Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](I)=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[CH3:18][C:19]1[NH:20][CH2:21][S:22][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].N#N>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:23]3[S:22][CH:21]=[N:20][C:19]=3[CH3:18])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: CC1=CSCN1
Agent: [Pd]
Agent: N#N
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)nn2c(-c3scnc3C)c(C)nc12
Temperature: 130 °C
Yield: 77.1 %

Procedure:
3.00 g of 8-(1-Ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (8.74 mmol), 4.32 g of 4-methyl-2H-thiazole (43.6 mmol), 453 mg of triphenylphosphine (1.73 mmol) and 5.85 g of cesium carbonate (18.0 mmol) are placed into the sealed tube with 20 ml of DMF and N2 gas is bubbled in for 40 min. 39 mg of Pd2 dba3 (0.43 mmol) is added and the tube is sealed and heated at 130° C. overnight. The cooled reaction mixture is filtered and applied onto silica-gel column (Hexane→Hexane:AcOEt=3:1) to give 2.12 g of the title compound (77%). 1H-NMR (DMSO-d6) δ 9.215 (s, 1H); 6.993 (s, 1H); 3.079 (m, 1H); 2.480 (s, 3H); 2.439 (s, 3H); 2.302 (s, 3H); 1.824-1.751 (m, 4H); 0.780-0.743 (m, 6H) ppm. MS, ES+=315.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13]1)[N:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:56]([O:58][CH2:59][CH2:60][CH2:61][CH3:62])=[CH2:57]>CN(C=O)C.O.C(O[Pd]OC(=O)C)(=O)C>[CH2:59]([O:58][C:56]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13]1)[N:8]=[CH:7]2)=[CH2:57])[CH2:60][CH2:61][CH3:62]
Reactant: C=COCCCC
Reactant: Brc1cccc2cnc(C3(c4ccccc4)CC3)nc12
Agent: CC(=O)O[Pd]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(OCCCC)c1cccc2cnc(C3(c4ccccc4)CC3)nc12
Temperature: 70 °C
Reaction time: 72 h
Yield: 61.3 %

Procedure:
A solution of 8-bromo-2-(1-phenylcyclopropyl)quinazoline (153.8 mg, 0.473 mmol), diacetoxypalladium (10.62 mg, 0.047 mmol), potassium carbonate (131 mg, 0.946 mmol), 1,3-bis(diphenylphosphino)propane (42.9 mg, 0.104 mmol), and 1-(vinyloxy)butane (0.067 mL, 0.520 mmol) in a mixture of DMF (2.0 mL) and water (0.400 mL) was stirred under argon in a sealed tube at 70° C. for 3 d. The mixture was adsorbed onto silica gel (DMF was removed in vacuo). Chromatographic purification (silica gel, 0-30% EtOAc/hexanes) furnished 8-(1-butoxyvinyl)-2-(1-phenylcyclopropyl)quinazoline (100.0 mg, 0.290 mmol, 61% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 9.21 (1H, s), 8.16 (1H, dd, J=7.4, 1.4 Hz), 7.73 (1H, dd, J=8.0, 1.4 Hz), 7.43-7.52 (2H, m), 7.32-7.40 (2H, m), 7.26-7.31 (2H, m), 5.32 (1H, d, J=2.0 Hz), 4.41 (1H, d, J=2.0 Hz), 3.81 (2H, t, J=6.5 Hz), 1.82-1.94 (4H, m), 1.69-1.80 (2H, m), 1.47-1.51 (2H, m), 0.93-1.03 (3H, m). m/z (ESI, +ve) 345.2 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22](=[O:24])[CH3:23])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.C(O)(=O)C.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22](=[O:24])[CH3:23])=[CH:11][CH:10]=1
Reactant: CC(=O)c1ccccc1Nc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)c1ccccc1Nc1ccc(O)cc1
Yield: 55.9 %

Procedure:
1-[2-(4-Benzyloxyphenylamino)phenyl]ethanone (9 g) in 900 ml of ethanol and 90 ml of acetic acid was hydrogenated in the presence of 1 g of 10% palladium-on-carbon catalyst. The product was isolated and recrystallized from acetonitrile to yield 3.6 g of 1-[2-(4-hydroxyphenylamino)phenyl]ethanone, orange solid, m.p. 168°-169° C.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[NH2:8][C@H:9]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14].C(OC(=O)C(=O)CCC1C=CC=CC=1)C.C(N(CC)CC)C.[H][H]>C(O)CCC.[Ni]>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH2:23]1[CH2:24][N:17]([C:15]([C@@H:9]([NH2:8])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[O:16])[C@@H:18]([C:19]([OH:21])=[O:20])[CH2:22]1
Reactant: NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: [H][H]
Agent: [Ni]
Agent: CCOC(=O)C(=O)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: NCCCC[C@H](N)C(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 2 h

