Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15](I)=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][S:27][C:28]1[N:33]=[C:32]([Sn](CCCC)(CCCC)CCCC)[CH:31]=[CH:30][N:29]=1.[F-].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:30]3[CH:31]=[CH:32][N:33]=[C:28]([S:27][CH3:26])[N:29]=3)=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3c(OCc4ccccc4)cccn3c2I)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(SC)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)nc3c(OCc4ccccc4)cccn23)n1
Temperature: 110 °C
Yield: 38.7 %

Procedure:
To a mixture of 8-(benzyloxy)-2-(4-fluorophenyl)-3-iodoimidazo[1,2-a]pyridine (0.15 g, 0.35 mmol) and dichlorobis(triphenylphosphine)palladium(II) (30 mg, 0.0035 mmol) in toluene (3 mL) was added 2-(methylsulfanyl)-4-(tributylstannyl)pyrimidine (0.19 g, 0.46 mmol). The mixture was heated to 110° C. in a sealed tube for 16 hours. The reaction was allowed to cool and was diluted with ethyl acetate before being poured into a 10% aqueous potassium fluoride solution. The mixture was extracted with ethyl acetate. The organic phase was concentrated and the residue purified by silica chromatography, eluting with dichloromethane and then 5% acetone in dichloromethane to yield 60 mg (39%) of 8-(benzyloxy)-2-(4-fluorophenyl)-3-[2-(methylsulfanyl)pyrimidin-4-yl]imidazo[1,2-a]pyridine. 1H NMR (CDCl3): δ 9.18 (d, 1H), 8.33 (d, 1H), 7.68 (dd, 2H), 7.54 (2H), 7.41 (m, 3H), 7.16 (t, 2H), 6.83 (m, 2H), 6.70 (d, 1H), 5.46 (s, 2H), 2.67 (s, 3H). MS m/z 443 (M+1).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][C:9](=[O:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]1([C:7]2[NH:8][C:9](=[O:18])[N:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCCCCBr
Reactant: O=C1N=C(c2ccccc2)C(c2ccccc2)=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCCCCCn1c(-c2ccccc2)c(-c2ccccc2)[nH]c1=O

Procedure:
4,5-Diphenylimidazol-2-one was treated with ethyl 8-bromooctanoate and potassium carbonate in butanone to give after work-up the title compound, m.p. 78°-79° C, Found:C, 73.7;H, 7.4;N, 6.7%;C25H30N2O3 requires: C, 73.9;H, 7.4;N, 6.9%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[NH:14])[C:12]3[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=4)=[N:16][NH:17][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.O1CCOCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:13]2[N:14]=[CH:9][N:10]=[C:11]3[NH:17][N:16]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=4)[C:12]=23)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(Nc2n[nH]c3ncn(-c4cccc(Cl)c4)c(=N)c23)c1
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Temperature: 0 °C

Procedure:
A mixture of 0.9 g (2.45 mmol) of 5-(3-chloro-phenyl)-1,5-dihydro-4-imino-3-(3-methoxy-phenylamino)-4H-pyrazolo[3,4-d]pyrimidine, 18 ml of dioxane and 18 ml of water is heated under reflux for 10 hours. Cooling to 0° C., filtering and recrystallization from methanol/water and from methanol yield the title compound; m.p. 203-204° C.
Reaction SMILES: [K].[CH3:2][C:3]1([CH3:10])[O:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[C:11]1([C:21](Cl)=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C>O1CCCC1>[CH3:2][C:3]1([CH3:10])[O:7][C:6](=[O:8])[N:5]([C:21]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:22])[C:4]1=[O:9]
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CC1(C)OC(=O)NC1=O
Agent: [K]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
5,5-Dimethyl-2,4-oxazolidinedione potassium salt (84 mg) was suspended in tetrahydrofuran (1 mL), 1-naphthoyl chloride (95 mg) was added, and the mixture was stirred at room temperature overnight. To the reaction solution was added 4 mL of ethyl acetate, and the solution was filtered with a membrane filter (0.25 μm). The resulting organic layer was purified by silica gel chromatography (hexane:ethyl acetate=2:1), and further recrystallized from ethyl acetate/IPE to obtain 61 mg of white crystals.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:29]=[CH:28][C:14]3[NH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([N+:25]([O-])=O)[CH:19]=4)=[N:17][C:13]=3[CH:12]=2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]>[Pd].C(OCC)(=O)C.CO>[CH2:1]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:29]=[CH:28][C:14]3[NH:15][C:16]([C:18]4[CH:19]=[C:20]([NH2:25])[C:21]([NH2:24])=[CH:22][CH:23]=4)=[N:17][C:13]=3[CH:12]=2)[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(c2ccc3[nH]c(-c4ccc(N)c([N+](=O)[O-])c4)nc3c2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCN1CCN(c2ccc3[nH]c(-c4ccc(N)c(N)c4)nc3c2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-[5-(4-butyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-2-nitro-phenylamine (1.0 g, 2.5 mmol) in 4:1 ethyl acetate/methanol (100 ml) under nitrogen, was added 5% palladium on carbon (120 mg) and the mixture was first evacuated and then stirred at room temperature under an atmosphere of hydrogen for 1 day. The reaction mixture was then filtered through Celite, washed with 1:1 ethyl acetate/methanol (10 mL) and the combined filtrate and washings were concentrated to give the crude 4-[5-(4-butyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-benzene-1,2-diamine as an orange solid that was used in the next step without any purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.Cl[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:5]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: Clc1ncccn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ncccn2)cn1
Yield: 68 %

