Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[N:18][CH:19]=1.CON(C)[C:24]([C:26]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][N:27]=1)=[O:25]>O1CCCC1>[Br:13][C:14]1[CH:15]=[C:16]([C:24]([C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:25])[C:17]([F:20])=[N:18][CH:19]=1
Reactant: Fc1ccc(Br)cn1
Reactant: COc1cccnc1C(=O)N(C)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cccnc1C(=O)c1cc(Br)cnc1F
Temperature: -20 °C
Yield: 63.1 %

Procedure:
Diisopropylamine (0.50 ml, 3.54 mmol) and tetrahyrofuran (40 ml) were combined and cooled to −20° C. with stirring. n-Butyl lithium (1.41 ml, 2.5 M in hexanes, 3.53 mmol) was slowly added and stirred at this temperature for 30 minutes. The temperature was decreased to −78 C and neat 5-bromo-2-fluoropyridine (0.38 ml, 3.69 mmol) was added (internal temperature was not allowed to exceed −68 C). The reaction mixture was stirred at −78° C. for 40 minutes. The reaction mixture was added to a solution of 3-methoxy-pyridine-2-carboxylic acid methoxy-methyl-amide (685 mg 3.49 mmol) in tetrahydrofuran (10 ml). This was stirred at −78 C for 1 hour. The reaction mixture was slowly warmed to room temperature, and quenched with saturated aqueous ammonium chloride. The reaction mixture was extracted with dichloromethane, dried over sodium sulfate, and concentrated. The crude product was purified by flash chromatography (0-50% ethyl acetate in hexanes) to give 685 mg (63%) of (5-bromo-2-fluoro-pyridin-3-yl)-(3-methoxy-pyridin-2-yl)-methanone. MS: m/z 310.6+312.9 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5](I)=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][N:25]=[N:24][CH:23]=1)CCC.[F-].[Cs+]>C(#N)C.[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.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:22]2[CH:27]=[CH:26][N:25]=[N:24][CH:23]=2)=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: Oc1cc(Cl)c(-c2cccc(F)c2)cc1I
Agent: [Cu]I
Agent: [Pd]
Agent: [Cs+]
Solvent: CC#N
Product: Oc1cc(Cl)c(-c2cccc(F)c2)cc1-c1ccnnc1
Temperature: 50 °C
Yield: 23.6 %

Procedure:
2-Chloro-3′-fluoro-5-iodobiphenyl-4-ol (Preparation 68, 480 mg, 1.38 mmol) and 4-(tributylstannyl)pyridazine (610 mg, 1.65 mmol) were dissolved in degassed acetonitrile (7 mL). Caesium fluoride (418 mg, 2.75 mmol) was added and the mixture further degassed. Tetrakis(triphenylphosphine) palladium (0) (159 mg, 0.14 mmol) and copper (I) iodide (79 mg, 0.41 mmol) were added and the reaction heated at 50° C. for 2 hours. The reaction mixture was cooled and filtered through celite, washing with ethyl acetate. The organic solution was washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by silica gel column chromatography (20% heptane in ethyl acetate) followed by trituration with dichloromethane to give the title compound (98 mg, 24%) as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:4]=1[O:5][C:6]1[C:15]([O:16][CH3:17])=[CH:14][C:13](N)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2.N([O-])=O.[Na+].[OH-].[Na+]>O>[F:2][C:3]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:4]=1[O:5][C:6]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2
Reactant: COc1cc(N)c2ncccc2c1Oc1ccc(F)cc1F
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2ncccc2c1Oc1ccc(F)cc1F
Temperature: 0 °C
Yield: 65.3 %

