Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[OH:25][CH:24]([C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[C:3]#[C:2][C:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH3:12])=[O:4]
Reactant: COc1ccc(C=O)cc1
Reactant: C#CC(=O)OCCOCCOC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCOCCOC(=O)C#CC(O)c1ccc(OC)cc1
Reaction time: 0.17 h

Procedure:
A solution of 10 g (58 mmol) of 2-(2-methoxyethoxy)-ethyl propiolate in 80 ml of tetrahydrofuran is treated at -78° under argon with 36 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 7 ml (58 mmol) of 4-methoxybenzaldehyde in 60 ml of tetrahydrofuran was added within 30 minutes. The reaction mixture was stirred at -78° for a further 30 minutes, then brought to room temperature and treated with 150 ml of saturated ammonium chloride solution. The aqueous phase was extracted twice with ether. The combined organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 500 g of silica gel (elution agent methylene chloride/ether 4:1). There was obtained 2-(2-methoxyethoxy)ethyl 4-hydroxy-4-(4-methoxyphenyl)-2-butynoate as a red oil.
Reaction SMILES: [C:1]([C:7]1[O:8][CH:9]=[CH:10][C:11]=1[C:12]([OH:14])=O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.ClC(OCC)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CC(C)=O.O>[C:1]([C:7]1[O:8][CH:9]=[CH:10][C:11]=1[C:12]([N:28]=[N+:29]=[N-:30])=[O:14])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)C(=O)c1occc1C(=O)O
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)C(=O)c1occc1C(=O)N=[N+]=[N-]
Temperature: 0 °C

Procedure:
2-Pivaloyl-3-furoic acid (1.96 g, 0.01 mol) was dissolved in acetone (40 ml) and the solution was stirred at 0° C. under nitrogen. Triethylamine (1.7 ml, 0.012 mol) was added, followed by ethyl chloroformate (1.24 ml, 0.013 mol) and the mixture was stirred for 11/2 hours. A solution of sodium azide (1.11 g, 0.017 mol) in water (4 ml) was added and the suspension was stirred for another 2 hours at 0° C. The solid was removed by filtration and the filtrate was diluted with water (25 ml). It was concentrated in vacuo to remove the acetone. The oil-water residue was extracted with ethyl acetate. The ethyl acetate extract was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated to an amber oil (2.06 g) of 87% purity by HPLC.
Reaction SMILES: [CH:1](=[C:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19]O.[OH-].[Na+].O>CO>[C:2]1([CH:1]2[C:8]3([C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])[O:19]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OO
Reactant: O=C1C(=Cc2ccccc2)C(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1c2ccccc2C(=O)C12OC2c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-benzylidene-1,3-indandione (20 g) in methanol (200 ml) was added 30% hydrogen peroxide (19 ml). The suspension was cooled to 5° C. and 1 N sodium hydroxide (2.1 ml) was added dropwise at such a rate as to keep the temperature below 15 ° C. After completed addition, stirring was continued at room temperature for 30 minutes. The mixture was then poured into water (1.2 L). The resulting crystalline precipitate was collected by filtration, washed on the filter with water (3×100 ml) and dried under high vacuum at room temperature for 24 hours, affording 3-phenylspiro[oxirane-2,2'-indan]-1',3'-dione as a yellow solid (17 g).