Procedure:
150 mmoles H-Nε -TFA-Lys-Pro-OH (50.9 g) were taken up in 120 ml n-butanol and approximately 50 ml n-butanol distilled off under vacuum. The solution was diluted with 500 ml ethanol. 22.5 g molecular sieve 3 A, 34 g 2-oxo-4-phenyl butyric acid ethyl ester and 30 mmoles triethylamine (4.2 ml) are added and the mixture agitated 2 hours under anhydrous conditions. Three teaspoons dehydrated Raney nickel were now added and the mixture was agitated for 4 hours at under an atmosphere of 4 bars of H2. After this time, the pressure was released, another 12.4 g 2-oxo-4-phenyl butyric acid ethyl ester was added and the mixture was reagitated for 2 hours. Then a pressure of 4 bars of hydrogen was applied and the mixture was hydrogenated a further 4 hours at this pressure. The catalyst was separated off (it can be directly reused) and the solution was evaporated to a small volume. Conversion (according to HPLC) relative to Nε -TFA-Lys-Pro: approximately 95%, product yield (according to HPLC): 90%, diastereomer ratio: SSS:RSS-isomer=95.5. The residue was suspended in 450 ml water and 450 ml 1,1,1-trichloroethane at 5° C., the pH was adjusted to 9.6 in the aqueous phase with 50% NaOH and the phases were thoroughly mixed. The organic phase was separated off and the aqueous product phase was post-extracted with 100 ml 1,1,1-trichloroethane. The pH of 4.6 was now adjusted to 5 in the aqueous phase and this phase was extracted twice with 400 ml 1,1,1-trichloroethane. The organic phase was evaporated to low volume and taken up in 250 ml methyl-tert.butyl ether. The solution was cooled down to 0° C. and seeded. Yield: 48 g (60% of theory), SSS diastereomer content: >99%, [α]D20 :-25.5° [(c=1 in MeOH/ ·1N HCl (1:1)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([C:15]2[C:16]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[C:20]([C:30]([NH:32][CH3:33])=[O:31])[C:19]=3[CH:34]=2)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[CH:12]1([C:15]2[C:16]([N:35]([C:6]3[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([F:1])[CH:7]=3)[S:36]([CH3:39])(=[O:38])=[O:37])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[C:20]([C:30]([NH:32][CH3:33])=[O:31])[C:19]=3[CH:34]=2)[CH2:14][CH2:13]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 100 °C
Yield: 28.9 %

Procedure:
A suspension of 2,4-difluoro-1-nitrobenzene (261 mg, 1.64 mmol) and 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide (600 mg, 1.49 mmol) in dimethoxyethane (0.8 mL) and water (0.2 mL) was treated with potassium carbonate (616.86 mg, 4.47 mmol) and heated to 100° C. for 24 hours. The reaction mixture was concentrated and purified by column chromatography to afford 5-cyclopropyl-6-(N-(3-fluoro-4-nitrophenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (230 mg, 0.43 mmol, 29% yield) as a yellow powder. LCMS (m/z, ES+)=542 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:12]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: O=Cc1ccc(Cl)cc1
Product: COc1ccc(C(=O)C=Cc2ccc(Cl)cc2)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-chlorobenzaldehyde and commercial 4-methoxyacetophenone, 3-(4-chlorophenyl)-1-(4-methoxyphenyl)-prop-2-en-1-one was obtained as yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[C:6]([CH3:8])=O)[CH3:2].[C:20]1(=[O:39])[N:24]([CH2:25][CH2:26][O:27][C:28](=[O:33])/[CH:29]=[C:30](\[NH2:32])/[CH3:31])[C:23](=[O:34])[C:22]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:21]12>C(O)C>[CH3:8][C:6]1[NH:32][C:30]([CH3:31])=[C:29]([C:28]([O:27][CH2:26][CH2:25][N:24]2[C:23](=[O:34])[C:22]3=[CH:35][CH:36]=[CH:37][CH:38]=[C:21]3[C:20]2=[O:39])=[O:33])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:19]
Reactant: C/C(N)=C/C(=O)OCCN1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1
Yield: 89 %

