Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:20]=[C:19]3[C:15]([CH2:16][C:17](=[O:21])[NH:18]3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[CH:29]=[C:30]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=2)[C:31](O)=[O:32])[CH:27]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[CH:29]=[C:30]([CH:34]=[C:35]([C:37]([F:40])([F:38])[F:39])[CH:36]=2)[C:31]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]([NH:11][C:12]3[CH:20]=[C:19]4[C:15]([CH2:16][C:17](=[O:21])[NH:18]4)=[CH:14][CH:13]=3)=[O:10])[CH:3]=2)=[O:32])[CH:27]=1
Reactant: Nc1cccc(NC(=O)Nc2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1cn(-c2cc(C(=O)O)cc(C(F)(F)F)c2)cn1
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: Cc1cn(-c2cc(C(=O)Nc3cccc(NC(=O)Nc4ccc5c(c4)NC(=O)C5)c3)cc(C(F)(F)F)c2)cn1
Reaction time: 24 h

Procedure:
1-(3-amino-phenyl)-3-(2-oxo-2,3-dihydro-1H-indol-6-yl)-urea (75 mg, 0.27 mmol) is dissolved in DMF (5 ml). To this solution is added 3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoic acid (73 mg, 0.27 mmol), N,N-diisopropylethylamine (105 mg, 0.81 mmol) and HATU (0.10 g, 0.26 mmol). It is stirred for 24 hours and then concentrated. 3-(4-methyl-imidazol-1-yl)-N-{3-[3-(2-oxo-2,3-dihydro-1H-indol-6-yl)-ureido]-phenyl}-5-trifluoromethyl-benzamide is obtained after HPLC purification. LC-MS: 535.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:13][OH:14])[CH2:7][CH:6]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[CH2:5][C:4]=2[N:3]=1.[CH3:20][N:21]([CH3:45])[CH2:22][CH2:23]ON=C1CC(C2C=CC(F)=CC=2)CC2N=C(N)N=C(C)C1=2>>[CH3:20][N:21]([CH3:45])[CH2:22][CH2:23][O:14][N:13]=[C:8]1[CH2:7][CH:6]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[CH2:5][C:4]2[N:3]=[C:2]([NH2:1])[N:11]=[C:10]([CH3:12])[C:9]1=2
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccco1)C2
Reactant: Cc1nc(N)nc2c1C(=NOCCN(C)C)CC(c1ccc(F)cc1)C2
Product: Cc1nc(N)nc2c1C(=NOCCN(C)C)CC(c1ccco1)C2

Procedure:
The title compound was prepared from 2-amino-7-furan-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (compound 33), following the procedure describing the synthesis of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-(2-dimethylamino-ethyl)-oxime (example 3/a stage 5).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:27])([CH3:26])[C@@H:11]([O:22][C:23](=[O:25])[CH3:24])[C:12]([O:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:13])(=[O:7])=[O:6].[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O>[N:28]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:27])([CH3:26])[C@@H:11]([O:22][C:23](=[O:25])[CH3:24])[C:12]([O:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:13])(=[O:7])=[O:6])=[N+:29]=[N-:30]
Reactant: CC(=O)O[C@@H](C(=O)OCc1cccnc1)C(C)(C)COS(=O)(=O)CCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@@H](C(=O)OCc1cccnc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, 3-pyridylmethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-acetyloxy-3,3-dimethylbutanoate (38a) (220 mg, 0.51 mmol) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 100 mg (1.5 mmol) of sodium azide (NaN3). After work-up, the crude title compound (38b) was used in the next step without further purification. MS (ESI) m/z 428.99 (M+H)+.
