Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1C=N[N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][OH:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:8]=2)[CH:6]=1.C1(C(C2C=CC=CC=2)[CH2:50][NH:51]C2N=C(N3C=C([N+]([O-])=O)C=N3)N=C3C=2N=CN3[C@@H]2C[C@H](NC(=O)CO)[C@@H](O)[C@H]2O)C=CC=CC=1>>[NH2:1][C:2]1[N:51]=[CH:50][N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][OH:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:8]=2)[CH:6]=1
Reactant: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc([N+](=O)[O-])cn4)nc32)[C@H](O)[C@@H]1O
Reactant: Nc1cnn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)c1
Product: Nc1cn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)cn1

Procedure:
The title compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-(4-amino-pyrazol-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZP3), by substituting N-{(1S,2R,3S,4R)-4-[6-(2,2-Diphenyl-ethylamino)-2-(4-nitro-imidazol-1-yl)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZU1) for N-{(1S,2R,3S,4R)-4-[6-(2,2-Diphenyl-ethylamino)-2-(4-nitro-pyrazol-1-yl)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate ZP2).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:13][CH2:12][C:5]2=[C:6]([C:9](O)=[O:10])[S:7][CH:8]=[C:4]2[CH2:3]1.Cl.[CH3:16][NH:17][O:18][CH3:19].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CS(C)=O>[CH3:19][O:18][N:17]([CH3:16])[C:9]([C:6]1[S:7][CH:8]=[C:4]2[CH2:3][C:2]([CH3:14])([CH3:1])[CH2:13][CH2:12][C:5]=12)=[O:10]
Reactant: CNOC
Reactant: CC1(C)CCc2c(csc2C(=O)O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CON(C)C(=O)c1scc2c1CCC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (20 g, 95 mmol) in DMSO (150 mL) is added N,O-dimethylhydroxylamine hydrochloride (12.06 g, 124 mmol) and DIPEA (65 mL, 380 mmol), followed by TBTU (33.59 g, 105 mmol, dissolved in DMF (70 mL)). The reaction mixture is stirred at rt for 2 h before it is poured into water/ice and extracted twice with diethyl ether (2×100 mL). The organic extracts are washed with sat. aq. NaHCO3 solution, 10% aq. citric acid solution and brine, dried over Na2SO4, filtered, evaporated and dried to give 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid methoxy-methyl-amide (23 g) as a brown oil; LC-MS: tR=1.01 min, [M+1]=254.14.
Reaction SMILES: C([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1)(C)(C)C.[C:14]([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)(=[O:17])[CH:15]=[CH2:16].Cl>C(O)(C)C.O>[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=1.[C:14]([O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)(=[O:17])[CH:15]=[CH2:16]
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Agent: C=CC(=O)OC1CCCCC1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: C=Cc1ccc(O)cc1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
Next, 130.5 g of poly(p-tert-butoxystyrene/cyclohexyl acrylate) was suspended in isopropanol. Subsequently, 30 ml of concentrated hydrochloric acid was added to the suspension, and agitated at 70 to 80° C. for four hours. The reaction liquid was cooled, and poured in 1500 ml of water, thereby precipitating a reaction product. The precipitated solid was collected by filtration, washed with water, and dried in vacuum. Thus, 85.5 g of poly(p-hydroxystyrene/cyclohexyl acrylate) was obtained as a white powdery crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]([F:21])([F:20])[F:19])=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]([F:21])([F:19])[F:20])=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(-n2nnnc2C(F)(F)F)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-n2nnnc2C(F)(F)F)cc1C(=O)O
Reaction time: 2 h

Procedure:
Combine methyl 2-methoxy-5-(5-trifluoromethyl-1H-tetrazol-1-yl)benzoate (1.46 g, 5.27 mmol) and an aqueous solution of sodium hydroxide (20 mL, 2M, 40 mmol) in methanol/tetrahydrofuran (20 mL/10 mL). After 2 hours, adjust the pH of the reaction mixture to about 2 using a 1M aqueous hydrochloric acid solution. Extract the reaction mixture with ethyl acetate and then dichloromethane. Dry the combined organic layers over MgSO4, filter, and evaporate in vacuo to give a the title compound: Rf =0.55 (silica gel, 85% chloroform/10% methanol/5% acetic acid).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[F:28][C@H:29]1[CH2:33][NH:32][C@H:31]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:30]1>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:32]1[CH2:33][C@H:29]([F:28])[CH2:30][C@H:31]1[C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](F)CN1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N2C[C@H](F)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 3.78 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 6-3 (13.5 mmol) as starting materials, respectively 2.06 g (Isomer A: colorless powder) and 2.74 g (Isomer B: colorless powder) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: C([O:5][C:6](=[O:24])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:23])[CH:13]([C:19]([F:22])([F:21])[F:20])[CH2:14][S:15][C:16](=[O:18])[CH3:17])(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:16]([S:15][CH2:14][CH:13]([C:19]([F:20])([F:21])[F:22])[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:24])=[O:5])=[O:23])(=[O:18])[CH3:17]
Reactant: CC(=O)SCC(C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)SCC(C(=O)N1CCC[C@H]1C(=O)O)C(F)(F)F

