Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:35]2[CH2:34][CH2:33][N:32]([C:26]3[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:25]=3[O:24][CH3:23])[CH2:37][CH2:36]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1ccc(C)cc1N1CCNCC1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Product: COc1ccc(C)cc1N1CCN(C(=O)Nc2cc3ccccc3nc2OC)CC1
Yield: 76 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(2-methoxy-5-methylphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:7][N:6]=1)(=O)=O.[NH3:26]>CN(C=O)C>[NH2:26][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:7][N:6]=1
Reactant: N
Reactant: CS(=O)(=O)c1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 120 °C

Procedure:
In a 75 mL stainless steel pressure vessel was added 5 mL DMF and 2-methylsulfonyl-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (420 mg, 1.0 mmol). Then excess ammonia gas was introduced into the vessel, and the vessel was sealed with a stainless steel nut. The vessel was heated at 120° C. for 18 h. The solvent was removed under high vacuum and product was obtained. HPLC/MS: m/e=351 (M+1); Rt=3.42 min; 1H-NMR 500 MHz (CDCl3): δ 4.8 (bs, 2H), 7.42 (d, J=9 Hz, 1H), 7.5-7.6 (m, 3H), 7.8 (m, 2H), 8.18 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:3]([NH:5][C@@H:6]([CH2:13][C:14]1[CH2:18][CH2:17][CH2:16][CH:15]=1)[C:7]([C@@:9]1([CH3:12])[CH2:11][O:10]1)=[O:8])=[O:4].[C:28]([O:32][C:33]([NH:35][C@@H:36]([CH3:40])[C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:14]1([CH2:13][C@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:37](=[O:38])[C@@H:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:30])([CH3:29])[CH3:31])[CH3:40])[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:7]([C@@:9]2([CH3:12])[CH2:11][O:10]2)=[O:8])[CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: COc1ccc(C[C@H](N)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
To (S)-2-amino-N-((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-(4-methoxyphenyl)propanamide (TFA salt, 2.00 g, 4.26 mmol) and (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (805 mg, 4.26 mmol) in DMF (10 mL) at 0° C. was added HATU (1.94 g, 5.11 mmol) followed by DIEA (4.37 mL, 25.6 mmol) and the mixture was stirred for 15 min then quenched with NaHCO3 (sat., aq.), extracted with EtOAc (2×), washed with brine, dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (1:1 hexanes/EtOAc) provided tert-butyl ((S)-1-(((S)-1-(((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (1.94 g, 84%) as a colorless oil. MS(EI) for C29H41N3O7, found 544.3 (MH)+.
Reaction SMILES: [Li].ClC1C=CC=CC=1C.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][CH:19]=[N:20][N:21]=2)=[CH:13][CH:12]=1.C([Li])CCCCC.C[O:30][B:31](OC)[O:32]C>O1CCCC1.CC(C)CC(=O)C.CO>[O:18]1[CH:19]=[N:20][N:21]=[C:17]1[C:14]1[CH:15]=[CH:16][C:11]([B:31]([OH:32])[OH:30])=[CH:12][CH:13]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc(-c2nnco2)cc1
Agent: [Li]
Agent: [Li]CCCCCC
Solvent: CC(=O)CC(C)C
Solvent: Cc1ccccc1Cl
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2nnco2)cc1
Temperature: -30 °C
Reaction time: 6 h
Yield: 75.5 %

Procedure:
Tetrahydrofuran was charged to lithium granules (7.6 g) under an argon atmosphere and the mixture cooled to −30° C. 2-Chlorotoluene (69.4 g) was slowly added at −30° C. The reaction was held at −30° C. for 6 hours then added to a suspension of 2-(4-bromophenyl)-1,3,4-oxadiazole (124.4 g) in tetrahydrofuran (800 g) at −65° C. The reaction was held at −65° C. for 30 minutes then a solution of n-hexyllithium (33% w/w in hexanes, 245 ml) was added at −65° C. The reaction was held at −65° C. for 30 minutes and then trimethylborate (230.8 g) was added at −65° C. The reaction was held at −65° C. for 30 minutes then methanol (175 ml) was added followed by 4-methyl-2-pentanone (600 g). The reaction mixture was warmed and the low boiling solvents distilled off under vacuum to a maximum temperature of 50° C. The reaction mixture was cooled to 5-10° C. and the pH adjusted to 6.5 by the addition of 5% w/w sulphuric acid (990.5 g). Product precipitated. The mixture was heated to 40° C. then cooled back to 10° C. Product was isolated, washed with THF and water, and dried yielding the title compound (79.3 g, 75.5%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13](N)=[CH:12][C:11]=1[F:25])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N([O-])=O.[Na+].[I-:30].[K+].[Cl-].[NH4+]>CN(C)C=O.O.[Cu](I)I>[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([I:30])=[CH:12][C:11]=1[F:25])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [I-]
Reactant: Nc1cc(F)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: I[Cu]I
Agent: Cl
