Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])(=O)[CH3:2].Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:1](=[N:12][OH:13])([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])[CH3:2]
Reactant: CC(=O)c1ccccc1N
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=NO)c1ccccc1N
Temperature: 25 °C

Procedure:
2-Acetylaniline, 33.8 gm, was added slowly to 300 ml of ethanol containing 18.3 gm of hydroxylamine hydrochloride and 27.7 gm sodium carbonate. After addition of the entire amount of 2-acetylaniline, the system was refluxed for 16 hours and then cooled to room temperature. After cooling, the ethanol was removed by stripping. Water was then added to the residue to give a precipitate. The precipitate was filtered and dried to give a pale yellow solid, m.p. 55°-60° C.
Reaction SMILES: [C:1]12([CH:11]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13]#[N:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>CCOC(C)=O.[Pd]>[C:1]12([CH2:11][CH:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:13]#[N:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: N#CC(=CC12CC3CC(CC(C3)C1)C2)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#CC(CC12CC3CC(CC(C3)C1)C2)c1ccccc1
Yield: 91.2 %

Procedure:
A solution of 3-(1-adamantyl)-2-phenylpropenenitrile (600 mg, 2.28 mmol) in EtOAc (30 mL) was treated with 10% Pd/C (70 mg), hydrogenated at 50 psi for 16 h, filtered through SiO2 and concentrated in vacuo. The residue was purified by chromatography [SiO2, EtOAc-heptane (1:1)] and the resulting solid recrystallised (heptane) to give the product (552 mg, 91%) as a white crystalline solid: mp 83-84° C; IR νmax (Nujol)/cm−1 2912, 2852, 2239, 1497, 1453, 1377, 1355, 1346, 1105, 749, 713 and 696; NMR δH (400 MHz, CDCl3) 1.50 (1H, dd, J 14.3, 3.2 Hz), 1.63 (9H, m), 1.72 (3H, m), 1.94 (1H, dd, J 14.3,10.4 Hz), 2.01 (3H, m), 3.79 (1H, dd, J 10.4, 3.2 Hz) and 7.35 (5H, m); Anal. Calcd for C19H23N: C, 85.99; H, 8.73; N, 5.28. Found: C, 85.96; H, 8.90; N, 5.27.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH2:14][NH:15][OH:16])=[C:8]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:7]=2[CH:24]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35].O>ClCCl.ClCCl.CC(C)=O>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[C:9]([CH2:14][N:15]([OH:16])[C:34](=[O:36])[CH3:35])=[C:8]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:7]=2[CH:24]=1
Reactant: CC(=O)Cl
Reactant: CC1(C)Oc2ccc(C(F)(F)F)cc2C(n2ccccc2=O)=C1CNO
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(=O)N(O)CC1=C(n2ccccc2=O)c2cc(C(F)(F)F)ccc2OC1(C)C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 44.9 %

Procedure:
A solution of 6-trifluoromethyl-2,2-dimethyl-3-(hydroxyamino)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.48 g, 1.31 mmol) in dichloromethane (13 ml) was cooled to 0° C. and treated with triethylamine (0.18 ml, 1.31 mmol) and acetyl chloride (0.1 ml, 1.31 mmol), and stirred at 0° C. for 45 minutes. Water was added, and the organic layer separated, washed with water and dried, and evaporated to give a crude product. Chromatography on silica gel eluting with dichloromethane/methanol (95/5) gave an oil which was crystallized from ether to give 0.24 g of 6-trifluoromethyl-2,2-dimethyl-3-(N-hydroxyacetamido)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 188° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].[C:7]1([CH2:13][CH2:14][C:15](Cl)=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(#N)C>[C:7]1([CH2:13][CH2:14][C:15]([NH:3][NH:2][C:1]([O:5][CH3:6])=[O:4])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COC(=O)NN
Solvent: CC#N
Product: COC(=O)NNC(=O)CCc1ccccc1
Reaction time: 15 h
Yield: 80.7 %