Procedure:
1-(3-Acetylthio-2-trifluoromethylpropanoyl)-L-proline tert-butyl ester (8 g.) is dissolved in a mixture of anisole (55 ml.) and trifluoroacetic acid (110 ml.). After one hour storage at room temperature the solvent is removed in vacuo and the residue is precipitated several times from ether-hexane to give 1-(3-acetylthio-2-trifluoromethylpropanoyl)-L-proline.
Reaction SMILES: Cl.CN.C[CH2:5][N:6](CC)CC.[Cl:11][C:12]1[CH:13]=[C:14]([S:19](Cl)(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[Cl:18].Cl>C(Cl)Cl.C(OCC)(=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([S:19]([NH:6][CH3:5])(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methylamine hydrochloride (5.5 g, 81.46 mmol) was dissolved in DCM (300 ml), and Et3N (40 ml, 285.11 mmol) was added thereto. The reaction solution was then cooled to 0° C.; 3,4-dichlorobenzenesulfonyl chloride (20.00 g, 81.46 mmol) dissolved in DCM (50 ml) was then added dropwise, and stirring was carried out overnight at room temperature (TLC monitoring, silica gel, ethyl acetate). When the reaction was complete, 0.5 N HCl was added, the phases were separated, and the organic phase was washed with water and dried (sodium sulfate). The solvent was removed using a rotary evaporator. Purification was carried out by column chromatography on silica gel (gradient heptane/ethyl acetate 4:1 to 2:1).
Reaction SMILES: [CH:1]1([CH:6]([CH3:11])[CH2:7][CH2:8][CH2:9][OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12](Cl)(=[O:15])[CH2:13][CH3:14]>>[C:12]([O:10][CH2:9][CH2:8][CH2:7][CH:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:11])(=[O:15])[CH2:13][CH3:14]
Reactant: CC(CCCO)C1CCCC1
Reactant: CCC(=O)Cl
Product: CCC(=O)OCCCC(C)C1CCCC1
Yield: 90.1 %

Procedure:
4-Cyclopentylpentan-1-ol (4.0 g; 23 mmol) was esterified with propionyl chloride (3.1 g; 34 mmol) according to example 3 to give 4.4 g (84.5% yield) of 4-cyclopentylpent-1-yl propanoate.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([OH:18])[C:13]([O:15]CC)=[O:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.C(O)C.[OH-].[K+]>O1CCOCC1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH:12]([OH:18])[C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: CCOC(=O)C(O)c1ccc(-n2cccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)C(O)c1ccc(-n2cccc2)cc1
Temperature: 27 °C
Reaction time: 3 h
Yield: 43.7 %

Procedure:
A mixture of ethyl 4-(1-pyrrolyl)phenylglycolate (0.49 g, 0.002 mole), ethanol (10 ml), dioxane (1.2 ml) and 2 M aqueous KOH (1.5 ml) was stirred at 27° C. for 3 hrs., and then evaporated to dryness. The residue was dissolved in H2O. The solution was acidified with acetic acid and extracted with ethyl acetate (3×15 ml). The combined extracts after washing with H2O and drying (MgSO4), evaporation and recrystallization of the residue from H2O gave 0.19 g (44%) of 4-(1-pyrrolyl)phenylglycolic acid, m.p. 168°-168.5° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].O1CCOC1.CO[C:17](OC)([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[CH3:18][C:17]1([CH3:19])[O:3][CH:2]([CH2:4][C:5]([OH:7])=[O:6])[C:1](=[O:9])[O:8]1
Reactant: O=C(O)CC(O)C(=O)O
Reactant: COC(C)(C)OC
Solvent: C1COCO1
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)C(CC(=O)O)O1