Procedure:
Prepared by a method analogous to that of Example 1(a) from 15.80 g (60 mmol) of 2-(3-nitrobenzylidene)-acetoacetic acid ethyl ester and 16.46 g (60 mmol) of 3-amino-crotonic acid-(2-phthalimidoethyl)ester in ethanol. 27.75 g (89%) of yellow crystals melting at 194°-195° C. are obtained.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH2:17][N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].[H-].[Na+].[CH3:34]I.S([O-])(O)(=O)=O.[K+]>C1COCC1>[CH3:34][O:1][C@H:2]([CH2:6][O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[CH2:17][N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[C:23](=[O:31])[C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[CH:13][CH:14]=1)[C:3]([OH:5])=[O:4]
Reactant: CI
Reactant: Cc1ccc(C(=O)c2cccn2C/C=C/c2ccc(COC[C@@H](O)C(=O)O)cc2)cc1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CO[C@H](COCc1ccc(/C=C/Cn2cccc2C(=O)c2ccc(C)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound of Example 69-2 (24 mg, 0.05 mmol) was dissolved in THF (1 ml), and thereto was added sodium hydride (5 mg, 0.11 mmol) under ice-cooling. The mixture was warmed to room temperature, and stirred for 30 minutes, and thereto was added methyl iodide (15 mg, 0.11 mmol). The mixture was stirred at room temperature for 2 hours, and thereto was added a 5% aqueous potassium hydrogen sulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:20](=O)[C:19]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])=[N:25][C:18]=2[O:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].[Cl-].[NH4+]>C1COCC1.C(OCC)C.O>[CH2:7]([N:14]1[CH2:20][C:19]2[CH:22]=[CH:23][C:24]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])=[N:25][C:18]=2[O:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1c2ccc(Oc3ccccc3Cl)nc2OCCN1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Clc1ccccc1Oc1ccc2c(n1)OCCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
To a mixture of lithium aluminum hydride (0.080 g) and THF-diethyl ether solution (2.5 mL-2.5 mL) was added a solution of the compound obtained in step 1 (0.54 g) in THF-diethyl ether (2.5 mL-2.5 mL), and the resulting mixture was stirred at room temperature for 2 hr under a nitrogen atmosphere. 1N Aqueous sodium hydroxide solution (0.080 mL), saturated aqueous ammonium chloride (0.080 mL) and water (0.080 mL) were added, and the resulting mixture was stirred at room temperature for 3 hr. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give 4-benzyl-8-(2-chlorophenoxy)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.30 g, 58%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:18]2[CH2:17][CH2:16][N:15]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=3)[CH2:20][CH2:19]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: FC(F)(F)c1ccc(NN2CCNCC2)cc1
Product: C[C@](O)(CN1CCN(Nc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 86.2 %

Procedure:
Using (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (0.610 g, 2.82 mmol) and N-(piperazin-1-yl)-4-trifluoromethylaniline (0.760 g, 3.09 mmol) gave (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethylphenylamino)piperazin-1-yl]propan-2-ol (1.125 g, yield 86%) as a colorless solid in the same manner as in Example 496.
Reaction SMILES: [C-:1]#[N:2].[Li+].[Cl:4][C:5]1[C:6]([NH:21][C:22](=[O:30])[CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([N:15]1[CH2:19][CH2:18][C@@H:17](O)[CH2:16]1)[CH:9]=[CH:8]2.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:4][C:5]1[C:6]([NH:21][C:22](=[O:30])[CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([N:15]1[CH2:19][CH2:18][C@H:17]([C:1]#[N:2])[CH2:16]1)[CH:9]=[CH:8]2
Reactant: [C-]#N
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@@H](O)C3)ccc12
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#C[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 60 °C