Procedure:
To a solution of 18 g. (0.2 moles) of methyl carbazate and 100 ml. of acetonitrile 33.7 g. (0.2 moles) of β-phenyl-propionyl chloride are added dropwise. The reaction mixture is heated to boiling for 15 hours, clarified and cooled. The crystals are filtered off. Thus 36.85 g. of the desired compound are obtained, yield 80.7%, m.p.: 118° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([OH:22])[CH:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:43][C:44]1[CH:45]=[CH:46][C:47]([F:53])=[C:48]([CH2:50][CH2:51]O)[CH:49]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:51][CH2:50][C:48]3[CH:49]=[C:44]([Cl:43])[CH:45]=[CH:46][C:47]=3[F:53])[CH:15]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:4]
Reactant: OCCc1cc(Cl)ccc1F
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)CCCCCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cc(Cl)ccc3F)c2)CCCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
The compound of step 2 (80 mg, 0.249 mmol) and triphenylphosphine (98 mg, 0.374 mmol) were dissolved in THF. 2-(5-Chloro-2-fluoro-phenyl)-ethanol (48 mg, 0.274 mmol) and DIAD (80.3 mg, 0.374 mmol) were added and the mixture was stirred at room temperature for 2 h. The volatiles were evaporated in vacuo and the residue was purified by preparative RP HPLC (water/ACN gradient) to give 85 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([Cl:19])=[O:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid (1.5 g, 6.3 mmol) in thionyl chloride (18 mL) is warmed to reflux for 1 hour. After cooling to room temperature, the reaction mixture is concentrated in vacuo to afford 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl chloride as a tan solid (1.6 g, 100%) which is used without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]2[S:29][CH:30]([CH2:33][C:34]([OH:36])=O)[CH2:31][N:32]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH:60]1[CH2:65][CH2:64][S:63](=[O:67])(=[O:66])[CH2:62][CH2:61]1>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O>[O:66]=[S:63]1(=[O:67])[CH2:64][CH2:65][N:60]([C:34](=[O:36])[CH2:33][CH:30]2[S:29][C:28]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[CH:13][C:12]([O:11][C:8]3[CH:9]=[N:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=3)=[CH:20][C:19]=4[O:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[N:32][CH2:31]2)[CH2:61][CH2:62]1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Reactant: O=S1(=O)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)N5CCS(=O)(=O)CC5)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.3 %

Procedure:
To a solution of {2-[5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (150 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (65 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg), and thiomorpholine-1,1-dioxide (76 mg), and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) and crystallized from acetonitrile to give the title compound (136 mg, yield 74%) as white crystals.
Reaction SMILES: [C:1]1([C:7]2([CH2:17][C:18]#[N:19])[CH2:16][CH2:15][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][OH:21].C(OCC)(=O)C.CCCCCC>C(O)C>[OH:21][NH:20][C:18](=[NH:19])[CH2:17][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9][C:10]2([O:11][CH2:12][CH2:13][O:14]2)[CH2:15][CH2:16]1
Reactant: NO
Reactant: N#CCC1(c2ccccc2)CCC2(CC1)OCCO2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: N=C(CC1(c2ccccc2)CCC2(CC1)OCCO2)NO
Temperature: 60 °C
Yield: 50.2 %

Procedure:
To a stirred solution of 8-phenyl-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (264) (1.5 g, 5.83 mmol) in ethanol (30 mL) was added NH2OH (50% aqueous solution, 1.1 mL, 17.49 mmol) and the reaction mixture was heated at 60° C. for 16 h. Silica thin layer chromatography was performed (ethyl acetate:Hexane=1:1, Rf=0.15). The reaction mixture was concentrated in vacuo to yield a crude mixture which was triturated with diethyl ether to obtain pure N-hydroxy-2-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-acetamidine (266) (850 mg, 50.22%) as an off-white solid which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[N:7]([CH2:12][CH3:13])[C:6](=[O:14])[C:5]2([CH3:16])[CH3:15].Br[C:18]#[N:19]>O.C1COCC1>[NH2:19][C:18]1[NH:1][C:2]2=[CH:3][C:4]3[C:5]([CH3:15])([CH3:16])[C:6](=[O:14])[N:7]([CH2:12][CH3:13])[C:8]=3[CH:9]=[C:10]2[N:11]=1
Reactant: CCN1C(=O)C(C)(C)c2cc(N)c(N)cc21
Reactant: N#CBr
Solvent: O
Solvent: C1CCOC1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(N)nc3cc21

Procedure:
Analogously to general procedure (III) 5,6-diamino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one (1.32 g) is cyclized using BrCN (3 M; 2.2 ml; 6.6 mmol) at RT in water (5 ml) and THF (13 ml). After aqueous work-up and re-crystallization from EtOAc the desired compound (1.03 g) is obtained as a solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[C:7]([CH2:9][CH2:10][NH:11][N:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:8].N1C=CC=CC=1>C(OCC)(=O)C>[C:7]([CH2:9][CH2:10][N:11]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[N:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:8]
Reactant: CCOC(=O)Cl
Reactant: N#CCCNN=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)N(CCC#N)N=Cc1ccccc1

