to reflux for 6 hr. The solvent was evaporated and the residue was partitioned between diethyl ether and 5% aq. NaHCO3. The organic phase was dried (MgSO4), evaporated, and the product purified by chromatography over silica gel to yield 10.0 g (97%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.92 (d, 1H), 8.58 (d, 1H).
Reaction SMILES: C([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH2:18][O:19][C:20](=[O:23])[C:21]=3[CH3:22])[CH2:13][CH2:12]2)[CH:10]([OH:26])[CH2:9]1)C1C=CC=CC=1>CO.[Pd].CC(O)=O>[OH:26][CH:10]1[CH2:9][NH:8][CH2:25][CH2:24][C:11]21[C:15](=[O:16])[N:14]([C:17]1[CH2:18][O:19][C:20](=[O:23])[C:21]=1[CH3:22])[CH2:13][CH2:12]2
Reactant: CC1=C(N2CCC3(CCN(Cc4ccccc4)CC3O)C2=O)COC1=O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC1=C(N2CCC3(CCNCC3O)C2=O)COC1=O
Reaction time: 16 h

Procedure:
To a solution of 8-benzyl-6-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (150 mg, 0.42 mmol) in MeOH (2 mL) was added palladium on carbon (45 mg, 0.42 mmol) and a few drops of HOAc. The mixture was allowed to stir under an atmosphere of hydrogen for 16 hours. LC indicated complete reaction. The catalyst was filtered off, and the crude material was used without further purification. LCMS: m/z 267 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=O)=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.6 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-fluoro-phenyl)2-oxo-1,2-dihydro-indol-3-ylidenemethyl]4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (26 mg, 23%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([C:33]([F:44])([F:43])[F:32])[CH:39]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(C(F)(F)F)c1)N1CCN(C2CCC2)CC1
Yield: 60 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (60%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=2)[O:6][CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)COc1cccc(C#N)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(-c2nc(=O)c3ccccc3s2)c1
Yield: 19.8 %

Procedure:
A mixture of tert-butyl (3-cyanophenoxy)acetate (4.64 g, 20 mmol), methyl thiosalicylate (3.70 g, 24 mmol), triethylamine (2.54 g, 25 mmol) and toluene (15 ml) was heated and refluxed for 20 hours under a nitrogen flow. After the solvent was distilled off under reduced pressure, the residue was applied to column chromatography using silica gel. From the fractions eluted with hexane-ethyl acetate (3:1, v/v), the title compound (1.46 g, 20%) was obtained as crystals.