Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)([S:16][CH3:17])[CH2:13][C@H:12]1[C:30]([OH:32])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33]O>>[C:21]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([C@@:14]2([S:16][CH3:17])[CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[C@H:12]([C:30]([O:32][CH3:33])=[O:31])[CH2:13]2)=[CH:23][CH:22]=1
Reactant: CS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Reactant: CO
Product: COC(=O)[C@@H]1C[C@@](SC)(c2ccc(-c3ccccc3)cc2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To an iced colorless solution of (2S,4R)-1-(benzyloxycarbonyl)-4-(biphenyl-4-yl)-4-(methylthio)pyrrolidine-2-carboxylic acid (288 mg, 0.644 mmol) in MeOH (5 mL) was added (trimethylslyl)diazomethane (3.54 mL, 7.08 mmol) dropwise until it turned into light yellow (bubble was generated). The formed light yellow solution was stirred at room temperature overnight. Diluted with EtOAc, washed with 5% citric acid, and brine, dried over MgSO4, filtered, evaporated, to afford the desired product (2S,4R)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-(methylthio)pyrrolidine-1,2-dicarboxylate (267 mg, 0.578 mmol, 90% yield) as a white wax. LC-MS (retention time: 3.25 min, method B), MS m/z 462 (M+H), 414 (M-MeSH).
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][N:3]=1.[OH-].[Na+].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:16]>CO>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:15](=[O:16])[CH2:14][S:1][C:2]2[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][N:3]=2)=[CH:18][CH:19]=1
Reactant: CCCCn1cnnc1S
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCn1cnnc1SCC(=O)c1ccc(OC)cc1

Procedure:
To a solution of 3-mercapto-4-n-butyl-1,2,4-triazole (10 g. or 0.063 mole) and sodium hydroxide (2.55 g. or 0.0637 mole) in 200 ml. of methanol was added α-bromo-p-methoxyacetophenone (15.3 g. or 0.067 mole). The reaction mixture was heated at reflux for 16 hours and the solvent removed in vacuum to leave a solid residue. The solid was washed with water and recrystallized from benzene-hexane to give 3-(p-methoxy-phenacylmercapto)-4-n-butyl-1,2,4-triazole melting at 79°-82° C. The structure was confirmed by its infrared and nuclear magnetic spectra.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][CH2:5][NH:4][C:3]1=[O:7].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C1COCC1>[CH3:1][C:2]1([CH3:8])[CH2:6][CH2:5][N:4]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:3]1=[O:7]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(C)CCNC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CCN(C(=O)OCc2ccccc2)C1=O
Temperature: -78 °C
Yield: 69.3 %

Procedure:
In an oven-dried 1000 ml flask under argon was dissolved 3,3-dimethyl-2-pyrrolidinone (0.0718 mol, 8.13 g) in 200 ml THF. The resulting solution was cooled to −78° C., and lithium hexamethyldisilazide (0.0790 mol, 79 ml of a 1M solution in THF) was added over 15 min. Stirring was continued for 30 minutes, at which time benzyl chloroformate (0.0790 mol, 13.5 g) was added and the reaction was allowed to warm to room temperature and stir for 16 hr. The mixture was concentrated to ⅓ total volume and diluted with 500 ml ethyl acetate and washed with 1M HCl (2×200 ml), water (1×200 ml), and brine (1×100 ml). The organic phase was dried over MgSO4, filtered and concentrated. Purification of the crude residue on 120 g silica (ethyl acetate/hexanes) yielded 12.3 g (69%) of phenylmethyl 3,3-dimethyl-2-oxo-1-pyrrolidinecarboxylate as a light yellow oil. LCMS (ESI+)=248 m/z (M+), 270 m/z (MNa+). 1H NMR (400 MHz, CDCl3) δ 7.48-7.46 (m, 2H), 7.39-7.36 (m, 3H), 5.31 (s, 2H), 3.77-3.73 (t, 2H, J=6.96 Hz), 1.91-1.88 (t, 2H, J=7.08 Hz), 1.23 (s, 6H). 13C NMR (CDCl3) δ 178.83, 151.86, 135.35, 128.60, 128.34, 128.10, 68.00, 42.79, 42.16, 32.95, 24.28.
