Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([CH3:17])([C:14]([OH:16])=O)[O:11][N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)(=O)C(Cl)=O.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl.CN(C)C=O>[C:24]([NH:28][C:14]([C:12]1([CH3:17])[O:11][N:10]=[C:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:13]1)=[O:16])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC1(C(=O)O)CC(c2cc(Cl)cc(Cl)c2)=NO1
Reactant: CC(C)(C)N
Agent: CN(C)c1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)C1(C)CC(c2cc(Cl)cc(Cl)c2)=NO1
Reaction time: 0.5 h

Procedure:
100 ml of CH2Cl2 and 70 mg of dimethylformamide were added to 5.00 g (18.2 mmol) of 3-(3,5-dichlorophenyl)-5-methyl-4,5-dihydro-1,2-oxazole-5-carboxylic acid. At RT, 3.47 g (27.4 mmol) of oxalyl chloride were added slowly with stirring. After 30 min, the solution was concentrated and used without further purification (crude yield 5.50 g). 200 mg (0.68 mmol) of this crude product were taken up in 3 ml CH2Cl2 and added dropwise to a solution of 50 mg (0.68 mmol) of tert butylamine, 69 mg (0.68 mmol) of triethylamine and 10 mg of dimethylaminopyridine in 50 ml of CH2Cl2 at C. For work-up, the mixture was extracted with water, with saturated NaHCO3 solution and once more with water. Drying of the organic phases, filtration and removal of the solvent under reduced pressure gave the product.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:20]=[N:21][N:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:23]=3[C:24]([F:27])([F:26])[F:25])[O:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([O:5]CC)=[O:4].CO.[Li+].[OH-]>C1COCC1>[OH:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:20]=[N:21][N:22]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:23]=3[C:24]([F:25])([F:26])[F:27])[O:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
(R/S)-Ethyl 2-hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetate (Int-VI, 1.95 g, 4.25 mmol) was dissolved in THF (11 mL) and MeOH (5.50 mL) was added. Then, 1N LiOH (4.25 mL, 4.25 mmol) was added. It was stirred for 10 min and additional 1N LiOH (0.85 mL, 0.85 mmol) was added. After 10 min, more 1N LiOH (0.42 mL, 0.42 mmol) was added. After stirring for 10 min, the solution was concentrated and then EtOAc was added. The EtOAc was washed with 1 N HCl aqueous. The organic layer was dried (MgSO4), filtered and concentrated to give (R/S)-2-hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII, 1.8 g, 4.1 mmol, 97%): LCMS=431.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH:16](C(OCC)=O)[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]1.C(O)C.Cl.C(OCC)C>O>[C:2]1(=[O:1])[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)C1CC=CCCCCCCC=CCCC1=O
Agent: CCOC(=O)C1C/C=C/CCCCCC/C=C/CCC1=O
Agent: Cl
Agent: O=C1CC/C=C/CCCCCC/C=C/CC1
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: O=C1CCC=CCCCCCCC=CCC1

Procedure:
The crude ethyl 15-oxocyclopentadeca-3E,11E-dienecarboxylate (prepared as described above) was treated with ethanol (10 ml) and 3N aqueous hydrochloric acid (20 ml) and heated to reflux for 20 hours. The solution was cooled and diethyl ether and water were added. The layers were separated and the organic fraction was dried with magnesium sulfate, filtered and evaporated to provide a brown oil which was purified by column chromatography (10% diethyl ether/hexane) to afford cyclopentadeca-4E,12E-dien-1-one (0.50 g, 17% yield from diethyl hexadeca-4E,12E-diene-1,16-dioate). C15H24O (220.36 g/mole). 1HNMR (500 MHz, CDCl3): 1.15 (m, 4H), 1.34 (m, 4H). 1.97 (m, 4H), 2.24 (m, 4H), 2.45 (m, 4H), 5.30 (m, 2H), 5.39 (m, 2H) ppm. 13CNMR (125 MHz, CDCl3): 26.7, 27.4, 28.4, 31.2, 42.8, 129.2, 131.3, 210.4 ppm. IR (νmax(cm−1)): 2990, 2950, 2910, 2850, 1720, 1440, 1400, 1360, 1080, 980, 720. MS (m/z): 220(M+), 177, 163, 149, 135, 121, 109, 95, 81, 67, 55, 41.
Reaction SMILES: [OH:1][C:2]([C@@H:4]1[CH:19]=[C:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH:11]=3)[N:6]([CH3:7])[CH2:5]1)=O.[CH2:21]([N:23](CC)[CH2:24][CH3:25])[CH3:22].N1CCCC1>ClCCl>[CH3:7][N:6]1[C@H:8]2[C:18]([C:17]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:20]=3[C:10](=[CH:11][NH:12]4)[CH2:9]2)=[CH:19][C@@H:4]([C:2]([N:23]2[CH2:24][CH2:25][CH2:22][CH2:21]2)=[O:1])[CH2:5]1
Reactant: CN1C[C@H](C(=O)O)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCNC1
Product: CN1C[C@H](C(=O)N2CCCC2)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
30 g (111.80 mmol) lysergic acid is dissolved in 400 ml dichloromethane and cooled to 0°-5° C., 31.16 ml (223.61, 2 eq.) triethylamine and 18.66 ml (223.61 mmol, 2 eq.) pyrrolidine is added and within 15 minutes 1.5 equivalents propanephosphonic acid anhydride (50% in ethyl acetate). The reaction mixture is stirred for 1 hour at room temperature, then it is poured onto ice and extracted with dichloromethane, the organic layer is dried with Na2SO4, evaporated and the residue (28.6 g) is purified by chromatography on silica eluting with dichloromethane:methanol 9:1 to give ((6aR,9R)-7-Methyl-4,6,6a,7,8,9-hexahydro-indolo[4,3-fg]quinolin-9-yl)-pyrrolidin-1-yl-methanone.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20]>>[C:11]1([CH2:10][C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:20])[N:18]([CH3:17])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:7][CH:6]=2)=[O:9])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(C(=O)Cc2ccccc2)cc1)c1ccccc1