Procedure:
1.08 g (10-2 moles) of ethyl chloroformate in solution in 5 ml of anhydrous ethyl acetate are added dropwise to a solution containing 10-2 moles of benzaldehyde (2-cyanoethyl)hydrazone and 0.79 g (10-2 moles) of anhydrous pyridine in 20 ml of anhydrous ethyl acetate, with stirring in the cold. The reaction mixture is slowly heated to reflux temperature and left stirring for 2 hours and then filtered hot.
Reaction SMILES: O1CCCC1.[C:6]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:24])[CH2:22][CH3:23])=[CH:17][CH:16]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:25]Br.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CCCCCC>[C:6]([O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21](=[O:24])[CH:22]([Br:25])[CH3:23])=[CH:19][CH:20]=1)(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: BrBr
Reactant: CCC(=O)c1ccc(OC(=O)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(Br)C(=O)c1ccc(OC(=O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 80 %

Procedure:
To a tetrahydrofuran solution (30 mL) of 3.00 g (11.9 mmol) of the p-(benzoyloxy)propiophenone, a hexane solution (5 mL) of 2.07 g (1.1 equivalents) of bromine was added at 5° C. The temperature of the mixture was elevated to room temperature, followed by 1 hour of stirring. To the resulting mixture, 30 mL of a saturated sodium hydrogen carbonate solution and 40 mL of ethyl acetate were added to conduct extraction. The organic layer was washed with 30 mL of a saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and subjected to distillation under a reduced pressure to remove the solvents. An yellow oily substance (5.54 g) was obtained as a result. This substance was crystallized from 5 mL of ethyl acetate and 30 mL of hexane. White crystals of 1-[4-(benzoyloxy)phenyl]-2-bromo-1-propanone were obtained as a result (3.147 g, isolation yield: 80%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][N:12]([CH:14](OC)OC)[CH3:13]>>[CH3:11][N:12]([CH3:14])/[CH:13]=[CH:9]/[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:10]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccc(C)c1
Product: Cc1cccc(C(=O)/C=C/N(C)C)c1
Yield: 35 %

Procedure:
The title compound was prepared in 35% yield from 1-(3-methylphenyl)ethanone and DMF-DMA according to the procedure for the preparation of Example 12, part A. 1H NMR (400 MHz, CDCl3): δ 2.39 (3H, s), 2.79-3.11 (6H, m), 5.70 (1H, d, J=12.4 Hz), 7.24-7.31 (2H, m), 7.66-7.71 (2H, m), 7.78 (1H, d, J=12.4 Hz).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[S:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1.C(O)C>>[CH3:19][C:17]1[CH:16]=[CH:15][C:14]([S:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:25][CH:26]=2)=[C:13]([NH:12][C:2]2[N:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[N:7]3)[CH:18]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Reactant: Clc1nccc2ncccc12
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(C)cc2Nc2nccc3ncccc23)cc1
Temperature: 100 °C