Procedure:
As described for Example 12, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (100 mg, 0.44 mmol) using 2-chloropyrimidine instead of 4-fluoroacetophenone was converted to the title compound (92 mg, 68%) which was obtained as an off-white solid. MS: m/e=304.0 [M+H]+.
Reaction SMILES: [H-].[Li+].C([Al+]CC(C)C)C(C)C.[H-].C([O:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:19]=1[O:27][CH2:28][CH2:29][CH3:30])CC>C1COCC1>[CH:24]([C:20]1[C:19]([O:27][CH2:28][CH2:29][CH3:30])=[C:18]([CH2:17][OH:16])[CH:23]=[CH:22][CH:21]=1)([CH3:26])[CH3:25]
Reactant: CCCOC(=O)c1cccc(C(C)C)c1OCCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCOc1c(CO)cccc1C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
Diisobutylaluminum lithium hydride (40.8 mL of a 1.0 M in hexanes, 40.8 mmol) was added dropwise to an ice-cold solution of 3-isopropyl-2-propoxybenzoic acid propyl ester (3.60 g, 13.6 mmol) in THF (30 mL). After the addition was complete, the ice bath was removed and the reaction mixture was stirred at ambient temperature for 18 h. The reaction was cooled to 0° C. and HCl (1N, 180 mL) was added until all the resulting solids returned to solution. The mixture was extracted with EtOAc (3×150 mL). The combined organics were washed with brine (2×200 mL), dried (Na2SO4) and concentrated to yield the title compound (2.76 g, 97%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.25 (d, J=6.3 Hz, 1H), 7.17 (d, J=5.9 Hz, 1H), 7.10 (t, J=7.5 Hz, 1H), 5.02 (t, J=5.6 Hz, 1H), 4.52 (d, J=5.5 Hz, 2H), 3.68 (t, J=6.4 Hz, 2H), 3.32-3.25 (m, 1H), 1.77-1.70 (m, 2H), 1.16 (d, J=6.9, 6H), 1.02 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].Cl>O1CCOCC1.O>[Cl:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20]([NH:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])=[O:21]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NS(=O)(=O)c1ccccc1)c1ccc(Cl)cc1Cl

Procedure:
To a mixture of phenylsulfonamide (0.16 mol; 25.12 g) and potassium carbonate (0.2 mol; 27.6 g) in 500 mL dioxane is added dropwise 2,4-dichlorobenzoyl chloride (0.13 mole; 18.0 mL). The mixture is warmed to reflux under nitrogen for 16 hr. The reaction is then diluted with water (500 mL), neutralized to pH 5 with concentrated hydrochloric acid, and extracted 3 times with ethyl acetate. The combined ethyl acetate layers are washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure to a white solid. The solid residue is subjected to silica gel chromatography, eluting with dichloromethane containing from 0–5% methanol. Fractions containing the product are combined and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[CH:7][CH:8]=1.CC1C=CC(S([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]2[C:26](=[O:42])[N:27]([C:38]([CH3:41])([CH3:40])[CH3:39])[S:28](=[O:37])(=[O:36])[C:29]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=O)=O)=CC=1>>[C:38]([N:27]1[C:26](=[O:42])[C:25]([NH:24][CH2:23][CH2:22][CH2:21][O:20][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=2)=[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:28]1(=[O:37])=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Reactant: COc1cccc(O)c1
Product: COc1cccc(OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)c1
Yield: 65 %