Agent: O=N[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(I)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
7 ml of 6M hydrochloric acid are added to a solution of 3.20 g (9.9 mmol, 1 eq) of 1,5-bis(benzyloxy)-2-fluoro-4-aminobenzene in 40 ml of N,N-dimethylformamide, cooled to 0° C. 683 mg (9.9 mmol, 1 eq) of sodium nitrite in solution in 7 ml of water are added and the reaction medium is stirred at 0° C. for 1 hour. 1.64 g (9.9 mmol, 1 eq) of potassium iodide in solution in 8 ml of water are added, followed by 190 mg (1.0 mmol, 0.1 eq) of copper iodide, and then the reaction medium is stirred at ambient temperature overnight. The reaction medium is treated with a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phases are combined, washed with a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and evaporated. The residue is chromatographed on silica gel, elution being carried out with 75/25 heptane/dichloromethane. 3.59 g of 1,5-bis(benzyloxy)-2-fluoro-4-iodobenzene are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:14]=O)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[NH2:37])[N:28]=1)=[O:26]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[N:37]=[CH:14][C:13]([OH:20])([C:16]([F:18])([F:19])[F:17])[CH2:12][C:11]([C:5]2[C:6]3[O:10][CH2:9][O:8][C:7]=3[C:2]([Cl:1])=[CH:3][CH:4]=2)([CH3:21])[CH3:22])[N:28]=1)=[O:26]
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccc(Cl)c2c1OCO2
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3ccc(Cl)c4c3OCO4)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 37, 70 mg (0.21 mmol) of 4-(7-chlorobenzo[1,3]dioxol -4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal is reacted with 50 mg (0.25 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester in 0.5 ml of concentrated acetic acid and 20 ml of toluene. After working-up and purification on silica gel with hexane-ethyl acetate (0–100%), 60 mg (55% of theory) of the product is obtained.
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:11]([F:12])=[CH:10][C:5]([CH:6]=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: COC(=O)c1cc(F)c(Br)cc1[N+](=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Product: O=Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a stirred solution of methyl 4-bromo-5-fluoro-2-nitrobenzoate (5.348 g, 19.24 mmol) in DCM (100 mL) at −78° C., a solution of diisobutylaluminum hydride in DCM (1.0 M, 25.0 mL, 25.0 mmol) was added dropwise over a period of 10 min. The mixture was stirred at −78° C. for 2 h. MeOH (10.0 mL) was then added. The reaction mixture was allowed to warm to room temperature. A 10 wt % aqueous solution of sodium tartrate (100 mL) was added to the mixture. The mixture was then stirred vigorously until a distinct bilayer was formed. The mixture was then diluted with DCM (100 mL), washed with water (2×100 mL), brine (2×100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-30% EtOAc in Hexanes) to give the sub-title compound as a pale yellow solid (4.19 g, 88%). LCMS calc. for C7H4BrFNO3 (M+H)+: m/z=247.9; found no ionization.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][NH:9][C:8](=[O:14])[CH2:7]2)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][NH:9][C:8](=[O:14])[CH2:7]2
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2CN1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CC(=O)NC2
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a suspension of 1,2-dihydro-6-nitroisoquinolin-3(4H)-one (10.3 g, 53.6 mmol) in MeOH (150 mL) was added 10% Pd/C (1.14 g, 1.07 mmol) and the mixture was stirred overnight under H2 (1 atm). After filtration, the filtrate was concentrated and the residue was suspended in acetone, filtered and precipitated with conc. HCl (10 mL). The resulting precipitate was collected, washed with H2O and acetone and recrystallized from MeOH/H2O to yield 6-amino-1,2-dihydroisoquinolin-3(4H)-one as a grey solid (6.7 g, 63% yield). 1H NMR (400 MHz, CD3OD): δ 7.22 (d, J=2.0 Hz, 1H), 7.20 (dd, J=8.4, and 2.4 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 3.01 (t, J=7.6 Hz, 2H), 2.59 (t, J=7.6 Hz, 2H); MS (ESI) m/z: 163.0 (M+H+).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[C:6]([NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[N:14][CH:13]=1)([CH3:9])([CH3:8])[CH3:7].CO.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[C:6]([NH:10][C:11](=[O:19])[C:12]1[C:17]([CH:1]([CH3:3])[CH3:2])=[CH:16][C:15]([Cl:18])=[N:14][CH:13]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)NC(=O)c1ccc(Cl)nc1
Reactant: CC(C)[Mg]Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc(Cl)ncc1C(=O)NC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