Procedure:
The product from Example 36e (0.040 g, 0.24 mmol) was reacted with the product from Example 22b as a 1.5M solution in ethanol (0.162 mL, 0.24 mmol) for 17.5 h at 100° C. following the procedure from Example 7g. Consumption of starting material required a second addition of the product from Example 36e (0.027 g, 0.16 mmol) and continued heating at 100° C. (24 h) giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.038 g, 27%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.02 (s, 3 H) 2.36 (s, 3 H) 7.12-7.37 (m, 5 H) 7.38-7.53 (m, 3 H) 7.73-7.92 (m, J=8.64, 4.60 Hz, 2 H) 8.94 (d, J=8.46 Hz, 1 H) 9.18 (d, J=4.04 Hz, 1 H) 9.99 (s, 1 H); MS (ESI+) m/z 401.3 (M+H)+; (ESI−) m/z 399.0 (M−H)−.
Reaction SMILES: Br[C:2]1[C:3]([NH:21][C:22]2[CH:26]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[NH:24][N:23]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([S:13]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])=[O:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:30]([Sn](CCCC)(CCCC)/C=C\C)[CH2:31][CH2:32]C>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:17]([NH:16][S:13]([C:11]1[S:12][C:8]([C:5]2[N:4]=[C:3]([NH:21][C:22]3[CH:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[NH:24][N:23]=3)[C:2](/[CH:30]=[CH:31]\[CH3:32])=[CH:7][N:6]=2)=[CH:9][CH:10]=1)(=[O:15])=[O:14])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Reactant: C/C=C\[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: C/C=C\c1cnc(-c2ccc(S(=O)(=O)NC(C)(C)C)s2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A mixture of 5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)-N-tert-butylthiophene-2-sulfonamide (497.4 mg, 1.0 mmol, 1.0 eq), Pd(PPh3)2Cl2 (28.0 mg, 0.1 mmol, 0.1 eq) and Bu4NBr (321.1 mg, 0.1 mmol, 1.0 equiv.) was flushed with nitrogen. Anhydrous dioxane (10 mL) was added and the reaction mixture was flushed with nitrogen. (Z)-tributyl(prop-1-enyl)stannane (475.4 mg, 1.5 mmol, 1.5 eq) was added and the reaction mixture was stirred at rt for 2 h. The mixture was extracted with EtOAc and washed with water, brine. The organic layers were concentrated to afford the residue, which was purified by silica gel chromatography (PE/EA/MeOH=2:1:0.06 as eluant) to afford (Z)—N-tert-butyl-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(prop-1-enyl)pyrimidin-2-yl)thiophene-2-sulfonamide (375.6 mg, 82.1%) as white solid. LC-MS (m/z)=459 [M+H]+.
Reaction SMILES: [C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[C@@H:19]1[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:21](O)[CH2:20]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Li][N:55]=[N+:56]=[N-:57].CCOC(/N=N/C(OCC)=O)=O>CN(C=O)C>[C:27]([O:26][CH2:25][C@H:23]1[O:24][C@@H:19]([N:14]2[C:15]3[N:16]=[CH:17][N:18]=[C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:11]=3[N:12]=[CH:13]2)[CH2:20][C@@H:21]1[N:55]=[N+:56]=[N-:57])(=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: [Li]N=[N+]=[N-]
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@@H](O)[C@@H](COC(=O)c2ccccc2)O1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
N6 -Benzoyl-9-(5-O-benzoyl-2-deoxy-β-D-threo-pentofuranosyl)adenine (7.0 g, 15.3 mmol), triphenylphosphine (6.0 g, 22.9 mmol), and LiN3 (2.8 g, 56.4 mmol) were dissolved in DMF (100 mL). To this stirring mixture was added diethylazodicarboxylate (3.6 mL, 22.9 mmol) in one portion, the reaction was stirred for 2.5 h at RT, and the reaction was quenched with H2O (10 mL). The solvents were removed in vacuo, the residual oil was redissolved in EtOAc (300 mL) and extracted with H2O (2×200 mL) and saturated. aq. NaCl (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residual oil was purified on SiO2 (2-5% MeOH/CH2Cl2) to afford 5'-O-Benzoyl-N2 -benzoyl-3'-azido-2',3'-dideoxyadenosine, 1a, as an amber foam, which was taken on directly to hydrogenation.
Reaction SMILES: [OH-].[K+].[CH:3]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])([CH3:5])[CH3:4].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>O>[CH:3]([CH:6]1[CH2:10][CH2:9][C:8](=[CH:17][C:16]2[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=2)[C:7]1=[O:11])([CH3:5])[CH3:4]
Reactant: CC(C)C1CCCC1=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)C1CCC(=Cc2ccc(Cl)cc2)C1=O
Temperature: 120 °C
Reaction time: 5 h
Yield: 94.2 %

Procedure:
A solution of 1.1 g of 85% strength aqueous potassium hydroxide solution and 100 ml of water was charged to a 0.31 stainless-steel autoclave, and then 25.2 g of 2-isopropylcyclopentanone and 28.1 g of 4-chlorobenzaldehyde were added, and the mixture was heated to 120° C. under the intrinsic pressure and subsequently stirred at this temperature (intrinsic pressure 1 bar) for 5 hours. After cooling to room temperature, the suspension was filtered with suction and the product was washed to neutrality with water and then dried in a vacuum oven at 55° C. In this way 46.8 g of 2-isopropyl-5-(4-chlorobenzylidene)-cyclopentanone (98.7% pure) were obtained. This corresponds to a yield of 93% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1O.[C:10]1([CH3:33])[CH:15]=[CH:14][C:13]([S:16]([O:19][CH2:20][CH2:21][O:22]S(C2C=CC(C)=CC=2)(=O)=O)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[C:10]1([CH3:33])[CH:11]=[CH:12][C:13]([S:16]([O:19][CH2:20][CH2:21][O:22][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:17])=[O:18])=[CH:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: COc1ccccc1O
Product: COc1cccc(OCCOS(=O)(=O)c2ccc(C)cc2)c1