Procedure:
Lithium cyanide (4 mL, 0.5M in DMF) was added to N-[6-chloro-2-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 33(a)) (0.21 g) in N,N′-dimethylformamide. The reaction mixture was heated at 60° C. for 10 hours. A saturated solution of sodium bicarbonate was added and the reaction mixture extracted with ethyl acetate. The combined organics were washed with brine, dried and concentrated. Purification (SiO2, iso-hexane:ethyl acetate 1:1 as eluant) gave the title compound as a solid (0.066 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[CH:15]2[CH:10]([C:11]3([C:20]#[N:21])[CH2:19][CH2:18][CH:14]2[CH:13]=[CH:12]3)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:23].[Na+].OO>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([N:8]1[C:16](=[O:17])[CH:15]2[CH:10]([C:11]3([C:20]([NH2:21])=[O:23])[CH2:19][CH2:18][CH:14]2[CH:13]=[CH:12]3)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: N#CC12C=CC(CC1)C1C(=O)N(Cc3ccccc3)C(=O)C12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: OO
Solvent: ClCCl
Product: NC(=O)C12C=CC(CC1)C1C(=O)N(Cc3ccccc3)C(=O)C12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
14.5 g (50 mmol) of 4-benzyl-1-cyano-4-azatricyclo[5.2.2.02,6 ]undec-8-ene-3,5-dione are dissolved in 25 ml of methylene chloride, 2.5 g of tetrabutylammonium hydrogen sulphate and 17.5 ml of 20% strength sodium hydroxide solution are added, and 24 ml of 30% strength H2O2 are added dropwise at 0° C. The mixture is stirred at 0° C. for 30 minutes and then overnight at room temperature and diluted with methylene chloride, and the organic phase is separated off and washed with sodium chloride solution. It is dried over MgSO4 and concentrated and the crystalline product is boiled up with xylene, any unreacted starting material dissolving. The product is filtered off hot with suction and dried in air.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:12][OH:13]>CCO>[OH:13][N:12]=[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1)[NH2:11]
Reactant: N#Cc1ccc2[nH]cnc2c1
Reactant: NO
Solvent: CCO
Product: NC(=NO)c1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 93.4 %

Procedure:
To a suspension of 1H-benzimidazole-5-carbonitrile obtained in step 1 (1 g; 6.99 mmol) in EtOH (20 mL) was added hydroxylamine (50% in water, 2.10 mL; 34.93 mmol) and the mixture was stirred at RT for 36 hours. The solution was concentrated under vacuum to give the title compound as a light pink solid (1.15 g, 93%). 1H NMR (DMSO-d6): δ 12.52 (br s, 1H), 9.51 (s, 1H), 8.23 (s, 1H), 7.89 (br s, 1H), 7.56 (s, 2H), 5.80 (s, 2H).
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Br:22][C:23]1[CH:28]=[N:27][CH:26]=[C:25]2[N:29]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([I:42])=[CH:38][C:37]=3[F:43])[C:30]([C:32]([O-])=[O:33])=[CH:31][C:24]=12.[Na+].[CH3:45][C:46]1([CH3:54])[O:50][C@@H:49]([CH2:51][O:52][NH2:53])[CH2:48][O:47]1.CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[CH3:45][C:46]1([CH3:54])[O:50][C@@H:49]([CH2:51][O:52][NH:53][C:32]([C:30]2[N:29]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([I:42])=[CH:38][C:37]=3[F:43])[C:25]3=[CH:26][N:27]=[CH:28][C:23]([Br:22])=[C:24]3[CH:31]=2)=[O:33])[CH2:48][O:47]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C([O-])c1cc2c(Br)cncc2n1Cc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](CONC(=O)c2cc3c(Br)cncc3n2Cc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 70 h
Yield: 68.6 %