Procedure:
A solution of 2.4 mL HCl in 24 mL H2O was heated to the boiling point and poured into 2.4 g (0.008 mol) of 5-(2,4-difluoro-phenoxy)-6-methoxy-quinolin-8-ylamine, then stirred while hot to dissolve as much solid as possible. The solution was cooled in an ice-salt mixture. When the temperature reached 15° C., 2.5 mL of conc. HCl were added to the reaction mixture. At 10° C. a solution of NaNO2 (1.1 g, 0.016 mol in 2 mL of water) was added dropwise during 10 min. The reaction mixture was stirred at 5–10° C. for 30 min., treated with ice-cold 30% H3PO4, and cooled at 0° C. overnight. After stirring for an additional 8 hours,at room temperature, the reaction mixture was neutralized with 1N NaOH, extracted with CH2Cl2, and the organic layer was dried (MgSO4). Solvent removal, followed by HPLC, eluting with 10–20% EtOAc/Hexane gave 1.5 g (66%) of 5-(2,4-difluoro-phenoxy)-6-methoxy-quinoline, which crystallized at room temperature.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2>S(=O)(=O)(O)O>[Cl:5][C:6]1[C:7]([N+:1]([O-:4])=[O:2])=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: Clc1ccc2ncccc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(Cl)ccc2ncccc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
HNO3 (90%, 7 mL) was added to 6-chloro-quinoline (4.45 g) in concentrated sulfuric acid (21 mL) at 0° C. The mixture was stirred at 0° C. for 1 h and at room temperature overnight. The reaction mixture was poured into ice, and the solid product (24.1) was collected by filtration, washed with water and dried. MS ESI (pos.) m/z: 209.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:15][O:14][N:13]=2)=O)[CH:5]=[CH:6][C:7]=1[F:8].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:32][OH:33]>C1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:15][O:14][N:13]=2)=[N:32][OH:33])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NO
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCN1CCOCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: c1ccccc1
Product: ON=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCN1CCOCC1
Reaction time: 1 h
Yield: 50.2 %

Procedure:
N-(3-Chloro-4-fluorophenyl)-4-(3-morpholin-4-ylpropyl)-1,2,5-oxadiazole-3-carboxamide (10.0 mg, 27 μmol) was suspended in benzene (0.4 mL) under an atmosphere of nitrogen and phosphorus pentachloride (6.2 mg, 29.8 μmol) was added. The solution was heated at reflux for 2.5 h. The volatiles were evaporated in vacuo. The reaction was dissolved in EtOH (0.3 mL) and hydroxylamine (40 μL, 0.7 mmol) (50% solution in water) was added to the reaction. After stirring for 1 h, the reaction solution was diluted with MeOH and purified by preparative LCMS to give the desired product (5.2 mg, 50%). LCMS for C16H20ClFN5O3(M+H)+: m/z=384.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1>C(N)C=C>[CH2:4]([NH:3][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1)[CH:5]=[CH2:6]
Reactant: Cc1cc(C)nc(Cl)n1
Solvent: C=CCN
Product: C=CCNc1nc(C)cc(C)n1
Yield: 196.9 %

Procedure:
20 g (0.14 mol) 2-chlor-4,6-dimethylpyrimidine are heated under reflux in 60 ml allylamine. After 4 hours the reaction is terminated. The excess allylamine is distilled off. Thereafter the residue is withdrawn in ethyl acetate and then washed with 150 ml saturated bicarbonate solution. After drying across Na2SO4 the solvent is discharged. In this manner are obtained 22.5 g (99% of theoretical) 2-allylamino-4,6-dimethylpyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[N:14]([CH3:39])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH2:37][CH3:38])[N:16]=3)(O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COCCN(S(F)(F)[F:50])CCOC>C1COCC1>[CH2:37]([C:29]1[N:28]([C:17]2[N:16]=[C:15]3[C:20]([N:21]=[C:13]([C:10]4([F:50])[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]4)[N:14]3[CH3:39])=[C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:18]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=1)[CH3:38]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(F)CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 79.2 %