Reaction SMILES: COCCOCCO.C(Cl)(Cl)=O.[NH2:13][C@H:14]([C:18]([OH:20])=[O:19])[CH:15]([CH3:17])[CH3:16].[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][C:29](Cl)=[O:30]>C1(C)C=CC=CC=1>[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][C:29]([NH:13][C@H:14]([C:18]([OH:20])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:30]
Reactant: COCCOCCOC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=C(Cl)Cl
Solvent: COCCOCCO
Solvent: Cc1ccccc1
Product: COCCOCCOC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
19.8 ml (168 mmol) of diethylene glycol monomethyl ether are added dropwise at 0° to 100 ml of a 20% solution of phosgene in toluene and the mixture is stirred overnight at RT. Excess phosgene is expelled with nitrogen and the reaction solution is washed with water and concentrated by evaporation. Analogously to Example 1c, 10 g (85.4 mmol) of (L)-valine are added to the crude 2-(2-methoxyethoxy)ethylchloroformate (15.6 g, 85.4 mmol) yielding the title compound in the form of a colourless resin. 1H-NMR (200 MHz, CD3OD): 4.18 (m, 2H), 4.05 d, J=6 Hz, 1H), 3.72-3.40 (m, 8H), 3.35 (s, 3H), 2.18 (m, 1H), 0.95 (t, J=7H, 6H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][N:16]([C:19]3[CH:27]=[CH:26][C:25]4[C:21](=[CH:22][N:23]([CH2:28][CH2:29][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[N:24]=4)[CH:20]=3)[C:15]2=[O:35])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CC(O)=O.[Pd]>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:18][CH2:17][N:16]([C:19]3[CH:27]=[CH:26][C:25]4[C:21](=[CH:22][N:23]([CH2:28][CH2:29][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[N:24]=4)[CH:20]=3)[C:15]2=[O:35])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=c1n(-c2ccc(Oc3ccccc3)cc2)ccn1-c1ccc2nn(CCN3CCCC3)cc2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1N(c2ccc(Oc3ccccc3)cc2)CCN1c1ccc2nn(CCN3CCCC3)cc2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1-(4-phenoxyphenyl)-3-[2-(2-pyrrolidin-1-ylethyl)-2H-indazol-5-yl]-1,3-dihydro-2H-imidazol-2-one (Example 84) (0.100 g, 0.215 mmol) was taken up in 20 mL of AcOH along with 100 mg of Pd/C (10% mol/mol) and the mixture was subjected to an atmosphere of hydrogen gas at a pressure of 60 psi in a Parr shaker apparatus. The mixture was shaken at room temperature for 6 hours after which the mixture was filtered through a bed of celite, and the solvents removed under reduced pressure. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.75–2.06 (m, 4 H) 3.02–3.15 (m, 2 H) 3.47–3.63 (m, 2 H) 3.74–3.87 (m, 2 H) 3.93–4.12 (m, 4 H) 4.82 (t, J=5.76 Hz, 2 H) 6.94–7.01 (m, 2 H) 7.03–7.14 (m, 3 H) 7.34–7.34 (m, 2 H) 7.62–7.70 (m, 4 H) 7.86 (dd, J=9.49, 2.03 Hz, 1 H) 8.39–8.46 (m, 1 H); MS (ESI) m/z 468 [M+H]+.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([F:9])[CH:8]=1.[CH2:11]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].[Cl-].[NH4+]>C1COCC1>[F:2][C:3]1[CH:4]=[C:5]([C:29]2[CH2:30][CH2:31][CH:26]([CH2:25][CH2:24][CH2:23][CH2:22][C@H:19]3[CH2:18][CH2:17][C@H:16]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:21][CH2:20]3)[CH2:27][CH:28]=2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CCCCC[C@H]1CC[C@H](CCCCC2CCC(=O)CC2)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](CCCCC2CC=C(c3cc(F)cc(F)c3)CC2)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Under a nitrogen gas stream, 3.13 g (129 mmol) of magnesium was added to 50 ml of THF, and while a reaction temperature was maintained at about 50° C., 300 ml of THF containing 22.7 g (118 mmol) of 3,5-difluoro-1-bromobenzene was added dropwise. After stirring for 1 hour at room temperature, 300 ml of THF containing 30.0 g (97.9 mmol) of 4-(4-(trans-4-pentylcyclohexyl)butyl)cyclohexanone was added dropwise. Next, after stirring at 50 to 60° C. for 2 hours, 200 ml of an aqueous saturated ammonium chloride solution was added, thereby terminating the reaction. The reaction mixture was filtered through Celite, and the solvent was then distilled off under reduced pressure, followed by extraction with 500 ml of toluene. The resulting organic layer was washed 3 times with 200 ml of water, and then dried over anhydrous magnesium sulfate. After drying, 1.50 g of p-toluenesulfonic acid monohydrate was added, and heating was done under reflux for 4 hours. The organic layer was washed 3 times with 200 ml of water, and then dried over anhydrous magnesium sulfate. Next, the solvent was distilled off under reduced pressure, and the resulting residue was purified through silica gel column chromatography (a developing solvent: heptane) to obtain 26.4 g of crude 1,3-difluoro-5-(4-(4-(trans-4-pentylcyclohexyl)butyl)cyclohexene-1-yl)benzene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:6]1[CH:10]=[C:9]([N+:11]([O-])=O)[N:8]=[CH:7]1)[CH3:2].[H][H]>[Pd]>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:6]1[CH:10]=[C:9]([NH2:11])[N:8]=[CH:7]1)[CH3:2]