Reaction SMILES: Cl.[I:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[N:9][C:10]=2[NH2:12])[N:5]([CH:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:4]=1.C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[I:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[N:9][C:10]=2[NH2:12])[N:5]([CH:13]2[CH2:17][CH2:16][N:15]([CH3:20])[CH2:14]2)[N:4]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ncnc2c1c(I)nn2C1CCNC1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CN1CCC(n2nc(I)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 170.3 %

Procedure:
To a solution of rac-3-iodo-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine monohydrochloride (0.400 g, 1.09 mmol) in dichloroethane (10 mL) was added formaldehyde (37% in water, 0.12 mL, 1.63 mmol), sodium triacetoxyborohydride (0.578 g, 2.73 mmol), and acetic acid (0.37 mL, 6.55 mmol). The reaction mixture was stirred at room temperature for 3 days and then additional formaldehyde (37% in water, 0.12 mL, 1.63 mmol), sodium triacetoxyborohydride (0.578 g, 2.73 mmol), and acetic acid (0.37 mL, 6.55 mmol) were added. The reaction mixture stirred for an additional 3 h and was then concentrated to afford rac-3-iodo-1-(1-methyltetrahydro-1H-3-pyrrolyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a pale yellow solid (0.639 g) which was used in subsequent reactions without further purification. RP-HPLC Rt 4.226 min, 96% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 345 (MH+).
Reaction SMILES: [Cl:1][Si:2](Cl)([C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:24][C:25]1[CH:26]=[C:27]([Li])[CH:28]=[C:29]([CH3:31])[CH:30]=1>C(OCC)C>[Cl:1][Si:2]([C:9]1[CH:14]=[C:13]([C:15]([CH3:17])([CH3:16])[CH3:18])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:10]=1)([C:27]1[CH:26]=[C:25]([CH3:24])[CH:30]=[C:29]([CH3:31])[CH:28]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [Li]c1cc(C)cc(C)c1
Reactant: CC(C)(C)c1cc(C(C)(C)C)cc([Si](Cl)(Cl)c2ccccc2)c1
Solvent: CCOCC
Product: Cc1cc(C)cc([Si](Cl)(c2ccccc2)c2cc(C(C)(C)C)cc(C(C)(C)C)c2)c1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
Under a nitrogen atmosphere, to a diethyl ether solution (70 mL) of dichloro(3,5-di-tert-butylphenyl)(phenyl)silane (7.00 g, 19.16 mmol), a solution of 3,5-dimethylphenyllithium (2.15 g, 19.16 mmol) dissolved in diethyl ether (22 mL) was added dropwise at −20° C. After the mixture was gradually warmed to room temperature, stirring was performed at room temperature. 3,5-Dimethylphenyllithium (1.26 g, 11.24 mmol) was added and further stirred at room temperature. After completion of the reaction, the solvent was removed under reduced pressure. Thereafter, hexane was added to the residue, and insoluble materials were removed by filtration. The solvent was removed from the filtrate under reduced pressure to obtain chloro(3,5-di-tert-butylphenyl)(3,5-dimethylphenyl)(phenyl)silane (7.21 g, yield 86.5%) as yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][C:7]=1[Cl:20])[CH3:2].[CH3:22]CCCCC.CCOC(C)=O>>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:18]3[N:19]=[CH:22]2)=[CH:8][C:7]=1[Cl:20])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Nc2ncccc2N)cc1Cl
Reactant: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(-n2cnc3cccnc32)cc1Cl

Procedure:
is obtained analogously to the method as described in Step 1.2 but using [4-(3-amino-pyridin-2-ylamino)-2-chloro-phenyl]-acetic acid ethyl ester instead of [4-(3-amino-pyridin-2-ylamino)-phenyl]-acetic acid methyl ester as a starting material. ES-MS: 316.1 [M+H]+; single peak at tR=4.24 min (System 1); Rf=0.16 (Hexane/EtOAc, 1:1).