Procedure:
The title compound was prepared as described for Example 12 from 3-methoxyphenol and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate with a reaction time of 15 mins. The reaction mixture was evaporated and the crude product was purified by silica gel column chromatography (Horizons Biotage) using 15% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.070 g, 65%). 1H NMR (500 MHz CDCl3): δ 7.54-7.45 (m, 2H), 7.45 (m, 3H), 7.18 (t, 1H), 6.53 (dd, 1H), 6.48-6.42 (m, 2H), 5.79 (t, 1H), 3.89 (t, 2H), 3.82 (s, 3H), 3.12-3.06 (m, 2H), 1.86-1.82 (m, 2H), 1.75 (s, 9H); 13C NMR (125 MHz CDCl3): δ 161.1, 159.8, 159.7, 135.3, 131.8, 130.2, 129.7, 128.8, 125.3, 107.2, 107.1, 106.6, 101.2, 66.2, 61.7, 55.5, 42.6, 28.9, 27.8; Mass Spectrum M+H+ 445.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:3]=[C:4]([CH3:9])[C:5]([NH2:6])=[CH:7][CH:8]=2)=[CH:13][CH:12]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(-c2ccc(Cl)cc2)ccc1N
Temperature: 80 °C
Yield: 70.8 %

Procedure:
To a stirred, degassed solution of 4-bromo-2-methylaniline (20 g, 0.107 mol) in toluene (1200 ml) and ethanol (400 ml), under an atmosphere of nitrogen, is added 4-chlorophenylboronic acid (20.32 g, 0.13 mol) and the reaction mixture is stirred and heated to 80° C. Tetrakis(triphenylphosphine)palladium(0) (2.48 g, 0.002 mol) is added to the reaction mixture, and to this is added 2M aqueous potassium carbonate solution (160 ml). The reaction mixture is refluxed for 4 hours, then cooled to room temperature. The reaction mixture is filtered through diatomaceous earth, and the filtrate is evaporated under reduced pressure. The residue is partitioned between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate (3×500 ml) and the organic extracts are combined and concentrated under reduced pressure to give 4′-chloro-3-methylbiphen-4-ylamine (16.5 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[CH2:13]([Mg]Cl)[CH2:14][CH2:15][CH3:16]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:11])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCCC[Mg]Cl
Product: CCCCC(O)c1ccc(C(=O)OC)cc1

Procedure:
This compound is made from 4-formyl-benzoic acid methyl ester and n-butyl magnesium chloride following the general method exemplified in Preparation 1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[C:7][CH2:8][CH2:9][CH:10]=O.[Cl-].[CH2:13]([N:17]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:18](=[O:20])[CH3:19])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([NH:17][C:18](=[O:20])/[CH:19]=[CH:10]/[CH2:9][CH2:8][C:7]#[C:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: O=CCCC#Cc1cccs1
Reactant: CC(=O)N(CC(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: CC(C)CNC(=O)/C=C/CCC#Cc1cccs1

Procedure:
N-isobutyl 7-thienyl-(2E)-hepten-6-ynamide was prepared from 5-thienyl-4-pentyn-1-al and N-isobutyl acetamidotriphenyl-phosphonium chloride as in Example 9 and then converted to the title product by semi-hydrogenation as in Example 9.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:12][C:13]([F:25])([F:24])[C:14]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)([F:16])[F:15]>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:21][C:20]1[CH:19]=[CH:18][C:17]([C:14]([F:15])([F:16])[C:13]([Cl:12])([F:24])[F:25])=[CH:23][CH:22]=1)=[O:9]
Reactant: Nc1ccc(C(F)(F)C(F)(F)Cl)cc1
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 9.3 using 5-bromo-6-chloronicotinic acid and 4-(2-chloro-1,1,2,2-tetrafluoroethyl)aniline (Stage 31.3) to afford a beige crystalline powder. HPLC (Condition 4) tR=6.77 min, UPLC-MS (Condition 3) tR=1.31 min, m/z=444.8 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([NH2:20])[N:3]=1.[H-].[Na+].BrCCCC[C:28]1[NH:29][CH:30]=[CH:31][N:32]=1>CN(C=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[O:13][CH2:11][CH2:12][CH2:14][CH2:16][N:29]2[CH:30]=[CH:31][N:32]=[CH:28]2)=[C:4]([NH2:20])[N:3]=1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: BrCCCCc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3OCCCCn3ccnc3)c2n1
Reaction time: 8 h