Reactant: CCCCCCC(C(=O)OCC)n1cnc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Product: CCCCCCC(C(=O)OCC)n1cnc(N)c1
Yield: 100.5 %

Procedure:
A mixture of 5.9 g of 4-nitro-α-hexyl-1H-imidazole-1-acetic acid ethyl ester, 3 g of palladium-on-carbon and 150 ml of absolute alcohol were subjected to catalytic hydrogenation. Both theoretical and actual hydrogen uptake was 73 pounds. The catalyst was removed by filtration and the filtrate concentrated in vacuo to provide 5.3 g of the desired title intermediate which was used directly.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][CH2:12][C:5]2=[C:6]([C:9]([OH:11])=O)[S:7][CH:8]=[C:4]2[CH2:3]1.[CH2:15](O)C>C(OCC)C.C1COCC1.C[Li].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:14][C:2]1([CH3:1])[CH2:13][CH2:12][C:5]2=[C:6]([C:9](=[O:11])[CH3:15])[S:7][CH:8]=[C:4]2[CH2:3]1
Reactant: CC1(C)CCc2c(csc2C(=O)O)C1
Reactant: CCO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1scc2c1CCC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (1051 mg, 5.0 mmol) in diethyl ether (15 mL) and THF (8 mL), methyllithium (7 mL of a 1.6 M solution in diethyl ether) is added. The mixture is stirred at rt for 15 min before the reaction is queched with ethanol. The mixture is diluted with 10% aq. citric acid and extracted with TBME. The organic extract is washed three times with sat. aq. NaHCO3, dried over Na2SO4 and evaporated to give crude 1-(5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (1.0 g) as a brownish oil; LC-MS: tR=1.03 min, [M+1]=209.07.
Reaction SMILES: Cl[C:2]1[C:3]([C@@H:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[S:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=3)=[CH:11][CH:10]=2)[CH3:8])=[N:4][S:5][N:6]=1.[OH-:25].[Na+]>CO>[F:22][C:21]([F:24])([F:23])[C:19]1[N:20]=[C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([C@H:7]([C:3]3[C:2]([OH:25])=[N:6][S:5][N:4]=3)[CH3:8])=[CH:10][CH:11]=2)[S:17][CH:18]=1
Reactant: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1nsnc1Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1nsnc1O
Temperature: 50 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
Intermediate 14b (1.09 g, 2.80 mmol) was dissolved in a solution of NaOH (0.11 g, 2.75 mmol) in CH3OH (10 ml). The reaction mixture was stirred for 1 h at 50° C. and then quenched with a saturated solution of NH4Cl (10 ml); the aqueous layer was extracted with CH2Cl2 (2×10 ml) and the combined organic phases, after drying over anhydrous Na2SO4, were evaporated under vacuum and crystallized from n-heptane to give the pure 4-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]-1,2,5-thiadiazol-3-ol (14) (0.625 g, 1.68 mmol) as a white solid (60%). [α]D=−33 (c=1; CH3OH); 1H-NMR (CDCl3): δ 9.25 (bs, 1H, NH), 8.35 (bs, 1H, OH), 7.40 (d, 2H, J=7 Hz), 7.25 (d, 2H, J=7 Hz), 7.00 (s, 1H), 3.85 (q, 1H, J=7 Hz) 1.75 (d, 3H, J=7 Hz).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][CH:9]=2)[C:5](=[O:23])[CH2:4]1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([N:6]2[C:5](=[O:23])[CH2:4][C@H:3]([NH:2][C:31](=[O:33])[CH3:32])[CH2:7]2)=[CH:13][CH:12]=1
Reactant: N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 11.3 mmol of (S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride in 86 ml of dichloromethane was treated with 23.8 mmol of triethylamine and cooled to 0° C. To this solution, 12.5 mmol of acetylchloride were added and stirring at 0° C. was continued for 15 min. For the working-up, the reaction mixture was extracted twice with 100 ml of water. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The crude product was triturated in 100 ml of toluene, then the solid collected on a filter funnel. In a second step, the product was triturated in 200 ml of tert-butylmethylether at RT. Again, the solid product was collected on a filter funnel and dried under high vacuum. There was obtained (S)-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide as a white solid. MS: m/e=343 (M+H)+; enantiomeric excess: >99.5%.
