Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Cl:7])=[C:3]1[C:8]([O:10]CC1C=CC=CC=1)=[O:9].Cl.C(OCC)C>CO.[Pd]>[NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Cl:7])=[C:3]1[C:8]([OH:10])=[O:9]
Reactant: Nn1ccc(Cl)c1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Nn1ccc(Cl)c1C(=O)O
Reaction time: 21 h
Yield: 103.7 %

Procedure:
To a solution of benzyl 1-amino-3-chloro-1H-pyrrole-2-carboxylate (20.56 g, 0.08 mol) in methanol (205 mL) was added 32.1 mL of a 3M methanolic solution of HCl (0.1 mol) and 7.7 g (0.07 mol) of 10% palladium on charcoal and this mixture was submitted to hydrogenation in a Parr apparatus working at 25 psi and room temperature during 21 hours. At the end of this period, the reaction was stopped filtering palladium catalyst through a pad of Celite® and the filtrate was concentrated in vacuum to give a light brown solid that was macerated with 40 mL of diethyl ether. This solid was filtrated and washed with petroleum ether to yield 13.32 g of the title compound with a purity of 55% (59% yield) being the dehalogenated compound the main impurity. No further purifications were done proceeding to the next step.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21](/[CH:23]=[CH:24]/[C:25](O)=[O:26])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21](/[CH:23]=[CH:24]/[C:25]([NH:28][CH2:29][CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:26])[N:22]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccc(-c2c(-c3nc(/C=C/C(=O)O)cs3)cnn2C(C)(C)C)cc1
Reactant: NCC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2c(-c3nc(/C=C/C(=O)NCC4CCOCC4)cs3)cnn2C(C)(C)C)cc1
Yield: 47.8 %

Procedure:
A solution of the compound (90 mg, 0.23 mmol) obtained in step 5, 4-(aminomethyl)tetrahydropyran (0.029 mL, 0.26 mmol), DIEA (0.049 mL, 0.28 mmol) and HATU (107 mg, 0.28 mmol) in DMF (2.0 mL) was stirred at room temperature for 14 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (solvent gradient; 50→80% ethyl acetate/hexane) and crystallized from ethyl acetate and hexane to give the title compound (52.7 mg, 0.110 mmol, 46.7%) as a white powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[N:6]=[C:5]([S:11][CH3:12])[CH:4]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([NH:1][CH2:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[N:6]=[C:5]([S:11][CH3:12])[CH:4]=1)(=[O:15])[CH3:14]
Reactant: CSc1cc(CN)nc(SC)n1
Reactant: CC(=O)OC(C)=O
Product: CSc1cc(CNC(C)=O)nc(SC)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 11 g (16.5 mmole) of 6-aminomethyl-2,4-bis(methylthio)pyrimidine and 75 ml of acetic anhydride was stirred at room temperature for 16 hours, then evaporated. The residue was isolated by filtration and washed with a small amount of methanol to provide white solid 6-acetylaminomethyl-2,4-bis(methylthio)pyrimidine. The structural assignment was supported by infrared spectral analysis.
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:40][O:41][C:42]([C:45]1[O:46][CH:47]=[C:48]([CH2:50][N:51]2[N:55]=[C:54]([NH2:56])[CH:53]=[N:52]2)[N:49]=1)([CH3:44])[CH3:43]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:40][O:41][C:42]([C:45]1[O:46][CH:47]=[C:48]([CH2:50][N:51]2[N:55]=[C:54]([NH:56][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:16])[CH:53]=[N:52]2)[N:49]=1)([CH3:44])[CH3:43]
Reactant: COC(C)(C)c1nc(Cn2ncc(N)n2)co1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(C)(C)c1nc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)co1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 5-phenyloxazole-4-carboxylic acid (18 mg, 0.10 mmol) in CH2Cl2 (1.0 mL) was treated at rt with DMAP (3.0 mg, 0.02 mmol), HOBt (15.7 mg, 0.12 mmol), EDC (46.5 mg, 0.24 mmol) and DIPEA (0.07 mL, 0.39 mmol) and the resulting mixture was stirred for 45 min at rt. A solution of 2-((2-(2-methoxypropan-2-yl)oxazol-4-yl)methyl)-2H-1,2,3-triazol-4-amine (23.0 mg, 0.10 mmol) in CH2Cl2 (0.5 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (10.0 mL), the layers were separated and the org. phase was washed with water (5.0 mL), dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a yellow oil. TLC: rf (50:50 hept-EA)=0.27. LC-MS-conditions 07: tR=0.86 min, [M+H]+=408.89.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([OH:15])[CH2:12][N:11]([N:16]=[C:17]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)SC)[C:10]1=O.[N-:35]=[N+]=[N-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([OH:15])[CH2:12][N:11]2[N:16]=[C:17]([NH:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:25][CH2:26]3)[N:35]=[C:10]12
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=NN1CC(O)CC(c2ccc(F)cc2Cl)C1=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3n(n2)CC(O)CC3c2ccc(F)cc2Cl)CC1
Temperature: 100 °C