Reaction SMILES: BrBr.[Cl:3][C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][C:10](=[O:23])[C:11]([CH3:22])([CH3:21])[CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:6][CH:5]=1.[NH:26]1[CH:30]=[N:29][CH:28]=[N:27]1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)(Cl)Cl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([N:26]2[CH:30]=[N:29][CH:28]=[N:27]2)[C:10](=[O:23])[C:11]([CH3:21])([CH3:22])[CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(CSc1ccc(Cl)cc1)C(=O)COc1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(CSc1ccc(Cl)cc1)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
48 g (0.3 mol) of bromine were added dropwise to 110.5 g (0.3 mol) of 1-(4-chlorophenoxy)-4-(4-chlorophenylmercapto)-3,3-dimethyl-butan-2-one in 750 ml of carbon tetrachloride at room temperature. The mixture was subsequently stirred at room temperature for one hour and was concentrated by distilling off the solvent in vacuo, and the residue was taken up in 750 ml of toluene. 73 g (1.06 mol) of 1,2,4-triazole and 150 g (1.06 mol) of potassium carbonate were added to this solution. The mixture was heated to 90° C. for 8 hours and allowed to cool to room temperature and the organic phase was separated off. This phase was extracted with dilute sodium hydroxide solution, rinsed with water, dried over sodium sulphate and concentrated in vacuo. 34 g (26% of theory) of 1-(4-chlorophenoxy)-4-(4-chlorophenylmercapto)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one of melting point 115° C. were obtained.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].O=[C:6]1[CH:10]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[CH2:9][CH2:8][CH:7]1[C:21](OCC)=[O:22].O>CO>[F:19][C:17]([F:18])([F:20])[C:14]1[N:13]=[CH:12][C:11]([CH:10]2[C:6]3[N:1]=[C:2]([OH:3])[N:4]=[C:21]([OH:22])[C:7]=3[CH2:8][CH2:9]2)=[CH:16][CH:15]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)C1CCC(c2ccc(C(F)(F)F)nc2)C1=O
Solvent: O
Solvent: CO
Product: Oc1nc(O)c2c(n1)C(c1ccc(C(F)(F)F)nc1)CC2
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a melt of urea (748 mg, 12.45 mmol) at 150° C. was added ethyl 2-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopentanecarboxylate (750 mg, 2.49 mmol) dropwise. The reaction was stirred overnight. The reaction mixture was cooled and the resulting solid mass was broken up and suspended in MeOH. The mixture was diluted with a large excess of water and cooled in an ice bath. The suspension was filtered and the residue was washed with water and dried to afford the semi-pure product, 7-(6-(trifluoromethyl)pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diol (334 mg, 1.124 mmol, 45.1% yield). LC-MS (M+H)+=298.0.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1F
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(F)cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Benzyl alcohol (3.25 g, 30 mmol) was slowly added to a stirred suspension of sodium hydride (1.15 g, 28.7 mmol) in toluene (50 mL) at room temperature. The mixture was stirred for 30 minutes and then 2,4-difluorobenzonitrile was added all at once and stirring continued overnight. The mixture was quenched with water, extracted three times with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and condensed. The crude product was dissolved in hot ethyl acetate and triturated with hexanes to give 2-(benzyloxy)-4-fluorobenzonitrile (5.4 g, 23.8 mmol, 88% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 5.30 (s, 2H), 6.99 (td, J=8.46, 2.42 Hz, 1H), 7.29-7.51 (m, 6H), 7.86 (dd, J=8.59, 6.44 Hz, 1H).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.[CH2:17](OCC)C.CO.Cl>S(Cl)(Cl)=O.[Li].[Cu]>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8](=[O:10])[CH3:17])=[CH:5][CH:6]=1
Reactant: CCOCC
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Agent: [Cu]
Agent: Cl
Agent: [Li]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: CC(=O)Cc1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Yield: 96 %

Procedure:
10.5 g of 4-biphenylylacetic acid was dissolved in 50 ml of thionyl chloride, and the solution was heated at 80° C. for 3 hours. Then, excess thionyl chloride was distilled off under reduced pressure. Benzene was added to the residue, and the solvent was again distilled off. This operation was repeated again. Then, the formed acid chloride was dissolved in 100 ml of ethyl ether. Separately, 23.7 g of cuprous iodide was suspended in 50 ml of ethyl ether, and 166 ml of a 1.5M methyllithiumethyl ether solution was added thereto with stirring under cooling with ice to obtain a uniform solution. This solution was dropwise added to the ethyl ether solution of the acid chloride obtained by the above reaction under a nitrogen atmosphere while stirring and cooling to -70° C. After completion of the dropwise addition, the mixture was stirred at the same temperature for further one hour. Then, methanol was added thereto to decompose the excess copper lithium reagent. Ethyl ether and 2N hydrochloric acid were added to the reaction solution. After removing the formed insoluble matters by filtration, the filtrate was subjected to liquid separation. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure to obtain 9.93 g (yield: 96%) of the above-identified compound as colorless oily substance.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4[CH:21]=O)[C:11]3=[O:23])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:38][C:39]1[NH:43][N:42]=[C:41]([NH2:44])[CH:40]=1>C(O)(=O)C>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][C:20]=4[CH2:21][NH:44][C:41]4[CH:40]=[C:39]([CH3:38])[NH:43][N:42]=4)[C:11]3=[O:23])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=Cc1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Reactant: Cc1cc(N)n[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(NCc2ccncc2N2CCN(c3ccc4ncsc4c3)C2=O)n[nH]1
Yield: 3.2 %

Procedure:
3-(3-benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-pyridine-4-carbaldehyde (I-177b: 100 mg, 0.308 mmol) was reacted with NaBH(OAc)3 (131 mg, 0.616 mmol), 5-methyl-1H-pyrazol-3-ylamine (40 mg, 0.370 mmol) and acetic acid (10 mL) to afford the crude product. Purification by column chromatography on silica gel (5% MeOH in CHCl3), followed by preparative HPLC afforded 4 mg of the product (7.7% yield).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[NH:27][C:26]3[C:28]4[C:22]([C:23](=[O:29])[NH:24][N:25]=3)=[CH:21][CH:20]=[CH:19][C:18]=4[N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:11]1([CH2:15][C:16]2[NH:27][C:26]3[C:28]4[C:22]([C:23](=[O:29])[NH:24][N:25]=3)=[CH:21][CH:20]=[CH:19][C:18]=4[N:17]=2)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(CC2=Nc3cccc4c(=O)[nH]nc(c34)N2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]nc2c3c(cccc13)N=C(CN1CCCNCC1)N2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Synthesized from compound 24. To a solution of 24 (1.5 g, 3.7 mmol) in 30 mL of CH2Cl2 was added 6 mL of TFA while stirring at room temperature. After 30 minutes, the solvents were evaporated and the residue was washed with acetonitrile to afford 1.0 g (90%) of analytically pure white solid. MP: 147-149° C.; MS (ES−): 297; 1H NMR (400 MHz, D2O): 1.96 (m, 2H), 2.82 (t, 2H), 3.01 (t, 2H), 3.28 (t, 4H), 3.53 (s, 2H), 7.22 (d, 1H), 7.47 (d, 1H), 7.61 (t, 1H). Anal. Calcd. for C15H18N6O. 1.1 CF3CO2H. 1.0H2O: C, 46.76; H, 4.81; N, 19.02. Found: C, 46.64; H, 4.98; N, 19.02.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(C)=O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f25) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5]C=1)#N.BrC1C=CC2[N:27]([CH:29]=[N:30][N:31]=2)C=1>>[N:31]1[N:30]=[CH:29][N:27]2[CH:5]=[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]3)[CH:7]=[CH:8][C:3]=12
Reactant: Brc1ccc2nncn2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3nncn3c2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 1.1, except 6-bromo-[1,2,4]triazolo[4,3-a]pyridine was used in place of 4-bromobenzonitrile. m/z (ES+) 303 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH2:24][C:25]([OH:27])=[O:26])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:23][CH2:22]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:28][C:29]1[CH:30]=[N+:31]([O-:58])[CH:32]=[C:33]([Cl:57])[C:34]=1[CH2:35][C@@H:36]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH:49]([F:51])[F:50])=[C:44]([O:52][CH2:53][CH:54]2[CH2:56][CH2:55]2)[CH:43]=1)[O:37][C:38](=[O:41])[CH2:39]O.C(Cl)CCl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH2:24][C:25]([O:27][CH2:39][C:38]([O:37][C@H:36]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH:49]([F:51])[F:50])=[C:44]([O:52][CH2:53][CH:54]3[CH2:56][CH2:55]3)[CH:43]=2)[CH2:35][C:34]2[C:33]([Cl:57])=[CH:32][N+:31]([O-:58])=[CH:30][C:29]=2[Cl:28])=[O:41])=[O:26])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:22][CH2:23]1)[S:9]([CH3:12])(=[O:10])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(c1cc(CC(=O)O)ccc1OCC1CC1)S(C)(=O)=O