Procedure:
To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (300 mg, 0.56 mmol) in THF (2 mL) at 5° C. was added a solution of bis-(2-methoxyethyl)aminosulfur trifluoride (275 μL, 0.62 mmol, 50% solution in THF) in THF (3 mL). The resulting mixture was allowed to stir at 5° C. for 15 min then warmed to r.t. and stirred for a further 15 min. The reaction mixture was partitioned between sat. aq. NaHCO3 and DCM, the organic phase dried (phase separator) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 35-85%) affording 828 as a pale yellow solid (238 mg, 79%). LCMS (method I): RT 4.65 min, [M+H]+ 537.4. 1H NMR (DMSO, 400 MHz): δ 8.05-8.04 (1 H, m), 7.64-7.64 (1 H, m), 7.26-7.25 (2 H, m), 4.77 (2 H, dd, J=20.08, 10.62 Hz), 4.60-4.10 (4 H, brd s), 4.48 (2 H, dd, J=21.54, 10.50 Hz), 3.79 (4 H, t, J=4.55 Hz), 3.76 (3 H, d, J=1.32 Hz), 3.28-3.27 (2 H, m), 1.42 (9 H, s), 1.34 (3 H, t, J=7.46 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.Br[CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([OH:16])=[O:15].C(O)(=O)C>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([OH:16])=[O:15])=[N:7][C:6]=2[CH:11]=1
Reactant: Sc1nc2cc(Cl)ccc2s1
Reactant: O=C(O)C(Br)c1ccccc1
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: O=C(O)C(Sc1nc2cc(Cl)ccc2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
50.0 g (0.248 m) 5-chloro-2-mercaptobenzothiazole and 53.0 g (0.248 m) α-bromophenylacetic acid are dissolved in 1.5 l acetone and the solution is heated for 4 hours in the presence of 50 ml glacial acetic acid. The solution is concentrated to a smaller volume (about 200 ml) and the residual solid (90 g) is collected. The resulting salt is suspended in 1 l of water and the mixture is stirred at room temperature overnight. The collected solid is recrystallized from 2.5 l acetonitrile to give a total of 64 g (85% yield) of title compound melting at 190°-2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]([C:15]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([CH3:25])[CH:18]=3)=[O:16])[CH2:13][CH2:12][C:11]3[N:10]=[C:9]([CH3:26])[NH:8][C:7]=3[C:6]=2[CH:27]=1.[BH4-].[Na+].[NH4+].[Cl-]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[NH2:22][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([C:15]([N:14]2[CH2:13][CH2:12][C:11]3[N:10]=[C:9]([CH3:26])[NH:8][C:7]=3[C:6]3[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=3)=[O:16])=[CH:18][C:19]=1[CH3:25]
Reactant: Cc1nc2c([nH]1)-c1cc(Cl)ccc1N(C(=O)c1ccc(C#N)c(C)c1)CC2
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: Cc1nc2c([nH]1)-c1cc(Cl)ccc1N(C(=O)c1ccc(CN)c(C)c1)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
A solution of 4-(9-chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-methyl-benzonitrile from E125.2 (80 mg, 0.2 mmol) in methanol (5 ml) at room temperature was treated with cobalt(II) chloride hexahydrate (101 mg, 0.4 mmol). The mixture was cooled to 0° C. then sodium borohydride (80 mg, 2.1 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 30 min. then for 2 h at room temperature then saturated NH4Cl was added. The mixture was stirred for 10 min then the solid was filtered off through Celite® filter agent and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:9% methanol:90% di-chloromethane) to yield the title compound (24 mg, 30%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[CH:7]([CH2:15][F:16])[CH2:6][NH:5]2.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](Cl)=[O:23].BrC1C=C2C(=CC=1)N(C(=O)C)[C@@H](C)CN2C(C1OC=CC=1)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[CH:7]([CH2:15][F:16])[CH2:6][N:5]2[C:22]([C:18]1[O:17][CH:21]=[CH:20][CH:19]=1)=[O:23]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(=O)N1c2ccc(Br)cc2NCC1CF
Agent: CC(=O)N1c2ccc(Br)cc2N(C(=O)c2ccco2)C[C@@H]1C
Product: CC(=O)N1c2ccc(Br)cc2N(C(=O)c2ccco2)CC1CF

Procedure:
1-(6-bromo-2-(fluoromethyl)-4-(furan-2-carbonyl)-3,4-dihydroquinoxaline-1(2H)-yl)ethan-1-one was synthesized from (1-(6-bromo-2-(fluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl)ethan-1-one and furan-2-carbonyl chloride according to the procedure outlined for (S)-1-(6-bromo-4-(furan-2-carbonyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone. MS (ESI, pos. ion) m/z 339, 341 [M−42 (acyl)]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([C:10]([C:12]1[C:17](F)=[CH:16][CH:15]=[CH:14][N:13]=1)=[O:11])=[CH:6][N:7]([CH3:9])C)[CH3:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:28]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1CN>CC(N(C)C)=O>[CH2:1]([O:3][C:4]([C:5]1[C:10](=[O:11])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][N:13]=2)[N:7]([CH2:9][C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:6]=1)=[O:19])[CH3:2]
Reactant: NCc1ccccc1-c1ccccc1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ncccc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cn(Cc2ccccc2-c2ccccc2)c2cccnc2c1=O
Temperature: 70 °C
Reaction time: 14 h
Yield: 39 %