Procedure:
Marketed DL-malic acid (with the 4 reference on the above schema) is protected in the dioxolane form in toluene reflux, in the presence of 2,2-dimethoxypropane. The reaction is quantitative. The obtained product (with the 5 reference in the above schema) is directly engaged in the following step.
Reaction SMILES: [CH2:1]1[O:5][CH:4]([CH:6]([OH:9])[CH2:7][OH:8])[C@@H:3]([OH:10])[CH:2]1[OH:11].[C:12](OC)(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CO.C[O-].[Na+].[PH2]([O-])=O.[Na+]>>[CH3:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]/[CH:21]=[CH:20]\[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]([O:8][CH2:7][CH:6]([OH:9])[C@H:4]1[O:5][CH2:1][C@H:2]([OH:11])[C@H:3]1[OH:10])=[O:30]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Reactant: OCC(O)C1OCC(O)[C@@H]1O
Agent: C[O-]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Temperature: 65 °C
Reaction time: 1 h

Procedure:
After 469 g of a 70% by weight sorbitan aqueous solution (aldehyde value of sorbitan: 5.0 ppm) and 947 g of methyl oleate were charged into a 2000 mL four-neck flask fitted with a stirring apparatus, a thermometer, and a nitrogen gas inlet, dehydration was performed at 110° C. under a nitrogen stream at normal pressure for 1 hour and further at 110° C. under a nitrogen stream at 4 kPa for 1 hour. The whole was cooled to 65° C. and, after 51.0 g of a 10% by weight sodium methoxide methanol solution and 0.64 g of sodium hypophosphite were added thereto, was heated under a nitrogen stream at normal pressure to 180° C. as a reaction temperature. After the temperature reached 180° C., the reaction was carried out under a nitrogen stream at normal pressure. At the time point when the spot of methyl oleate as a raw material disappeared on thin-layer chromatography, it was judged that the reaction was completed. The reaction time was 12 hours and, after the completion of the reaction was confirmed, the product was filtrated at 80° C. to obtain sorbitan monooleate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.[CH2:29]([N:36]1[CH2:40][CH2:39][CH:38](O)[CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:38]4[CH2:39][CH2:40][N:36]([CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:37]4)=[CH:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: OC1CCN(Cc2ccccc2)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC3CCN(Cc4ccccc4)C3)cc2)cc1
Yield: 95.2 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)benzo[b]thiophene (1.17 g, 3.00 mmol), 1-benzyl-3-hydroxypyrrolidine (1.06 g, 6.00 mmol), triphenyiphosphine (1.57 g, 6.00 mmol), and DEAD (6.0 mmol) were converted to product by the procedure of Example 1 to g ive 1.57 g of the title compound. Yield: 95.3%. MS(FD) 549(M+). IR (CHCl3) ν max 3033, 3010, 2971, 2842, 1646, 1599, 1476, 1254, 1167.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:2]=1.[C:16]([O-:20])(=[O:19])[CH2:17][CH3:18].[Na+].C(OC(=O)CC)(=O)CC.[OH-].[Na+]>>[CH3:18][C:17](=[CH:12][C:11]1[CH:14]=[CH:15][C:8]([O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:9][CH:10]=1)[C:16]([OH:20])=[O:19]
Reactant: O=Cc1ccc(Oc2cccnc2)cc1
Reactant: CCC(=O)[O-]
Agent: CCC(=O)OC(=O)CC
Agent: [Na+]
Agent: [OH-]
Product: CC(=Cc1ccc(Oc2cccnc2)cc1)C(=O)O
Yield: 55.7 %