Reactant: O=C(CO)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(c1cc(CC(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)ccc1OCC1CC1)S(C)(=O)=O

Procedure:
To a solution of 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-(cyclopropylmethoxy)phenyl)acetic acid (0.200 g, 0.501 mmol) in DCM (5 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-hydroxyacetoxy)ethyl)pyridine 1-oxide (0.239 g, 0.501 mmol), EDC (0.288 g, 1.502 mmol), and DMAP (0.0306 g, 0.250 mmol) were added, and the mixture was reacted for 5 hours. A 1N solution of HCl was added, and the desired compound was extracted with DCM (3×) recovering the crude desired product (0.450 g, yield considered to be quantitative, MS/ESI+ 859.3 [MH]+) that was used in the following step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4]([Cl:8])[C:5]([CH3:7])=[O:6].[H-].[Na+].[Li]CCCC.[Cl:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][C:28]([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>C1COCC1>[CH3:1][O:2][C:3](=[O:9])[CH:4]([Cl:8])[C:5](=[O:6])[CH2:7][C:28]([CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)([OH:29])[CH2:27][CH2:26][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([Cl:17])[CH:19]=1
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: COc1ccc(CCC(=O)C2CCCC2)cc1Cl
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(Cl)C(=O)CC(O)(CCc1ccc(OC)c(Cl)c1)C1CCCC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Methyl-2-chloroacetoacetate (2.5 g, 16.9 mmol) was added to a cooled 0° C. suspension of NaH (0.68 g, 16.9 mmol, 60% dispersion in mineral oil) in THF (30 ml). After 15 min the solution was cooled to −40° C. and n-BuLi (10.6 mL, 16.9 mmol, 1.6M in hexanes) was added. The resulting dianion was stirred for an additional 30 min and then treated with a solution of 3-(3-Chloro-4-methoxy-phenyl)-1-cyclopentyl-propan-1-one (1.5 g, 5.6 mmol, prepared from Heck route) in THF (10 ml). After stirring for 1 h at −40° C., the reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The organic layers were washed with brine, dried with Na2SO4 and concentrated to an orange oil that was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C(N(CC)CC)C.[CH3:17][CH:18]([CH3:22])[C:19](Cl)=[O:20]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:19](=[O:20])[CH:18]([CH3:22])[CH3:17])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1ccc(N)cc1Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)C(C)C)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Into a solution of 1.0 g (5.40 mmol) of 3-bromo-4-methylaniline and 0.91 mL (6.50 mmol) of triethylamine in 10 mL THF at 0° C. was slowly added 0.68 mL (6.50 mmol) of 2-methylpropanoyl chloride. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed with H2O, followed by brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give 1.37 g (5.35 mmol, 99%) of the desired product: ESMS m/e: 255.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26]C(OC(C)(C)C)=O)=[CH:21][CH:20]=1)[CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[CH3:2].Cl.O1CCOCC1>C(O)C>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][NH2:26])=[CH:23][CH:24]=1)[CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH3:14])[CH2:15][CH2:16][CH3:17])[CH3:2]
Reactant: CCCN(CCC)CCCCN(CC(=O)OCC)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCCN(CCC)CCCCN(CC(=O)OCC)Cc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
The compound (21.265 g) obtained in Example 72-1 was dissolved in ethanol (100 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (140 ml) and the whole was stirred at room temperature for 1 hour. Subsequently, the solution was stirred at 40° C. for 1 hour. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution to make the pH thereof to 12. The solution was subjected to extraction with chloroform and dried with magnesium sulfate. The solvent was distilled off, thereby obtaining the subject compound (16.46 g) as a colorless oily substance.