Procedure:
To a solution of tert-butyl 4-(((3SR,5SR)-3-(2-chloro-4-fluorophenyl)-5-hydroxy-2-oxopiperidin-1-ylimino)(methylthio)methylamino)piperidine-1-carboxylate (1.1 g, 2.1 mmol) in DMF (5.5 mL) was added sodium azide (0.2 g, 3.2 mmol) and the reaction heated to 100° C. for 48 hours. The reaction was then concentrated to dryness, redissolved in ethyl acetate, washed with water, brine, dried with sodium sulfate and the solvent was evaporated. The residue was redissolved in THF, trimethylphosphine added (2.1 mL, 1 M in toluene, 2.1 mmol) and the reaction heated to 160° C. in a micowave for 12 hours. The reaction was then concentrated in vacuo and the residue was purified by column chromatography on silica gel using ethyl acetate/MeOH (v/v 1:0 to 9:1) as eluent. The title compound was obtained as a light yellow foam (0.2 g, 20%), an inseparable 1:1 mixture of diasteriomers.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]2[O:20][CH2:21][CH2:22][C:23]=2[C:24]([O:26]CC)=O)=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:24](=[O:26])[C:23]3[CH2:22][CH2:21][O:20][C:19]=3[NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Cl)cc2F)OCC1
Agent: [Na]
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCO3)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-4-fluoro-5-{3-[3-(ethoxycarbonyl)-4,5-dihydro-furan-2-yl]ureido}-benzoate with sodium isopropylate in an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-4-fluoro-5-{1,2,5,6-tetrahydro-2,4-dioxo-furo[2,3-d]pyrimidin-3(4H)-yl}-benzoate, m.p. 213°-215° C.,
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].CS(O[CH:21]([CH3:34])[CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])(=O)=O.O>C1(C)C=CC=CC=1>[C:24]1(=[O:33])[N:23]([CH2:22][CH:21]([N:11]([C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH3:3])[S:12]([CH3:15])(=[O:14])=[O:13])[CH3:34])[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]12
Reactant: Cc1cccc(C)c1NS(C)(=O)=O
Reactant: CC(CN1C(=O)c2ccccc2C1=O)OS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(C)c1N(C(C)CN1C(=O)c2ccccc2C1=O)S(C)(=O)=O
Reaction time: 10 h
Yield: 23.8 %