Procedure:
A mixture of 7 g of 4-(3-pyridyloxy)benzaldehyde, 4 g of sodium propionate and 8 ml of propionic anhydride was heated at a temperature of 135° to 140° C. for 2 hours. After allowing the mixture to cool, the mixture was rendered alkaline with an aqueous solution of sodium hydroxide, washed with dichloromethane and rendered acidic with acetic acid. The precipitated crystals were separated by filtration, washed with water and recrystallized from methanol to obtain 5 g (56% yield) of 2-methyl-3-[4-(3-pyridyloxy)phenyl]propenoic acid as colorless prisms having a melting point of 191°-194° C.
Reaction SMILES: [NH2:1]/[C:2](/[CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[C:3](/[C:7]#[N:8])\[C:4](Cl)=O.C([O-])(O)=O.[Na+]>C(#N)C.O>[NH2:1]/[C:2](/[CH:9]([CH2:10][CH3:11])[CH2:12][CH3:13])=[C:3](\[C:7]#[N:8])/[CH3:4]
Reactant: CCC(CC)/C(N)=C(\C#N)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCC(CC)/C(N)=C(\C)C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
3 g (15 mmol) of (2Z)-3-amino-2-cyano-4-ethyl-2-hexenoyl chloride dissolved in acetonitrile were added dropwise to a solution of 2.6 g (30 mmol) NaHCO3 in water. The solution was stirred at 25° C. for 30 min, then concentrated to dryness and the residue was taken up in methanol. The precipitate was seperated and the filtrate concencentrated to dryness again. The residue was dissolved in water and saturated KHSO4-solution was added. Filtration of the precipitate gave 2 g of the title compound (73% of theory) as a colorless solid (m. p. 150° C.)
Reaction SMILES: [CH:1]1([C:7]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[CH:19]=[CH:20][C:15]=4[N:14]4[CH:25]=[N:26][N:27]([CH3:28])[C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([C:7]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:15]=4[N:14]4[CH:25]=[N:26][N:27]([CH3:28])[C:13]4=[CH:12][N:11]23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(c1)-c1cc3c(C4CCCCC4)cccc3n1C=C1N(C)N=CN12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN1N=CN2C1=Cn1c(cc3c(C4CCCCC4)cccc31)-c1cc(C(=O)O)ccc12
Temperature: 70 °C
Yield: 78.8 %

Procedure:
To a solution of methyl 10-cyclohexyl-1-methyl-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine-7-carboxylate (173 mg, 0.406 mmol) in THF (7 mL) and MeOH (3.5 mL), was added aq NaOH (1.0N, 1.8 mL, 1.8 mmol). The reaction mixture was heated at 70° C. for 2 h and the solvents were removed. The resulting white solid residue was washed with water, isolated by centrifuge and dried under N2 to yield 10-cyclohexyl-1-methyl-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine-7-carboxylic acid (132 mg, 0.320 mmol, 79%) as a white solid, which was used without further purification. 1H NMR (500 MHz, d6-DMSO) δ 1.13-1.24 (m, 1H), 1.35-1.51 (m, 3H), 1.66-1.75 (m, 2H), 1.85-2.08 (m, 4H), 2.48 (s, 3H), 2.79-2.89 (m, 1H), 4.90 (d, J=15.6 Hz, 1H), 5.80 (d, J=15.6 Hz, 1H), 7.65-7.72 (m, 5H), 7.78-7.83 (m, 1H), 8.15 (s, 1H). LCMS: m/e 413 (M+H)+, ret time 2.01 min.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][C:12]=2[Cl:21])=[O:9])=[CH:4][CH:3]=1.[CH2:24]=O>C(O)C.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:6]2[CH2:7][C:8](=[O:9])[N:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17](=[O:19])(=[O:20])[NH2:18])=[CH:13][C:12]=3[Cl:21])[CH2:24]2)=[CH:22][CH:23]=1
Reactant: Cc1ccc(NCC(=O)Nc2ccc(S(N)(=O)=O)cc2Cl)cc1
Reactant: C=O
Solvent: O
Solvent: CCO
Product: Cc1ccc(N2CC(=O)N(c3ccc(S(N)(=O)=O)cc3Cl)C2)cc1
Temperature: 0 °C

Procedure:
2-(p-Methylanilino)-N-(2-chloro-4-sulphamoylphenyl)-acetamide (15g) was dissolved in ethanol (200 ml) and paraformaldehyde (2.5 g) in water (400ml) added thereto. The mixture was refluxed for 3 hours, cooled in ice/water and filtered to yield the title compound (6.45g), m.p. 223°-226° (ethanol).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(N(CC)CC)C.[CH2:21]([OH:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C(=O)C>[CH2:21]([O:31][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCCCCCCCCCO
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCCCCCCCCCOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
In a 1 liter flask were charged 1-fluoro-2,4-dinitrobenzene (40.94 g, 0.22 mol), triethylamine (24.29 g, 0.24 mol), 1-decanol (34.82 g, 0.22 mol), 220 g of N,N-dimethylacetamide and stirred at room temperature for 24 hours under a nitrogen atmosphere. The resultant etherified product was extracted with 1 liter of ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain crude product. Isolation and purification of the target product by silica gel chromatography afforded 57.80 g (yield: 81%) of 4-decyloxy-1,3-dinitrobenzene as yellow crystals.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH3:26][C:27]1[S:31][CH:30]=[N:29][CH:28]=1>>[CH3:26][C:27]1[S:31][C:30]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])=[N:29][CH:28]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Reactant: Cc1cncs1
Product: Cc1cnc(C(=O)c2cn(-c3cccc(-c4ccccc4C#N)c3)cn2)s1