7.0 ml (14.1 mMol) iso-Propylmagnesium chloride solution (2M in THF) were added over 5 minutes to a solution of 1.0 g (4.7 mMol) N-tert.-butyl-6-chloro-nicotinamide in 5.0 ml THF cooled to 0° C. and the reaction mixture was stirred 18 hours at room temperature. After cooling to 0° C., 1.14 ml (28.2 mMol) methanol were added over 10 minutes, followed, after 15 minutes, by 1.17 g (5.2 mMol) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. After stirring 30 minutes at room temperature, the red-brown solution was concentrated under reduced pressure to about 10 g, heated to 50° C. and 20 ml tert.-butyl-methylether were added. The resulting suspension was stirred 1 hour at 55° C., then 1 hour at room temperature and filtered. The filtrate was concentrated under reduced pressure and digested in 9 ml n-hexane/ethyl acetate 4:1 to yield 0.67 g (56%) N-tert.-butyl-6-chloro-4-(prop-2-yl)-nicotinamide as a beige powder of m.p.=130-140° C. (dec.)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([N+:21]([O-])=O)=[CH:16][C:15]=2[F:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]([F:24])=[CH:16][C:17]([NH2:21])=[CH:18][C:19]=2[F:20])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)cc(N)cc2F)CC1
Yield: 92.2 %

Procedure:
To a solution of 4-(2,6-difluoro-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (Intermediate II) (30 g, 0.09 mol), in methanol (500 mL) under argon atmosphere was added 10% Pd/C (4.5 g, 15 mol% by weight). Flask was evacuated and hydrogen was introduced with the help of balloon. The reaction mixture was stirred under hydrogen and progress of the reaction was monitored by TLC. On completion, the reaction mixture was filtered through celite pad using methanol as solvent. The filterate was evaporated to provide title compound (26 g, 95%) as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.CN(C)CCN(C)C.C([Li])CCC.[O:31]=[C:32]1[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]1>O1CCCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:32]3([OH:31])[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:33]3)[N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(C2(O)CCCN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4-(2-chloro-9-methyl-9H-purin-6-yl)morpholine (5.0 g) and N,N,N′,N′-tetramethylethylenediamine (4.46 mL) in tetrahydrofuran (80 mL) at −78° C. was added 2.5 M of n-Butyllithium in THF (17 mL). The solution was stirred at −78° C. for 15 mins then the temp was raised to −40° C. until the solution became clear and dark red (indicating full lithiation). The solution was lowered back to −78° C. and tert-butyl 3-oxopiperidine-1-carboxylate (8.64 g) in 10 mL THF was added slowly over 5 minutes and stirred for 1.5 hrs then quenched with water. The reaction mixture was diluted with ethyl acetate and extracted with a saturated ammonium chloride solution. The organic layer was dried, filtered and concentrated. Any remaining starting material was removed by trituration with hot ether to afford the crude product tert-butyl 3-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)-3-hydroxypiperidine-1-carboxylate as an orange oil in quantitative yield.
Reaction SMILES: [N:1]1([C:10]2([CH2:15][C:16]([OH:18])=O)[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([N:22](CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(OCC)(=O)C>CN(C)C=O.CCCCCC.O>[N:1]1([C:10]2([CH2:15][C:16]([NH2:22])=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)CC1(n2ccc3cccnc32)CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CC1(n2ccc3cccnc32)CCCC1
Reaction time: 1 h
Yield: 63.2 %

Procedure:
To a stirred solution of (1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl)-acetic acid (397) (2.7 g, 11.05 mmol) in dimethylformamide (60 mL) was added N,N-diisopropylethylamine (5.8 mL, 33.16 mmol) followed by (NH4)2CO3 (5.2 g, 33.16 mmol) and HATU (6.3 g, 16.58 mmol) and stirring was continued for 1 h at room temperature (TLC, 50% ethyl acetate in hexane, Rf=0.5), Water (200 mL) was added and the mixture was extracted with ethyl acetate (2×200 mL), organic part was washed with water (2×100 mL) and brine (2×100 mL). The organic phase was thereafter dried and concentrated. The crude product was purified by Combi-Flash column chromatography (eluted at 30-40% ethyl acetate in hexane) to get 2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl)acetamide (398) (1.7 g, 63%) as a yellow solid.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([C:60]5[NH:61][N:62]=[CH:63][CH:64]=5)=[C:53]([O:58][CH3:59])[CH:54]=4)[O:49][C:48]=3[C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([C:60]5[NH:61][N:62]=[CH:63][CH:64]=5)=[C:53]([O:58][CH3:59])[CH:54]=4)[O:49][C:48]=3[C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: COc1cc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2cc1-c1ccn[nH]1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1cc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc2cc1-c1ccn[nH]1