Procedure:
0.15 g of a 80% mineral oil dispersion of sodium hydride are added in some portions to a solution of 1.0 g (5 mmoles) of N-(2,6-dimethylphenyl)-methanesulfonamide in 20 ml of dry toluene, and the mixture is heated to 100°-105° C. within one hour. A solution of 1.4 g (5 mmoles) of N-(β-methanesulfonyloxy-propyl)-phthalimide in 15 ml of toluene is added dropwise to the mixture within 0.5 hours at the same temperature, and the mixture is stirred then at 100°-105° C. for 10 hours. The mixture is cooled, 20 ml of water are added dropwise to it, thereafter the toluene phase is separated, washed twice with 10 ml of 1 n aqueous sodium hydroxide solution and thrice with 20 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The solid residue is triturated with dry diethyl ether. 0.46 g (23.8%) of crude 1-phthalimido-2-[N-(2,6-dimethylphenyl)-methanesulfonamido]-propane are obtained. The crude product is stirred at room temperature in 100 ml of diethyl ether for one hour to obtain a purified product melting at 196°-198° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.[OH-:9].[NH4+]>S(=O)(=O)(O)O>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:8])=[O:9])[CH2:3][CH2:2]1
Reactant: N#CC1CCNCC1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)C1CCNCC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
4-(4-chloro-phenyl-amino)-1-phenylmethyl)-4-piperidine-carbonitrile (29.3 g) was dissolved in 150 ml conc. sulfuric acid and stirred for 1 h at room temperature and 1 h at 70° C. Then the reaction mixture was cooled to room temperature and poured on ice, adjusted to pH 10 by addition of 30% aqueous ammonium hydroxide and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and evaporated to yield 4-(4-chloro-phenyl-amino)-1-phenylmethyl)-4-piperidine-carboxamide as an brownish oil which crystallized upon addition of 50 ml diethyl ether and 50 ml pentane. Off-white powder (11.84 g), m.p. 167-170° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH:7]([C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=1)Br)([CH3:4])([CH3:3])[CH3:2].C1COCC1.[CH3:30][NH:31][CH3:32]>>[C:1]([O:5][C:6](=[O:24])[CH:7]([C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=1)[N:31]([CH3:32])[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)C(Br)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: C1CCOC1
Product: CN(C)C(C(=O)OC(C)(C)C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Intermediate 19 (0.8654 g, 2.17 mmol) in 8 mL, THF was bubbled in dimethylamine. The reaction was stirred at ambient temperature overnight. The solvent was removed in vacuo. The residue was taken up in ethyl acetate, washed with brine, dried over MgSO4, and concentrated. The crude product was chromatographed on silica eluting with 5% to 20% EtOAc/hex. The resulting yellow oil crystallized to a yellow solid under high vacuum overnight
Reaction SMILES: [CH3:1][S:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19].C(OCC)(=O)C>C(Cl)Cl>[CH3:1][S:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:18](=[O:20])[CH3:19])=[CH:6][CH:5]=1
Reactant: CSSc1ccc(N)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CSSc1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 39a (50 mg, 0.3 mmol) in dry CH2Cl2 (3 ml) was added triethylamine (127 μL, 0.9 mmol, 3 eq.), followed by acetyl chloride (32 μL, 0.45 mmol). The reaction was stirred at RT for 1 hr., then was diluted with dichloromethane, washed with water, then 5% aq. HCl, then 5% aq. NaHCO3. Dried over MgSO4, then concentrated in vacuo to give a yellow oil which solidified on standing. Chromotography (1:1 petroleum ether:ethyl acetate) gave 18 mg (29%) as a light brown solid. 1H NMR (400 MHz, CDCl3): δ 7.47 (s, 4H); 2.41 (s, 3H); 2.16 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=1)[CH3:2].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][NH2:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:8]=[C:9]([Cl:14])[CH:10]=[C:11]([NH:23][CH2:22][CH2:21][C:20]2[CH:24]=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=2)[N:12]=1)[CH3:2]
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Reactant: NCCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1nc(Cl)cc(NCCc2ccc(Cl)cc2)n1

Procedure:
A mixture of 10.7 g of (4,6-dichloro-2-pyrimidinylthio] acetic acid ethyl ester, 6.2 g of p-chlorophenethylamine, and 4.24 g of sodium carbonate in 150 ml. of ethanol was heated under reflux for 15 minutes. The reaction mixture was filtered and the filtrate was cooled in ice. The crystalline product which was deposited was collected and recrystallized from ethanol giving 3.6 g of product, mp. 105°-108°C.
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@@H:16]([F:37])[CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:24]=[C:25]3[CH2:36][CH2:35][NH:34][CH2:33][C:26]3=[N:27][C:28]=2[NH:29][CH:30]([CH3:32])[CH3:31])[CH2:19][CH2:18]1.C(OC(=O)C)(=O)C.N1C=CC=CC=1>C(Cl)Cl>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@@H:16]([F:37])[CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:24]=[C:25]3[CH2:36][CH2:35][N:34]([C:2](=[O:1])[CH3:4])[CH2:33][C:26]3=[N:27][C:28]=2[NH:29][CH:30]([CH3:32])[CH3:31])[CH2:19][CH2:18]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)Nc1nc2c(nc1N1CCC([C@H](F)c3ccc(F)cc3F)CC1)CCNC2
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCc2nc(N3CCC([C@H](F)c4ccc(F)cc4F)CC3)c(NC(C)C)nc2C1