Procedure:
This compound is prepared by method C using compound 12d and 5-methylthiazole
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:42])[C:25](=[O:41])[C:26]4[N:34]5[C:29]([CH2:30][CH2:31][CH2:32][CH2:33]5)=[CH:28][C:27]=4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:5]=1.[CH3:43]I>C1COCC1.C(Cl)Cl>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:18]=[CH:19][C:20]([N:23]([CH3:43])[C:24](=[O:42])[C:25](=[O:41])[C:26]4[N:34]5[C:29]([CH2:30][CH2:31][CH2:32][CH2:33]5)=[CH:28][C:27]=4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)[CH:5]=1
Reactant: CI
Reactant: Cc1cc(C)nc(N2CCN(c3ccc(NC(=O)C(=O)c4c(-c5ccccc5)cc5n4CCCC5)cc3)CC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(C)nc(N2CCN(c3ccc(N(C)C(=O)C(=O)c4c(-c5ccccc5)cc5n4CCCC5)cc3)CC2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 59.2 %

Procedure:
Sodium hydride (55% dispersion in oil, 24 mg, 0.56 mmol) was added to an ice-cold solution of N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetamide (prepared as described in Example 3, 200 mg, 0.37 mmol) in THF, and stirred for 10 minutes at 0° C. Methyl iodide (0.036 mL, 0.56 mmol) was added, the mixture warmed to room temperature and stirred for 30 min. The solvent was evaporated and the residue partitioned between ice-water and DCM. The organic layer was separated and washed successively with water, sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated to give a residue. This was dissolved in the minimum amount of DCM and re-precipitated by addition of petroleum ether to afford N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-N-methyl-2-oxo-2-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetamide (120 mg, 58%) as light yellow powder.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([N:17]1[CH2:22][C@@H:21]([CH3:23])[O:20][C@@H:19]([CH3:24])[CH2:18]1)[N:5]=2.[F-].[Cs+].[OH:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>C(#N)C.O.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>[CH3:24][C@@H:19]1[O:20][C@H:21]([CH3:23])[CH2:22][N:17]([C:6]2[N:5]=[C:4]3[C:9]([N:10]=[C:2]([C:32]4[CH:33]=[C:28]([OH:27])[CH:29]=[CH:30][CH:31]=4)[NH:3]3)=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:7]=2)[CH2:18]1
Reactant: OB(O)c1cccc(O)c1
Reactant: C[C@@H]1CN(c2nc(N3CCOCC3)c3nc(Br)[nH]c3n2)C[C@H](C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CC#N
Product: C[C@@H]1CN(c2nc(N3CCOCC3)c3nc(-c4cccc(O)c4)[nH]c3n2)C[C@H](C)O1
Temperature: 115 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
To a round bottom flask were added, 8-bromo-2-((2S,6R)-2,6-dimethyl-morpholin-4-yl)-6-morpholin-4-yl-9H-purine (38.2 mg, 0.096 mmol), cesium fluoride 58.4 mg, 0.39 mmol), 3-hydroxyphenylboronic acid (39.8 mg, 0.29 mmol) and tetrakis(triphenylphosphine)palladium (8.9 mg, 7.69 mmol) followed by 1 mL of acetonitrile/water solvent mixture (10/1 ratio). Suspension was heated to 115° C. and stirred overnight. Upon completion of the reaction, the suspension was cooled and solids filtered off. Solvent was removed under reduced pressure and the crude was purified directly by preparative HPLC to provide 3-[2-((2S,6R)-2,6-dimethyl-morpholin-4-yl)-6-morpholin-4-yl-9H-purin-8-yl]-phenol (18.5 mg, 47%) as yellow solid. LC/MS analysis method 7, mass (ES+) m/z 411.2, retention time 1.40 min. 1HNMR (CDCl3): 7.34 (1H, d), 7.24 (2H, m), 6.87 (1H, d), 4.35 (2H, d), 4.30 (4H, brs), 3.80 (4H, m), 3.57 (2H, m), 2.53 (2H, t), 1.16 (6H, d).