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14])[CH:7]=[O:8].[C-:17]#[N:18].[K+].OS([O-])=O.[Na+]>C(OCC)(=O)C.O>[F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH:7]([OH:8])[C:17]#[N:18])[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14]
Reactant: [C-]#N
Reactant: O=Cc1ccc(OC(F)F)c(OC(F)F)c1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC(O)c1ccc(OC(F)F)c(OC(F)F)c1
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To 132A (470 mg, 2.0 mmol) in ethyl acetate (5 mL) was added a solution of KCN (676 mg) and NaHSO3 (1.08 g) dissolved in H2O (5 mL). It was left stirring overnight before it was extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried and concentrated. The crude product was purified by silica gel chromatography to give 132B (383 mg, 72% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.56 (d, J=5.27 Hz, 1H) 6.32-6.77 (m, 2H) 7.32-7.36 (m, 1H) 7.40-7.44 (m, 1H) 7.45 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([NH2:14])=[C:12]([C:15]2[CH:16]=[N:17][N:18]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:19]=2[C:20]([F:23])([F:22])[F:21])[O:11][N:10]=1.O.[CH:32](O)=[O:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([NH:14][CH:32]=[O:33])=[C:12]([C:15]2[CH:16]=[N:17][N:18]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:19]=2[C:20]([F:21])([F:23])[F:22])[O:11][N:10]=1
Reactant: Nc1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Reactant: O=CO
Solvent: O
Product: O=CNc1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
3-(2-chloro-6-fluorophenyl)-5-(1-(3-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazol-4-amine (example B-36) (40 mg, 0.1 mmol) was dissolved in formic acid (3 mL). The mixture was stirred at room temperature overnight. To the reaction mixture was added water. The resulting precipitate was collected, washed with water and dried under vacuum. The product was purified by pTLC (EE/PE 2:1) to give 32 mg of the desired product (example B-48) (yield 75%). Result of LC/MS MH+: 484.82; NMR (CDCl3): 6.63 (t, 1H), 7.22 (m, 1H), 7.38-7.59 (m, 6H), 8.02 (s, 1H) 8.22 (s, 1H)
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][C:17]=1[F:30].Cl>O1CCCC1.C1(C(F)(F)F)C=CC=CC=1>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:5]([C:4](=[O:3])[CH2:11][CH2:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:17]([F:30])[CH:18]=1)#[N:29]
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(F)c1
Reactant: CCCC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: FC(F)(F)c1ccccc1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a mixture of 3′-fluoro-4′-methylbiphenyl-2-carbonitrile (110 g), N-bromosuccinimide (97.3 g) and benzotrifluoride (1.0 L) was added azobisisobutyronitrile (1.71 g), and the mixture was heated to an internal temperature of 78° C. and stirred for 16 hr. The reaction mixture was cooled to around 40° C., and the insoluble material was removed to give a solution of 4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile in benzotrifluoride. To a suspension of sodium hydride (60% in oil, 25 g) in tetrahydrofuran (750 mL) was added dropwise a solution of ethyl 3-oxohexanoate (164 g) in tetrahydrofuran (250 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hr, and a solution of 4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile in benzotrifluoride above mentioned was added at 0° C. The reaction mixture was further stirred at room temperature for 16 hr, and added to 1 M hydrochloric acid (1.0 L), and the obtained mixture was concentrated under reduced pressure. The obtained mixture was extracted with ethyl acetate, and the obtained extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless oil (145 g, 76%).