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.[C:29]([C:31]1[CH:32]=[C:33]([NH:37][C:38](=[O:51])[O:39][CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45](Br)=[CH:44][C:43]=2[CH2:49][CH3:50])[CH:34]=[CH:35][CH:36]=1)#[N:30]>>[C:29]([C:31]1[CH:32]=[C:33]([NH:37][C:38]([O:39][CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([B:25]([OH:27])[OH:26])=[CH:44][C:43]=2[CH2:49][CH3:50])=[O:51])[CH:34]=[CH:35][CH:36]=1)#[N:30]
Reactant: CCc1cc(Br)ccc1CCOC(=O)Nc1cccc(C#N)c1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Product: CCc1cc(B(O)O)ccc1CCOC(=O)Nc1cccc(C#N)c1
Yield: 61 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 56A (630 mg, 1.69 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 56B (350 mg, 61%) as a solid. 1H NMR (400 MHz, MeOD-d4) δ ppm 0.98 (t, 3 H) 2.42 (q, 2 H) 2.73 (t, 2 H) 4.10 (t, 2 H) 6.82 (d, 1 H) 7.02 (d, 1 H) 7.09 (t, 2 H) 7.15 (t, 1 H) 7.36 (d, 1 H) 7.58-7.63 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N+:9]([O-])=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][N:14]=[C:13]([NH:18][C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20])[CH:12]=2.P(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]3[CH2:22][CH2:23]3)=[O:20])[N:14]=[CH:15]2)=[CH:10][N:9]=1
Reactant: O=C(Nc1cc2c[n+]([O-])c(-c3ccccc3Cl)cc2cn1)C1CC1
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1cc2cnc(-c3ccccc3Cl)cc2cn1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
To a slurry of 3-(2-chlorophenyl)-7-(cyclopropanecarboxamido)-2,6-naphthyridine 2-oxide (170 mg, 0.5 mmol) in dichloromethane (2 mL) was added phosphorus trichloride (0.048 mL, 0.55 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then diluted with dichloromethane (50 mL) and washed with saturated sodium bicarbonate solution (30 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 12 g, ISCO, 0-60% ethyl acetate in heptane) to afford the title compound as a white solid (75 mg, 46%). 1H NMR (400 MHz, DMSO) δ 11.17 (s, 1H), 9.46 (s, 1H), 9.35 (s, 1H), 8.66 (s, 1H), 8.23 (s, 1H), 7.76-7.67 (m, 1H), 7.63 (m, 1H), 7.55-7.43 (m, 2H), 2.14-2.06 (m, 1H), 0.88 (m, 4H). LCMS (Method D): RT=13.170 min, M+H+=324.0.
Reaction SMILES: [O:1]=[C:2]1[C@@:6]2([CH2:11][CH2:10][CH2:9][N:8](C(OCC3C=CC=CC=3)=O)[CH2:7]2)[CH2:5][CH2:4][N:3]1[C@H:22]1[CH2:27][CH2:26][C@H:25]([O:28][Si:29]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:24][CH2:23]1.CO>[Pd]>[CH2:32]([Si:29]([CH2:30][CH3:31])([CH2:34][CH3:35])[O:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([N:3]2[CH2:4][CH2:5][C@:6]3([CH2:11][CH2:10][CH2:9][NH:8][CH2:7]3)[C:2]2=[O:1])[CH2:23][CH2:24]1)[CH3:33]
Reactant: CC[Si](CC)(CC)O[C@H]1CC[C@H](N2CC[C@]3(CCCN(C(=O)OCc4ccccc4)C3)C2=O)CC1
Agent: [Pd]
Solvent: CO
Product: CC[Si](CC)(CC)O[C@H]1CC[C@H](N2CC[C@]3(CCCNC3)C2=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of benzyl (5S)-1-oxo-2-{trans-4-[(triethylsilyl)oxy]cyclohexyl}-2,7-diazaspiro[4.5]decane-7-carboxylate (2.4 g, 0.0048 mol) in methanol (10 mL, 0.2 mol) was added Pd/C, and the suspension was stirred at rt under a H2 balloon for 1.5 h. The inorganics were filtered and the filtrate was concentrated to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[CH:10][S:11][CH:12]=2)=[C:4]([O:20][CH3:21])[CH:3]=1.[H-].[Na+].Cl[CH2:25][O:26][CH3:27]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:25][O:26][CH3:27])=[CH:15][CH:14]=3)=[CH:10][S:11][CH:12]=2)=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: COc1cc(Cl)ccc1-c1cscc1-c1ccc(O)cc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(-c2cscc2-c2ccc(Cl)cc2OC)cc1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 4-(4-(4-chloro-2-methoxyphenyl)thiophen-3-yl)phenol (700 mg, 2.1 mmol) in anhydrous THF (5 mL) was added NaH (90 mg, 2.3 mmol) at 0° C. After the mixture was stirred at the temperature for 0.5 h, chloro(methoxy)methane (184 mg, 2.3 mmol) was added. The mixture was stirred at 0° C. for 1 hour, and at room temperature for 2 hours. When TLC indicated the starting material was consumed, the mixture was quenched with water, and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give the crude product, which was purified by column to give 3-(4-chloro-2-methoxyphenyl)-4-(4-(methoxymethoxy)phenyl)thiophene (720 mg, 90%) which was taken forward to Step 3.