Procedure:
Analogously to Method I, 0.500 g of methoxyphenol and 4.385 g of ethylene di(p-toluenesulphonate) are reacted. The title compound is obtained as a colourless solid. Rf=0.51 (1:1 EtOAc-heptane); Rt=4.68.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][S:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][N:20]1[C:32]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[C:24]([NH2:33])[C:23]=2[N:22]=[C:21]1[CH2:34][CH2:35][CH3:36]>C(Cl)(Cl)Cl>[CH3:12][S:13]([CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][N:20]1[C:32]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[C:24]([NH2:33])[C:23]=2[N:22]=[C:21]1[CH2:34][CH2:35][CH3:36])=[O:6]
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCOCCCSC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCOCCCS(C)=O
Reaction time: 0.33 h
Yield: 42 %

Procedure:
3-Chloroperoxybenzoic acid (0.62 g of ˜77%, 2.8 mmol) was added in portions over a period of 5 minutes to a solution of 1-{2-[3-(methylthio)propoxy]ethyl}-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.8 mmol) in chloroform (14 mL). After 20 minutes analysis by TLC showed that all of the starting material had been consumed. The reaction mixture was partitioned between dichloromethane (100 mL) and saturated aqueous sodium carbonate (50 mL). The organic layer was washed sequentially with saturated aqueous sodium carbonate (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a white foam. This material was purified by column chromatography (silica gel eluting with 95/5 dichloromethane/methanol) followed by recrystallization from ethyl acetate (60 mL) to provide 0.44 g of 1-{2-[3-(methylsulfinyl)propoxy]ethyl}-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as crystalline plates, mp 148-151° C. 1H NMR (300 MHz, DMSO-d6) δ 8.07 (d, J=8.1 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.40 (t, J=8.1 Hz, 1H), 7.22 (t, J=8.1 Hz, 1H), 6.43 (bs, 2H), 4.72 (t, J=5.0 Hz, 2H), 3.84 (t, J=5.0 Hz, 2H), 3.40 (t, J=6.2 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H), 2.46 (m, 2H), 2.39 (s, 3H) 1.86 (sextet, J=7.6 Hz, 2H) 1.71 pentet, J=7.6 Hz, 2H) 1.04 (t, J=7.6 Hz, 3H); MS (APCI) m/z 375 (M+H)+; Anal. Cacld for C19H26N4O2S: C, 60.94; H, 7.00: N, 14.96. Found: C, 60.73; H, 6.82; N, 14.85.
Reaction SMILES: O1CCOC1C[CH2:7][CH2:8][CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1.[C:34](=[O:37])([O-])O.[Na+]>CC(C)=O.Cl>[C:28]1([C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:13]2[CH:14]=[C:10]([CH2:9][CH2:8][CH2:7][CH:34]=[O:37])[N:11]=[CH:12]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc(CCCCC3OCCO3)c2)cc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: O=CCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
A suspension of the product from step b (19.8 g, 46.6 mmol) in a mixture of acetone (300 ml) and 2M hydrochloric acid (50 ml) was stirred at room temperature for 20 h. The mixture was neutralised with sodium hydrogen carbonate, filtered and the filtrate extracted with dichloromethane (3×100 ml). The combined extracts were dried over magnesium sulfate, filtered and evaporated to give the product as a colourless oil (16.1 g, 91%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=O)[CH2:22][CH2:23][C:24](OCC)=[O:25])=[C:17]([F:30])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:32][NH2:33]>C(O)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH2:22][CH2:23][C:24](=[O:25])[NH:33][N:32]=3)=[C:17]([F:30])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C3=NNC(=O)CC3)c(F)c2)CC1

Procedure:
In a 250 mL round bottom flask, 4-[4-(3-ethoxycarbonyl-propionyl)-3-fluoro-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (4.1 g, 9.68 mmol), and hydrazine monohydrate (0.97 mL, 19.4 mmol), in isopropanol (100 mL) was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. Purification with silica gel chromatography eluting with methylene chloride/methanol (95:5) produced 945 mg (25%). Mp 146-148° C. MS m/z 392 (M+H).