Procedure:
To a stirred solution of 3-dimethylamino-2-(3-fluoro-pyridine-2-carbonyl)acrylic acid ethyl ester (4) (18 mg, 0.067 mmol) in dimethylacetamide (2 mL) was added K3PO4 (28 mg, 0.14 mmol) followed by C-biphenyl-2-yl-methylamine (5) (11 mg, 0.06 mmol) at room temperature. The mixture was stirred at 70° C. for 14 h. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified using normal silica gel column chromatography (3% methanol:dichloromethane) to get 1-biphenyl-2-ylmethyl-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester (6) (9 mg, 35%) as a sticky solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2[nH]cc(-c3ccc(F)cc3)c2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)C(c1ccc(F)cc1)CN2
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To the cooled solution of 3-(4-fluorophenyl)-5-methyl-1H-indole (2 g, 0.0088 mol) in TFA (60 mL) was added triethylsilane (6 mL) dropwise at 0° C., and the reaction mixture was stirred for 4 h at RT. After completion of reaction (monitored by TLC), solvent was removed under reduced pressure, the residue treated with saturated sodium bicarbonate solution, and extracted with EtOAc (3×150 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the product purified by column chromatography (10% EtOAc:hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to provide the desired compound as a yellow colored oil (1.2 g, 60% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1.[CH:17]1([CH2:20]Br)[CH2:19][CH2:18]1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH2:20][CH:17]3[CH2:19][CH2:18]3)[C:6]=2[CH:16]=1
Reactant: BrCC1CC1
Reactant: O=c1[nH]c2cc(Cl)ccc2c2ccncc12
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cnccc2c2ccc(Cl)cc2n1CC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.9 %

Procedure:
To a stirred solution of 8-chlorobenzo[c][2,7]naphthyridin-5(6H)-one (100 mg, 0.434 mmol) (as prepared in Ex. 12, Part B) in anhydrous DMF (2 mL) at 0° C. was added cyclopropyl methyl bromide (0.088 g, 0.650 mmol) under nitrogen. The reaction mixture was allowed to warm to RT and stirred for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to 8-chloro-6-(cyclopropylmethyl)benzo[c][2,7]naphthyridin-5(6H)-one (100 mg, 0.351 mmol, 81% yield, 53% pure by LC/MS). LC/MS (ESI) m/e 285.1 [(M+H)+, calcd for C16H14ClN2O 285.1]; LC/MS retention time (method D): tR=0.91 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][C:17]1[CH:18]=[C:19]([C:22]#[N:23])[S:20][CH:21]=1.[H-].[Na+]>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH2:16][C:17]2[CH:18]=[C:19]([C:22]#[N:23])[S:20][CH:21]=2)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cc(CBr)cs1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(Cc2csc(C#N)c2)C1=O
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of (2-oxopyrrolidin-3-(S)-yl)carbamic acid tert-butyl ester (3.2 g, 16 mmol) in 80 mL of THF:DMF (10:1) at 0° C. is added 4-bromomethylthiophene-2-carbonitrile (3.23 g, 16 mmol) and sodium hydride (60%) (0.67 g, 16.8 mmol). After addition, the solution is allowed to warm to ambient temperatures. After 2 hours, the solution is quenched by the addition of sat NH4Cl. The solution is diluted with H2O and EtOAc. The layers are separated. The organic layer is washed with H2O and sat. NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with gradient of 20% EtOAc/CH2Cl2 to 30% EtOAc/CH2Cl2 to afford the title compound (4 g, 13.8 mmol) as a white solid.
Reaction SMILES: [Na+].[Cl-].[O:3]([CH2:10][C:11]([OH:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl[C:17]([O:19][CH:20]([CH2:22][CH3:23])[CH3:21])=[O:18]>C(OCC)C>[C:17](=[O:18])([O:19][CH:20]([CH3:21])[CH2:22][CH3:23])[O:12][C:11](=[O:13])[CH2:10][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCC(C)OC(=O)Cl
Reactant: O=C(O)COc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCC(C)OC(=O)OC(=O)COc1ccccc1
Temperature: 7.5 °C
Yield: 81 %

Procedure:
To a well-stirred reaction vessel equipped with a thermometer and a pH electrode were added 100 ml of diethyl ether, 40 ml of a 25 wt % aqueous NaCl solution, and 0.4 g of Arquad CB50. After cooling the reaction mixture to 5-10° C., 0.066 mole of phenoxy acetic acid was added. The pH was adjusted to a value between 6 and 7 using a 25 wt % aqueous NaOH solution. Then, 0.066 mole of sec-butyl chloroformate was dosed within 5 min at 5-10° C. During this time and a post-reaction time of 40 min at 5-10° C. the pH was kept at 6-7. The reaction mixture was allowed to separate. After removal of the diethyl ether, 15 g of phenoxyacetyl 1-methyl-1-propyl carbonate having a content of 90% were obtained in a yield of 81%.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=O)[NH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([Cl:17])=[N:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]cc(Br)c2c1
Product: COc1ccc2c(Cl)ncc(Br)c2c1
Yield: 65 %