Reaction SMILES: [CH2:1]([NH2:5])[C:2](=[CH2:4])[CH3:3].Cl[CH2:7][CH2:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:12]1([S:9]([CH2:8][CH2:7][NH:5][CH2:1][C:2](=[CH2:3])[CH3:4])(=[O:11])=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=C(C)CN
Reactant: O=S(=O)(CCCl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C(C)CNCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A solution of methallylamine (8.0 g; 1.12 mol), in toluene (20 ml) was added dropwise to a solution of 1-chloro-2-phenylsulphonylethane (11.54 g; 56.4 mmol) in toluene (100 ml) at 0° C. When the addition was complete the reaction mixture was allowed to warm to room temperature and stirred for 1 hr. Thin layer chromatography indicated that all of the starting material had been consumed. Ether (150 ml) was added and the precipitate filtered off. Removal of the solvent from the filtrate produced a colourless oil which was subjected to silica gel column chromatography using ethyl acetate as eluent. Fractions containing the component Rf=0.37 (ethyl acetate) were combined and evaporated to give the title amine as a colourless oil, in 75% yield.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:36]=[CH:35][CH:34]=[CH:33][C:14]=1[C:15]([C:17]1[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:18]=1[NH:24][C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=O>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:36]=[CH:35][CH:34]=[CH:33][C:14]=1[C:15]1[C:17]2[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:18]=2[NH:24][C:25](=[O:32])[C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CC(=O)Nc1sc(CC)cc1C(=O)c1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c(-c2ccccc2Cl)c2cc(CC)sc2[nH]c1=O
Yield: 33.1 %

Procedure:
To a solution of DBU (5.2 g) in toluene (50 ml) was added dropwise a solution of 3-(2-chlorobenzoyl)-2-ethoxycarbonylacetylamino-5-ethylthiophene (6.5 g) in toluene (30 ml) over one hour with stirring under reflux. After refluxing for 7 hours, the mixture was washed with water and dried over MgSO4, and then the solvent was distilled off. The residue was chromatographed on a silica gel column and eluted with hexane-acetone (5:1). The solvent was distilled off and hexane was added to obtain ethyl 4-(2-chlorophenyl)-6,7-dihydro-2-ethyl-6-oxothieno[2,3-b]pyridine-5-carboxylate as crystals (2.05 g, 33.1%). The crystals were recrystallized from ethanol to obtain light yellow prisms, mp: 126°-127° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].F[C:38](F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCCCC1CCCN(C(OCC2C=CC=CC=2)=O)C1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][CH:24]1[CH2:23][CH2:22][CH2:21][N:20]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:38]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Reactant: O=C(O)C(F)(F)F
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C(OCc1ccccc1)N1CCCC(CCCCBr)C1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCCN(C(=O)OCc4ccccc4)C3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and phenylmethyl 3-(4-bromobutyl)-1-piperidinecarboxylate. LCMS (System B): tRET=3.08 min; MH+ 511
Reaction SMILES: [N:1]([O-:3])=O.[Na+].C(CC(O)=O)C1C=CC=CC=1.[CH2:16]([O:23][C:24](=[O:29])[CH2:25][C:26]([CH3:28])=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.C(O)(=O)C>[CH2:16]([O:23][C:24](=[O:29])[CH2:25][C:26]([CH:28]=[N:1][OH:3])=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)CC(=O)OCc1ccccc1
Reactant: O=N[O-]
Agent: O=C(O)CCc1ccccc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(C=NO)CC(=O)OCc1ccccc1

Procedure:
450 g of Sodium nitrite in 600 ml of water are added dropwise, at 0° over 3 hrs. to a solution of 1000 ml acetoacetic acid benzylester (benzylacetate) in 1000 ml of glacial acetic acid and the mixture stirred for 18 hrs. at room temperature. After the addition of 3000 ml of water the mixture is extracted three times with 1500 ml portions of dichloromethane. The combined extracts are washed twice with 500 ml portions of water. Potassium carbonate is added with thorough stirring until the aqueous phase is neutral. The organic phase is separated, dried with magnesium sulphate and the solvent removed in vacuum. The residue is taken up in 5000 ml of di-isopropyl ether, the insoluable material filtered off and the solution again evaporated to dryness. Trituration with petroleum ether and filtration yields the title product.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[NH:10][CH:11]([CH2:31][OH:32])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>N1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:33])[NH:10][CH:11]([CH2:31][O:32][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:15]([C:27]([CH3:30])([CH3:28])[CH3:29])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(CC(CO)NC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(CC(COS(C)(=O)=O)NC(=O)OCc2ccccc2)ccc1OCc1ccccc1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of 2-(4-benzyloxy-3-t-butylphenyl)-1-hydroxymethylethylcarbamic acid benzyl ester (1.87 g, 4.18 mmol) in pyridine (42 ml), methanesulfonyl chloride (0.36 ml, 4.60 mmol) was added under cooling with ice. After stirring for 1 hour, the mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure, giving the titled compound (1.93 g, 88%).