Procedure:
A solution of (S)-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (56.0 mg, 0.105 mmol) in DCM (1.05 mL) at 0° C. was treated with acetic anhydride (19.8 μL, 0.210 mmol) and pyridine (25.5 μL, 0.315 mmol). The reaction mixture was concentrated under reduced pressure, taken up in MeOH, filtered, and purified by HPLC Method B. Fractions containing product were concentrated under reduced pressure. The material was repurified by HPLC Method A to give the title compound, as a TFA salt, as a pale yellow solid (5.4 mg, 8.9%). 1H NMR (500 MHz, methanol-d4, mixture of rotamers) δ ppm 1.31 (m, 6H), 1.45 (d, J=11.7 Hz, 1H), 1.67 (m, 2H), 2.00 (m, 1H), 2.11 (m, 1H), 2.19 (s, 1.1H), 2.21 (s, 1.9H), 2.80 (m, 4H), 3.53 (m, 2H), 3.82 (t, J=5.9 Hz, 1.3H), 3.86 (t, J=5.9 Hz, 0.7H), 4.11 (m, 1H), 4.60 (s, 0.7H), 4.64 (s, 1.3H), 5.53 (m, 1H), 7.02 (m, 2H), 7.50 (m, 1H); ESI-MS m/z [M+H]+ 462.5.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:17]2[CH:18]=[C:19]([C:24]([CH3:27])=[CH:25][CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])[CH:13]=[CH:14][C:15]=1[OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:29][CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:17]2[CH:18]=[C:19]([C:24]([CH3:27])=[CH:25][CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])[CH:13]=[CH:14][C:15]=1[O:16][CH2:29][CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCI
Reactant: COC(=O)c1cc(-c2ccc(O)c(CNC(=O)OC(C)(C)C)c2)ccc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOc1ccc(-c2ccc(C)c(C(=O)OC)c2)cc1CNC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
170 mg of Methyl 3-(3-{[(t-butoxycarbonyl)amino]-methyl}-4-hydroxyphenyl)-6-methylbenzoate was dissolved in 5 ml of acetonitrile, 0.5 ml of iodoethane and 500 mg of cesium carbonate were added successively thereto and the mixture was stirred overnight at 50° C. The reaction mixture was diluted with ethyl acetate and successively washed with water and brine, dried over magnesium sulfate, filtered, and the solvent was concentrated, to give 185 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH2:12][C:13]([O:15]C)=[O:14])=[CH:5][CH:4]=1.[OH-].[Li+]>C1COCC1.O>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH2:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1
Reactant: COC(=O)Cn1ccc2ccc(C(F)(F)F)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1ccc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
Methyl 2-(6-(trifluoromethyl)-1H-indol-1-yl)acetate (120 mg, 0.467 mmol) was dissolved in a mixture (1/1) of THF/H2O (4 ml), and lithium hydroxide (112 mg, 4.67 mmol) was added. The mixture was stirred at room temperature for 2 hours. The organic solvent was evaporated and 2N HCl was added to the resulting mixture (pH=5). The precipitate was collected by filtration affording 2-(6-(trifluoromethyl)-1H-indol-1-yl)acetic acid (90 mg, 0.370 mmol, 79% yield). MS/ESI+ 244.0 [MH]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1.CN(C)C=O.[N:25]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]=[O:27]>C(N(CC)CC)C>[CH2:33]([O:32][C:30]([CH2:29][CH2:28][NH:25][C:26](=[O:27])[NH:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)CCN=C=O
Reactant: Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Temperature: 20 °C
Reaction time: 90 h
Yield: 37.8 %