Procedure:
EDCI (99 mg, 0.52 mmol) and HOBt (78 mg, 0.58 mmol) were added to a suspension of sodium 4-bromo-1-(2-fluoro-4-iodo-benzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (0.23 g, 0.41 mmol) in THF (4 ml). The suspension was warmed gently for 1 minute before the addition of a solution of O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (85 mg, 0.58 mmol) in THF (1 ml), followed by DIPEA (73 μl, 0.42 mmol). The reaction mixture was stirred at room temperature for 70 hours, poured into ethyl acetate (40 ml) then washed sequentially with 0.1M HCl (10 ml), saturated NaHCO3 solution (10 ml) and brine (10 ml). The organic layer was isolated then dried over magnesium sulphate and concentrated in vacuo to provide a solid residue. Purification of the residue by flash chromatography (Si-SPE, dichloromethane:ethyl acetate 100:0 to 70:30 to 40:60 to 0:100) afforded the title compound as a waxy white solid (0.17 g, 68%). LCMS (method B): RT=3.51 min, M+H+=604, 606.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([C:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH:32]=2)=[N:24][C:25]=1[CH3:26].O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:30]1[CH2:31][CH:32]=[C:27]([C:23]2[CH:22]=[CH:21][C:20]([CH3:19])=[C:25]([CH3:26])[N:24]=2)[CH2:28][CH2:29]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: Cc1ccc(C2=CCNCC2)nc1C
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C2=CCN([C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CC2)nc1C
Yield: 44.7 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.83 g, 3.3 mmol) and 5,6-dimethyl-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine (5.18 g, 27.5 mmol) were dissolved in acetonitrile (50 ml), and lithium perchlorate trihydrate (7.48 g, 46.6 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.67 g of the intended substance (yield 44.7%).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][O:9][C:10]1[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([O:18][CH3:19])=[C:12]([CH3:20])[C:11]=1[CH2:21][CH2:22]/[C:23](/C)=[CH:24]\CO>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:5]([O:4][CH2:1]/[CH:2]=[C:23](/[CH3:24])\[CH2:22][CH2:21][C:11]1[C:12]([CH3:20])=[C:13]([O:18][CH3:19])[C:14]([CH3:17])=[C:15]([CH3:16])[C:10]=1[O:9][CH3:8])(=[O:7])[CH3:6]
Reactant: COc1c(C)c(C)c(OC)c(CC/C(C)=C\CO)c1C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1c(C)c(C)c(OC)c(CC/C(C)=C\COC(C)=O)c1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Acetic anhydride (0.2 ml) was dissolved at 0° C. in pyridine (10 ml) together with (Z)-5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3-methyl-2-penten-1-ol (0.39 g; 1.4 mmol). A spatula tip of 4-dimethylaminopyridine was added and the reaction mixture was left at 0° C. for 20 minutes. Thereafter, the mixture was poured into 150 ml of ice-cold 2N hydrochloric acid and extracted with ether. The extracts were washed with water, dried briefly and freed from solvent, yielding 0.39 g of (Z)-5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenyl acetate as an almost colourless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[N:12][C:11]([C:14](N)=[O:15])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH-].[Na+].C([O-])(O)=[O:20].[Na+]>Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:13]=[N:12][C:11]([C:14]([OH:15])=[O:20])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: O=C([O-])O
Reactant: CN1CCN(c2ccc(C(N)=O)nn2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(c2ccc(C(=O)O)nn2)CC1
Temperature: 25 °C

Procedure:
A suspension of 6-(4-methylpiperazin-1-yl)pyridazine-3-carboxamide (221 mg, 1.00 mmol) in sodium hydroxide (2.0M aqueous) (10.000 mL, 20.00 mmol), was stirred at reflux for 3 h and then allowed to cool to room temperature. The reaction mixture was adjusted to pH7 by addition of 2M HCl (10 mL) and saturated NaHCO3. The crude product was purified by ion exchange chromatography, using a SCX2 column. The desired product was eluted from the column using methanol and the fractions were evaporated to dryness to afford 6-(4-methylpiperazin-1-yl)pyridazine-3-carboxylic acid as a white solid. This material was suspended in methanol (10.00 ml) at 0° C. and treated with thionyl chloride (0.729 ml, 10.00 mmol), over a period of 5 mins. The resulting suspension was stirred at ambient temperature for 18 h. Sodium bicarbonate solution was added until basic and then the mixture was extracted with ethyl acetate (2×75 mL). The solution was further extracted with 1-butanol (100 mL). The organic extracts were combined and evaporated to dryness to give methyl 6-(4-methylpiperazin-1-yl)pyridazine-3-carboxylate a white solid, 212 mg.
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.C([Li])CCC.[CH3:23][C:24]([CH3:26])=[O:25]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:24]([OH:25])([CH3:26])[CH3:23])[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: CC(C)=O
Reactant: Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(C(C)(C)O)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 0 °C

Procedure:
4-(2-Chloro-9-methyl-9H-purin-6-yl)morpholine (233 mg) was cooled in 5 mL of anhydrous THF to −78° C. before adding 2 eq of a 2.5 M solution of n-butyl lithium. The reaction was stirred for 1 hour at −78° C. upon which 3 eq of acetone were added. The reaction was subsequently warmed to 0° C. after 30 minutes. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was concentrated to give crude 2-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)propan-2-ol (95 mg).