Procedure:
2,6-Diamino-(9-β-D-ribofuranosyl)purine (5.0 g) in DMF (400 ml) was treated with sodium hydride (0.78 g). After stirring an additional 30 min a further portion of sodium hydride (2.6 g) was added immediately followed by bromobutylimidazole (9.9 g) in DMF (25 ml). The reaction mixture was stirred overnight and quenched with H2O. The reaction mixture was filtered through celite and evaporated to yield an oily product. TLC showed a mixture of isomers.
Reaction SMILES: C(O[C:5]1[CH:19]=[CH:18][C:8]([NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][N:23]2[CH3:28])[CH:6]=1)(=O)C.Cl.[OH-:30].[Na+]>>[OH:30][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:8]2[CH:18]=[CH:19][CH:5]=[CH:6][C:7]=2[CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][N:23]2[CH3:28])=[O:17])=[CH:12][CH:13]=1
Reactant: [OH-]
Reactant: CC(=O)Oc1ccc(NC(=O)c2ccccc2)c(CCC2CCCCN2C)c1
Agent: Cl
Agent: [Na+]
Product: CN1CCCCC1CCc1ccccc1NC(=O)c1ccc(O)cc1

Procedure:
4'-Acetoxy-2'-[2-(1-methyl-2-piperidyl)-ethyl]benzanilide suspended in 1N sodium hydroxide is stirred until solution takes place. The pH of the aqueous solution is adjusted to 9 with 6N hydrochloric acid and an oil precipitates which is extracted with ethyl acetate. The product isolated by removal of the ethyl acetate solvent is crystallized from ethanol to provide analytically pure 4-hydroxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, m.p. 178.5°-182.5° C. (corr.).
Reaction SMILES: Cl[CH:2]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:6])[CH3:3].CN1CCOCC1.[C:32]([OH:37])(=[O:36])[CH:33]([CH3:35])[CH3:34]>ClCCl>[C:32]([O:37][CH:2]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:6])[CH3:3])(=[O:36])[CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)CC(CNC(=O)OC(C)Cl)CC(=O)OCc1ccccc1
Reactant: CC(C)C(=O)O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)CC(CNC(=O)OC(C)OC(=O)C(C)C)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of (40) (0.53 g, 1.50 mmol) in isobutyric acid (1 mL) was added to a mixture of isobutyric acid (0.96 mL, 10.8 mmol) and N-methylmorpholine (1.14 mL, 10.4 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with dichloromethane, washed successively with water, 10% aqueous NaHCO3 solution and brine, then dried over anhydrous Na2SO4. After filtration and removal of the solvent in vacuo, the residue was purified by flash chromatography on silica gel, eluting with 5% ethyl acetate in hexane to afford the title compound (41) as a mixture of two diastereomers (400 mg, 66%). 1H—NMR (CDCl3, 400 MHz): δ 0.85 (m, 6H), 1.14 (m, 8H), 1.44 (m, 3H), 1.62 (m, 1H), 2.13 (m, 1H), 2.32 (m, 2H), 2.51 (m, 1H), 3.06 (m, 1H), 3.24 (m, 1H) 4.95 (m, 1H), 5.10 (s, 2H), 6.76 (q, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([C:10]([O:12]CC)=O)[NH:4][N:3]=1.[OH-].[NH4+:16]>>[CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([C:10]([NH2:16])=[O:12])[NH:4][N:3]=1
Reactant: CCOC(=O)c1[nH]nc(C)c1[N+](=O)[O-]
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Yield: 95.8 %