Reaction SMILES: [OH:1][C:2]1([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:6][C:5](=[O:8])[CH:4]=[CH:3]1.[H][H]>C(O)C.[Pd]>[OH:1][C:2]1([C:9]([F:10])([F:11])[F:12])[CH2:3][CH2:4][C:5](=[O:8])[CH2:6][CH2:7]1
Reactant: O=C1C=CC(O)(C(F)(F)F)C=C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1CCC(O)(C(F)(F)F)CC1

Procedure:
A solution of 100 mg of 4-hydroxy-4-trifluoromethyl-2,5-cyclohexadien-1-one in 1 mL of absolute ethanol was treated with a few mg of 5% palladium on carbon, hydrogenated in a Parr shaker for one hour under 50 psig of hydrogen, and filtered. Gas chromatographic/mass spectral analysis indicated that the major component of the filtrate was 4-hydroxy-4-trifluoromethylcyclohexanone: mass spectrum (70 eV) m/z (relative intensity) 182 (11, M+), 55 (100), 42 (40).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=O)=[CH:5][C:4]=1[CH3:13].[C:14](P(=O)(OCC)OCC)#[N:15].[C-]#N.[Li+].[Cl-].[Na+].B(F)(F)F.CCOCC>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6](=[CH:5][C:4]=1[CH3:13])[CH2:7][CH:8]=[C:9]2[C:14]#[N:15]
Reactant: COc1cc2c(cc1C)CCC2=O
Reactant: CCOP(=O)(C#N)OCC
Agent: FB(F)F
Agent: [C-]#N
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COc1cc2c(cc1C)CC=C2C#N
Temperature: 45 °C
Reaction time: 16 h
Yield: 24.8 %

Procedure:
A solution of 10.7 grams (0.061 mole) of 6-methoxy-5-methylindan-1-one (ii), 29.7 grams (0.182 mole) of diethyl cyanophosphonate, and 6.1 grams (0.182 mole) of lithium cyanide in 250 mL of anhydrous THF was stirred at ambient temperature for five hours. GC analysis of the reaction mixture indicated that the reaction was not complete. The reaction mixture was warmed to 45° C., where it was stirred for about 16 hours. After this time, an aliquot of the reaction mixture was placed water and the mixture was extracted with ethyl acetate. GC analysis of the extract indicated that the reaction was about 10% complete. An additional 0.182 mole each of diethyl cyanophosphonate and lithium cyanide were added to the reaction mixture, and heating at 45° C. was continued for about an additional eight hours. After this time, the reaction mixture was poured into about 300 mL of an aqueous solution saturated with sodium chloride, and then it was extracted with two 300 mL portions of ethyl acetate. The combined extracts were then washed with three portions of an aqueous solution saturated with sodium chloride and dried with sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in toluene and again concentrated under reduced pressure to a residue. The residue was taken up in 500 mL of toluene and 20.7 grams (0.182 mole) of boron trifluoride diethyl etherate was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about six hours. The reaction mixture was treated as set forth above, yielding a residue. The residue was purified by column chromatography on silica gel using mixtures of hexane and diethyl ether as an eluant. The appropriate fractions of eluate were combined and concentrated under reduced pressure, yielding 2.8 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[C:21]4[C:16](=[CH:17][C:18]([C:22]5[CH:23]=[CH:24][C:25]6[N:29]=[C:28]([C@H:30]7[CH:35]8[CH2:36][C@H:32]([CH2:33][CH2:34]8)[N:31]7[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[NH:27][C:26]=6[CH:44]=5)=[CH:19][CH:20]=4)[O:15][CH2:14][C:13]=3[CH:45]=2)O1.Br[C:48]1[NH:52][C:51]([C@@H:53]2[CH2:57][CH2:56][CH2:55][N:54]2[C:58](=[O:68])[C@@H:59]([NH:63][C:64](=[O:67])[O:65][CH3:66])[CH:60]([CH3:62])[CH3:61])=[N:50][CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:66][O:65][C:64]([NH:63][C@@H:59]([CH:60]([CH3:62])[CH3:61])[C:58]([N:54]1[CH2:55][CH2:56][CH2:57][C@H:53]1[C:51]1[NH:52][C:48]([C:9]2[CH:10]=[CH:11][C:12]3[C:21]4[C:16](=[CH:17][C:18]([C:22]5[CH:23]=[CH:24][C:25]6[N:29]=[C:28]([C@H:30]7[CH:35]8[CH2:36][C@H:32]([CH2:33][CH2:34]8)[N:31]7[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[NH:27][C:26]=6[CH:44]=5)=[CH:19][CH:20]=4)[O:15][CH2:14][C:13]=3[CH:45]=2)=[CH:49][N:50]=1)=[O:68])=[O:67]