Procedure:
The preparation is carried out as in Example 32 but from 4 g of 8-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one hydrochloride, 86 ml of dimethylformamide, 7.3 ml of triethylamine and 4.42 g of ethyl 3-isocyanatopropionate and the reaction mixture is stirred at a temperature in the region of 20° C. for 90 hours. After evaporation of the dimethylformamide, 300 ml of water are added and the precipitate formed is filtered, washed with water (50 ml) and then with acetone (2×50 ml) and dried at 60° C. under vacuum (1 mm Hg, 0.13 kPa). There are obtained 2.1 g of 8-[3-(2-ethoxycarbonylethyl)ureido]-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one in the form of a beige solid melting above 260° C. (Analysis, % calculated C: 59.84, H: 5.02, N: 18.36, O: 16.78, % found C: 59.5, H: 5.1, N: 18.5).
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]2[CH:16]=[C:15]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[S:14][C:9]=2[N:10]=[C:11]([CH3:13])[N:12]=1)(=O)=O.CC#N.[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>O>[CH:17]1([C:15]2[S:14][C:9]3[N:10]=[C:11]([CH3:13])[N:12]=[C:7]([CH2:6][NH:31][CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[C:8]=3[CH:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1nc(COS(C)(=O)=O)c2cc(C3CCCCC3)sc2n1
Reactant: NC1CCCC1
Solvent: O
Solvent: CC#N
Product: Cc1nc(CNC2CCCC2)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of (6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl methanesulfonate (500 mg) and CH3CN (10 mL) was added cyclopentylamine (1.0 mL), followed by stirring at room temperature for 3 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by basic silica gel column (hexane/EtOAc) and silica gel column (hexane/EtOAc) to obtain N-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]cyclopentaneamine (326 mg).
Reaction SMILES: FC1C=C(F)C=CC=1NC1C=CC(C(C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=C(C)C=1.Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]([C:43]2[CH:48]=[C:47]([N:49]3[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]3)[CH:46]=[CH:45][C:44]=2[CH3:57])=[O:42])=[C:37]([CH3:58])[CH:36]=1.[NH2:59][C:60]1[CH:61]=[C:62]([CH:65]=[CH:66][CH:67]=1)[C:63]#[N:64]>>[OH:56][CH2:55][CH2:54][C:52]1[N:51]=[N:50][N:49]([C:47]2[CH:46]=[CH:45][C:44]([CH3:57])=[C:43]([CH:48]=2)[C:41]([C:38]2[CH:39]=[CH:40][C:35]([NH:59][C:60]3[CH:61]=[C:62]([CH:65]=[CH:66][CH:67]=3)[C:63]#[N:64])=[CH:36][C:37]=2[CH3:58])=[O:42])[CH:53]=1
Reactant: N#Cc1cccc(N)c1
Reactant: Cc1cc(Br)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Agent: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Product: Cc1cc(Nc2cccc(C#N)c2)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 452 (0.13 mmol) and 3-amino-benzonitrile (0.13 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM/petroleum ether (40-60) 0:50:50, 0:100:0 and 5:95:0 as the eluent to afford the title compound as yellow solid. 13C NMR (DMSO-d6) δ 196.5, 146.5, 145.7, 142.4, 142.1, 142.1, 135.4, 135.0, 134.5, 132.2, 130.7, 127.7, 124.9, 123.3, 121.1, 120.7, 120.6, 118.8, 118.6, 118.5, 112.2, 60.2, 29.2, 21.9, 18.9
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:21][C:22]([NH2:24])=[O:23]>CN(C=O)C.C(OCC)(=O)C.CO>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:21][C:22]([NH2:24])=[O:23])=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Oc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Reactant: NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=O)COc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Temperature: 60 °C

Procedure:
To a mixture of 4-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)phenol (58 mg, 0.2 mmol) and sodium hydride (55-65%, 18 mg, 0.4 mmol) in DMF (6 ml), 2-chloroacetamide (19 mg, 0.2 mmol) was added and the mixture was heated to 60° C. for 1 h. Column chromatography on silica using ethyl acetate/methanol as eluent afforded the title compound.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:14])([CH3:13])[NH:10][C:11](=[O:12])[C:5]2=[CH:4][CH:3]=1.COC1C=CC(CN2CCN3C(=O)C([NH:32][C:33]4[CH:38]=[CH:37][N:36]=[CH:35][N:34]=4)=CC=C3C2=O)=CC=1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:13][C:9]1([CH3:14])[N:6]2[C:7](=[O:8])[C:2]([NH:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][N:34]=3)=[CH:3][CH:4]=[C:5]2[C:11](=[O:12])[NH:10]1
Reactant: CC1(C)NC(=O)c2ccc(Cl)c(=O)n21
Reactant: COc1ccc(CN2CCn3c(ccc(Nc4ccncn4)c3=O)C2=O)cc1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC1(C)NC(=O)c2ccc(Nc3ccncn3)c(=O)n21
Temperature: 100 °C
Reaction time: 10 h

Procedure:
To a solution of 6-chloro-3,3-dimethyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (4, 0.25 g, 1.18 mmol) in 1,4-dioxane (8 mL), pyrimidin-4-amine (5, 0.14 g, 1.41 mmol), Brettphos (0.19 g, 0.23 mmol) and cesium carbonate (0.76 g, 2.36 mmol) were added and the reaction mixture was degassed with argon for 5 min. Tris dibenzylideneacetone dipalladium (0) (0.11 g, 0.12 mmol) was added. The reaction was degassed with argon for another 5 min and then stirred at 100° C. for 10 h. The reaction mixture was cooled to room temperature, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in dichloromethane to afford 3,3-dimethyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 2) as a light yellow solid. Yield: 0.036 g, 11%; MS (ESI) m/z 272[M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 9.42 (s, 1H), 8.81-8.73 (m, 2H), 8.37 (d, J=5.9 Hz, 1H), 7.40-7.34 (m, 1H), 6.87 (d, J=7.7 Hz, 1H), 1.82 (s, 6H).