Procedure:
A solution of 4-bromo-6-methoxyisoquinolin-1(2H)-one (1.5 g, 5.90 mmol) in POCl3 (15 ml) was refluxed for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The combine organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get desired compound (1.1 g, 65%) as white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.53(s, 1H), 8.27-8.24 (d, J=12 Hz, 1H), 7.56-7.53 (d, J=12 Hz, 1H), 7.41 (s, 1H), 4.02 (s, 3H); MS: MS m/z 273.99 (M++1).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH:15]1([CH2:21][C:22]2[NH:23][C:24](=O)[C:25]3[CH:30]=[N:29][N:28]([CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[C:26]=3[N:27]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH:15]1([CH2:21][C:22]2[NH:23][C:24](=[S:2])[C:25]3[CH:30]=[N:29][N:28]([CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[C:26]=3[N:27]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCC(CC)n1ncc2c(=O)[nH]c(CC3CCCCC3)nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCC(CC)n1ncc2c(=S)[nH]c(CC3CCCCC3)nc21
Temperature: 0 °C

Procedure:
74 mg (0.33 mmol, 2 equiv.) of diphosphorus pentasulfide are added to a solution of 50 mg (0.17 mmol) of 6-(cyclohexylmethyl)-1-(1-ethylpropyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 3) in 1 ml of pyridine at room temperature, and the mixture is then stirred under reflux overnight. After cooling, the reaction solution is mixed with 20 ml of ice-cold 2.5% strength sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases are washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The crude product is purified by preparative HPLC.
Reaction SMILES: C([O-])(=O)C.[NH4+].C[O:7][C:8](=O)[CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=O.C([BH3-])#[N:22].[Na+]>CO>[NH:22]1[C:8](=[O:7])[CH2:9][CH:10]2[CH2:18][C:17]3[C:12]([CH:11]12)=[CH:13][CH:14]=[CH:15][CH:16]=3
Reactant: COC(=O)CC1Cc2ccccc2C1=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: O=C1CC2Cc3ccccc3C2N1
Reaction time: 0.5 h

Procedure:
A solution of ammonium acetate (3.77 g, 48.9 mmol) was coevaporated in anhydrous methanol. Then, (1-Oxo-indan-2-yl)-acetic acid methyl ester H1 (1.00 g, 4.89 mmol) in methanol (40 mL) was added followed by molecular sieves (4.9 g). The solution was stirred for 30 min and sodium cyanoborohydride (0.92 g, 14.9 mmol) was added. The suspension was refluxed for 40 h. The solution was filtered through celite. A saturated solution of sodium hydrogenocarbonate was added and the solution was extracted with ethyl acetate (3*50 mL). The combined organic layers were washed with hydrogen chloride (1N), brine, dried and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate and then ethyl acetate/methanol (95/5) to give 3,3a,4,8b-tetrahydro-1H-indeno[1,2-b]pyrrol-2-one G1 (White solid, 300 mg, 35%). LCMS (method A) RT 1.17; ES 196, 174; IR 3233, 1689 cm−1; Mp: 150-153° C.; 1H NMR (400 MHz, CD3OD) δ 7.34 (1H, d), 7.12-7.27 (3H, m), 5.04 (1H, d), 3.22-3.37 (2H, m), 2.83 (1H, d), 2.70 (1H, dd), 2.15 (1H, dd) ppm.
Reaction SMILES: [CH:1]1([C:4]2([CH:10]3[CH2:12][CH2:11]3)[CH2:8][C:7](=[O:9])[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=O)C.Cl>C(OCC)C>[CH:10]1([C:4]2([CH:1]3[CH2:3][CH2:2]3)[CH2:8][CH:7]([OH:9])[CH:6]=[CH:5]2)[CH2:12][CH2:11]1
Reactant: O=C1C=CC(C2CC2)(C2CC2)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OC1C=CC(C2CC2)(C2CC2)C1
Reaction time: 0.33 h
Yield: 27.8 %

Procedure:
To a solution of 4,4-dicyclopropyl-2-cyclopenten-1-one (1.88 g) in diethyl ether (20 ml) was added diisobutylaluminum hydride (0.94N in n-hexane, 14 ml) at -70° C. to -64° C. under nitrogen atmosphere. After being stirred for 20 minutes, ethyl acetate (6 ml) was added thereto and the solution was acidified with dil. hydrochloric acid and extracted with diethyl ether. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo to give 4,4-dicyclopropyl-2-cyclopenten-1-ol (0.53 g). Since this compound was not so stable, it was used in the next reaction without purification.