Reactant: CC(C)(C)OC(=O)N1[C@H]2CCC(C2)[C@@H]1c1nc2ccc(-c3ccc4c(c3)OCc3cc(B5OC(C)(C)C(C)(C)O5)ccc3-4)cc2[nH]1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(Br)[nH]1)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)COc2cc(-c4ccc5nc([C@H]6C7CC[C@@H](C7)N6C(=O)OC(C)(C)C)[nH]c5c4)ccc2-3)[nH]1)C(C)C
Temperature: 85 °C
Yield: 20.2 %

Procedure:
To a solution of (1S,3R)-tert-butyl 3-(6-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo[c]chromen-3-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (275 mg, 0.44 mmol), methyl (S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (221 mg, 0.55 mmol), tetrakis(triphenylphosphine) palladium(0) (20 mg, 0.02 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (26 mg, 0.04 mmol) in a mixture of 1,2-dimethoxyethane (5.0 mL) and dimethylformamide (1 mL) was added a solution of potassium carbonate (2M in water, 0.7 mL, 1.3 mmol). The resulting mixture was degassed and then heated to 85° C. under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield (1S,3R)-tert-butyl 3-(6-(8-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methyl-butanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-benzo[c]chromen-3-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (70 mg, 20%). LCMS-ESI+: calculated for C45H51N7O6: 785.95; observed [M+1]+: 786.85.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:32]([O:39][C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[CH2:47]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:47][CH:43]3[CH2:44][CH2:45][CH2:46][N:42]3[C:40]([O:39][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:41])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:27])([F:28])[F:29])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN2C(=O)OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CC2CCCN2C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Yield: 50.2 %

Procedure:
In a dry round bottom flask, charge 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.5 g; 0.0036 mol; 1.0 equiv) in dry DMF (30 mL) and cool to 0° C. Add NaH (0.26 g; 0.011 mol; 3.0 equiv) in portions under nitrogen and stir at RT for 30 min. Add 2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid benzyl ester (2.46 g; 0.0072 mol; 2.0 equiv) at RT and heat at 40° C. overnight. Quench with cold water and extract in EA. Wash the organic layer with water and brine. Dry over anhydrous sodium sulfate and concentrate. Purify the crude residue on silica (100-200 mesh) with 10 to 20% EA/hexanes to give the title compound (1.14 g; 51.6%). (ES+): m/z=631 (M+H).
Reaction SMILES: C[O-].[Na+].[CH2:4]=[C:5]1[CH:11]2[CH2:12][CH:8]([CH2:9][CH2:10]2)[C:7](=[O:13])[O:6]1.[Cl:14][C:15]1[C:23]([Cl:24])=[C:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18].C(Cl)(=O)C(Cl)=O>C1(C)C=CC=CC=1.CN(C)C=O.C1(C)C=CC=CC=1.C(#N)C.CO>[O:13]=[C:7]1[CH:8]2[CH2:12][CH:11]([CH2:10][CH2:9]2)[C:5]([O:6][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[C:23]([Cl:24])[C:15]=2[Cl:14])=[CH:4]1
Reactant: C=C1OC(=O)C2CCC1C2
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c(Cl)c1Cl
Agent: C[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C(=O)OC2=CC(=O)C3CCC2C3)c(Cl)c1Cl
Temperature: 20 °C
Reaction time: 1 h

Procedure:
3.6 g of a 30% sodium methanolate solution (0.022 mol) are heated to a column head temperature of 108° C. in a mixture of 19 ml of toluene and 1 ml of dimethylformamide, methanol being removed by distillation. With removal of methanol by distillation being continued, 2.76 g (0.02 mol) of 4-methylene-3-oxabicyclo[3.2.1]octan-2-one dissolved in 3 ml of toluene are then added dropwise. After stirring for one hour, the mixture is cooled to a temperature of 20° C. and, while controlling the temperature, a solution in 1:1 toluene/acetonitrile of 6.32 g (0.022 mol) of 2,3-dichloro-4-methanesulfonylbenzoyl chloride freshly prepared with oxalyl chloride is introduced. After stirring briefly, extraction is carried out with a small amount of ethyl acetate against a slightly alkaline-aqueous solution at pH 10. 