Yield: 75 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, (1-{4-[6-methoxy-4-oxo-2-phenyl-7-(2H-pyrazol-3-yl)-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester was reacted to give the title compound as a pale yellow solid (34 mg, 75%). 1H NMR (400 MHz, DMSO-d6): δ 13.32-13.18 (br s, 1H), 8.21 (s, 1H), 7.88-7.72 (br s, 1H), 7.60-7.56 (br s, 1H), 7.44-7.30 (m, 7H), 7.19-7.14 (m, 2H), 6.97 (s, 1H), 4.01 (s, 3H), 2.45-2.36 (m, 2H), 2.20-2.10 (m, 2H), 2.08-1.97 (m, 1H), 1.72-1.61 (m, 1H). LCMS (Method E): RT=3.39 min, [M+H]+=464.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[NH:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.[C:11]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([O:10][CH3:11])=[N:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1
Reactant: Cn1[nH]c(=O)c(Br)cc1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nn(C)c(=O)cc1Br
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a solution 4-bromo-1-methyl-1,2-dihydropyridazine-3,6-dione (216 mg, 1.05 mmol) in DMF (3.0 mL) was added K2CO3 (437 mg, 3.16 mmol), CH3I (299 mg, 2.11 mmol), the reaction mixture was stirred at 50° C. for 30 minutes. The mixture was cooled to ambient temperature, diluted with EtOAc (20 mL), washed with sodium bicarbonate (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified with silica gel column (Petroleum ether:ethyl acetate=4:1) to obtain product (120 mg, yield: 52.2%): LC/MS m/z=219.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:4]=1.[N+:16]([O-])([OH:18])=[O:17].[OH-].[Na+]>S(=O)(=O)(O)O>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)=[CH:10][C:11]=1[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: COc1ccnc(-c2ccc(F)cc2)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccnc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-(4-methoxypyridin-2-yl)fluorobenzene (0.71 g) in sulfuric acid (10 ml) was added fuming nitric acid (0.176 ml) dropwise at 0° C., and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was poured into an aqueous sodium hydroxide solution (4N) and extracted with ethyl acetate. The separated organic layer was washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure to give 2-fluoro-5-(4-methoxypyridin-2-yl)nitrobenzene (831 mg).
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][CH2:7][CH2:8]OC1C=CC(Cl)=CC=1C=O)(C)(C)C.C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.C[Si](Cl)(C)C.[CH2:40]([N:42](CC)CC)C.C(Cl)(=O)C>>[CH3:1][Si:5]([CH3:20])([CH3:19])[O:6][C:7](=[CH2:8])[N:42]=[CH2:40]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)cc1C=O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CC(=O)Cl
Product: C=NC(=C)O[Si](C)(C)C

Procedure:
In a manner similar to the method described in example 1b, 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-benzaldehyde (5.2 g, 17 mmol) prepared in example 131a was reacted with 1,1,1,3,3,3-hexamethyldisilazane (2.4 g, 15 mmol), n-butyllithium (2.5 M, 6 mL, 15 mmol), trimethylsilyl chloride (1.6 g, 15 mmol), triethylamine (1.6 g, 20 mmol) and acetyl chloride (1.5 g, 20 mmol) to give 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene as yellow oil and used for the next step without further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][O:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][O:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)OCc3ccccc34)cnc12
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(CC3)OCc3ccccc34)cnc12
Yield: 33.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(3H-spiro[isobenzofuran-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.130 g, 0.269 mmol) obtained in step 2 and methanesulfonamide (0.127 g, 1.34 mmol), the title compound (0.050 g, 33%) was obtained.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][CH2:11][CH2:12][NH2:13].[NH2:17][C:18]1[C:21](=[O:22])[C:20](=[O:23])[C:19]=1OCCCC>CO>[NH2:17][C:18]1[C:21](=[O:22])[C:20](=[O:23])[C:19]=1[NH:13][CH2:12][CH2:11][CH2:10][O:9][C:8]1[CH:14]=[CH:15][CH:16]=[C:6]([CH:2]2[O:3][CH2:4][CH2:5][O:1]2)[CH:7]=1
Reactant: NCCCOc1cccc(C2OCCO2)c1
Reactant: CCCCOc1c(N)c(=O)c1=O
Solvent: CO
Product: Nc1c(NCCCOc2cccc(C3OCCO3)c2)c(=O)c1=O
Reaction time: 21 h
Yield: 99.5 %

Procedure:
A solution of 3-[3-(1,3-dioxolan-2-yl)phenoxy]propylamine (12.62 g, 56.5 mmole) and 1-amino-2-butoxy-1-cyclobutene-3,4-dione (10.0 g, 56.5 mmole) in 250 mL of methanol was stirred at ambient temperature. After 21 hours, the thick reaction mixture was filtered and the filter cake was washed with cold methanol. The collected solid was dried in vacuo to give 17.9 g of the title compound.