Procedure:
Ethyl 3-methyl-4-nitropyrazole-5-carboxylate (82.5 g, 0.41 mol) was heated at reflux in 600 ml of concentrated ammonium hydroxide for 2 hours. Concentrated ammonium hydroxide (100 ml) was added and the solution was heated at reflux for an additional three hours. The solution was concentrated in vacuo until the product began to crystallize. The crude material was recrystallized from 700 ml of water to give 47 g product, m.p. 218°-220° (decomp). From the mother liquor was recovered 25 g of 3-methyl-7-nitropyrazole-5-carboxylic acid. Based on the amount of nitro acid consumed, the yield was 95.8%.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][C:2]1=[O:8].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:1]2[CH:6]=[CH:5][C:4](=[O:7])[NH:3][C:2]2=[O:8])=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccn(-c2ccc([N+](=O)[O-])cc2)c(=O)[nH]1
Temperature: 80 °C

Procedure:
A mixture of 3.5 g 1H-Pyrimidine-2,4-dione and 3 g 1-Fluoro-4-nitro-benzene and 13.8 g Cs2CO3 in 60 mL DMF was heated to 80° C. for 12 h. This solution was poured on to 200 mL of water and the resulting precipitate was collected by filtration to yield a bright yellow crystalline product, which was dried under reduced pressure. Yield: 2.6 g.
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10](=[O:18])[C:11]([CH3:17])([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])([CH3:8])([CH3:7])[CH3:6].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:29][C:30](=[O:64])/[CH:31]=[CH:32]/[C@:33]34[CH2:59][C:58](=[O:60])[C:57]([CH:61]([CH3:63])[CH3:62])=[C:34]3[C@@H:35]3[C@@:48]([CH3:51])([CH2:49][CH2:50]4)[C@@:47]4([CH3:52])[C@@H:38]([C@:39]5([CH3:56])[C@@H:44]([CH2:45][CH2:46]4)[C:43]([CH3:54])([CH3:53])[C@@H:42](O)[CH2:41][CH2:40]5)[CH2:37][CH2:36]3)[CH2:28][CH2:27]2)=[CH:22][CH:21]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:16][C:11]([CH3:17])([CH2:12][C:13]([O:15][C@H:42]1[CH2:41][CH2:40][C@@:39]2([CH3:56])[C@@H:44]([CH2:45][CH2:46][C@:47]3([CH3:52])[C@@H:38]2[CH2:37][CH2:36][C@H:35]2[C@@:48]3([CH3:51])[CH2:49][CH2:50][C@@:33]3(/[CH:32]=[CH:31]/[C:30]([NH:29][C:26]4([C:23]5[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=5)[CH2:27][CH2:28]4)=[O:64])[CH2:59][C:58](=[O:60])[C:57]([CH:61]([CH3:63])[CH3:62])=[C:34]32)[C:43]1([CH3:53])[CH3:54])=[O:14])[C:10]([O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[O:18]
Reactant: CC(C)(C)OC(=O)C(C)(C)CC(=O)O
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2(c3ccc(Cl)cc3)CC2)CC1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2(c3ccc(Cl)cc3)CC2)CC1=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
To a solution of DMAP (647 mg, 5.30 mmol), EDC (1016 mg, 5.30 mmol) and 4-tert-butoxy-3,3-dimethyl-4-oxobutanoic acid (663 mg, 3.18 mmol) (11) in Dichloromethane (10 mL) stirred at 20° C. for 30 min was added (E)-N-(1-(4-chlorophenyl)cyclopropyl)-3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)acrylamide (685 mg, 1.060 mmol). The reaction mixture was stirred at 20° C. for 2 h. The mixture was washed with saturated ammonium chloride, water, and saturated NaHCO3, water, and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel column eluting with Petrol ether/Ethyl acetate (5:1) to afford the product 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((1-(4-chlorophenyl)cyclopropyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (480 mg, 0.542 mmol, 51.2%) as a light yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].Cl[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(N(CC)CC)C>ClCCl>[OH:4][CH2:3][CH2:2][NH:1][C:6](=[O:7])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
944 mg(15.46 mmol) of 2-aminoethanol was dissolved in 50 ml of dichloromethane, and then 1.8 ml(12.88 mmol) of benzyl chloroformate and 2.7 ml(19.32 mmol) of triethylamine were added thereto. The mixture was stirred at room temperature for one hour. After the reaction was completed, the mixture was concentrated and 50 ml of water was added thereto to obtain a white solid. The obtained white solid was filtered and dried to give 1.94 g(9.93 mmol) of the title compound in a yield of 77%.