2,3-Dichloro-4-methanesulfonylbenzoic acid 4-oxobicyclo[3.2.1]oct-2-en-2-yl ester is obtained in the form of an amorphous crystallisate in a yield of 5.5 g (71%). 1H-NMR (DMSO-D6): 8.19 ppm, 2H, 5.85 ppm, s, 1H, 3.48 ppm, s, 3H, 3.07 ppm, m, 1H, 2.84 ppm, m, 1H, 1.9–2.2 ppm, 4H, 1.7 ppm, 2H.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17].[CH3:20][O:21][C:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)=[O:23]>>[CH3:20][O:21][C:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:13]2[C:14]3[C:2]([CH3:1])=[C:3]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:4]=[CH:5][C:6]=3[C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:26][CH:25]=1)=[O:23]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COC(=O)Cc1ccc2c([nH]c3ccccc32)c1C
Product: COC(=O)Cc1ccc2c3ccccc3n(Cc3ccc(C(=O)OC)cc3)c2c1C

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using methyl (1-methylcarbazol-2-yl)acetate and 4-methoxycarbonylbenzyl bromide as starting materials, the title compound was obtained as an oil.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:38][CH2:37][CH2:36][C:35]2=[O:39])[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:33][CH:32]([N:34]5[CH2:38][CH2:37][CH2:36][C:35]5=[O:39])[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: O=C1CCCN1C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCCC4=O)C3)n(C)c2n1
Reaction time: 65 h
Yield: 63.7 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (165 mg, 0.42 mmol), 1-azetidin-3-ylpyrrolidin-2-one (65 mg, 0.46 mmol) and 4 Å powdered molecular sieves in DCE (4 mL) was stirred at room temperature for 2 h before the addition of sodium triacetoxyborohydride (180 mg, 0.84 mmol). The reaction mixture was stirred for 65 h then filtered through celite, washing with DCM. The organic phase was washed with brine and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-15%) affording 588 as an orange foam (138 mg, 64%). LCMS (method I): RT 2.42 min [M+H]+ 516.2 1H NMR (CDCl3, 300 MHz): δ 8.00 (m, 1 H), 7.76 (m, 1 H), 7.27 (m, 2 H), 4.83 (t, J=6.9 Hz, 1 H), 4.35 (m, 4 H), 3.89-3.82 (m, 9 H), 3.67-3.54 (m, 4 H), 3.36 (m, 4 H), 2.42 (t, J=8.1 Hz, 2 H), 2.07 (m, 2 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[N:17]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:28][CH:27]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: Nc1ccc(CN2CCCC2)cc1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2C1=CNc1ccc(CN2CCCC2)cc1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
To a suspension of crude 6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (56.4 mg, 0.2 mmol) in N,N-dimethylformamide (500 μL) is added 4-pyrrolidin-1-ylmethyl-phenylamine (35.2 mg, 0.2 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours. Upon cooling to room temperature, the product precipitated out. The precipitate is then filtered off, rinsed with copious amounts of ether, and dried to yield 78.8 mg of 6-Bromo-4-[(4-pyrrolidin-1-ylmethyl-phenylamino)-methylene]-4H-isoquinoline-1,3-dione.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[N:22]3[CH:23]=[CH:24][N:25]=[C:26]([CH3:27])[C:21]3=[CH:20][N:19]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:29]N1C(=O)CCC1=O>CN(C)C=O>[Br:29][C:20]1[N:19]=[C:18]([C@H:15]2[CH2:16][CH2:17][C@H:12]([CH2:11][NH:10][C:9](=[O:28])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:14]2)[N:22]2[CH:23]=[CH:24][N:25]=[C:26]([CH3:27])[C:21]=12
Reactant: Cc1nccn2c1cnc2[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To benzyl((trans)-4-(8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)methylcarbamate (3.52 g, 9.05 mmol) in N,N-dimethylformamide (35 ml) was added N-bromosuccinimide (1.611 g, 9.05 mmol) and the mixture was stirred at room temperature for four hours. The reaction was quenched with saturated aqueous sodium hydrogencarbonate and subsequently extracted three times with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane with gradient 0 to 5% of methanol) to yield benzyl ((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)methylcarbamate (3.01 g).