Procedure:
The title product was prepared from benzyl 4-hydroxyphenyl ketone and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (68%, light yellow oil). HPLC-MS: m/z=431.2 (M+1); Rt: 3.55 min.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]([C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=2)=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)(C)(C)C.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH3:26][O:25][C:23]([C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:17]=[CH:18][C:9]([CH2:8][CH2:7][C:6]([OH:29])=[O:5])=[C:10]3[C:15]=2[N:14]=[CH:13][CH:12]=[CH:11]3)=[CH:28][CH:27]=1)=[O:24]
Reactant: COC(=O)c1ccc(-c2ccc(CCC(=O)OC(C)(C)C)c3cccnc23)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-c2ccc(CCC(=O)O)c3cccnc23)cc1

Procedure:
A mixture of Example 201G (1.26 g, 3.22 mmol) and triethylsilane (1.12 g, 9.66 mmol) in TFA (10 mL) was heated to 50° C. for 16 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% methanol/ethyl acetate to provide the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=[N:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:6](=[O:8])[CH3:7])[CH3:2].S(Cl)([Cl:23])(=O)=O>C(O)(=O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][O:10][N:9]=[C:5]([C:6](=[O:8])[CH2:7][Cl:23])[C:4]([O:3][CH2:1][CH3:2])=[O:19])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(=NOCc1ccc(F)cc1)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)C(=NOCc1ccc(F)cc1)C(=O)CCl
Yield: 40.9 %

Procedure:
Ethyl2-(4-fluorobenzyloxyimino)-3-oxobutyrate (syn isomer, 64.0 g.) and sulfuryl chloride (35.6 g.) and acetic acid (70.0 ml.) were treated in a similar manner to that of Preparation 14-(1) to give ethyl 2-(4-fluorobenzyloxyimino)-3-oxo-4-chlorobutyrate (syn isomer, 29.55 g.).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][C:13]([OH:15])=O)[CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[NH2:25][CH2:26][CH:27]([OH:39])[CH2:28][N:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>CN(C=O)C>[CH2:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:37][CH2:38][N:29]1[CH2:28][CH:27]([OH:39])[CH2:26][NH:25][C:13](=[O:15])[CH2:12][O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: O=C(O)COc1cccc2cccnc12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(COc1cccc2cccnc12)NCC(O)CN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 4.2 %

Procedure:
To a stirred mixture of 2-(quinolin-8-yloxy)acetic acid (100 mg, 0.492 mmol) in DMF (5 mL) was added DIEA (95 mg, 0.738 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (100 mg, 0.492 mmol) and BOP-Cl (151 mg, 0.591 mmol). The mixture was stirred at 25° C. for 48 hours then the reaction mixture was quenched by addition of water (20 mL) and extracted with DCM (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was then purified by prep-HPLC to afford the desired product (8 mg, Yield: 4%). 1H NMR (400 MHz, MeOD) δ=8.91 (d, J=4.3 Hz, 1H), 8.42 (d, J=8.3 Hz, 1H), 7.69-7.54 (m, 3H), 7.30 (d, J=7.3 Hz, 1H), 7.12-6.96 (m, 4H), 4.78 (s, 2H), 4.18-4.07 (m, 1H), 3.71 (s, 2H), 3.60-3.49 (m, 1H), 3.48-3.40 (m, 1H), 2.89 (d, J=5.8 Hz, 2H), 2.84 (d, J=4.8 Hz, 2H), 2.65-2.61 (m, 2H). LCMS (m/z): 392.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Na].Br[CH:16]([CH2:22][CH3:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[O:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH:16]([CH2:22][CH3:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: CCOC(=O)C(Br)CC
Reactant: Oc1ccc(C2CCOCC2)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CC)Oc1ccc(C2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 44.6 g of 4-(p-hydroxyphenyl)-tetrahydropyran in 50 ml of ethanol was added at 20° C to a mixture of 5.75 g of sodium in 250 ml of ethanol and the mixture was stirred for one hour and then was cooled to 0° C. 55.1 ml of ethyl 2-bromo-butyrate were added to the reaction mixture which was then allowed to return to 20° C and was refluxed overnight. The ethanol was evaporated and the residue was taken up in 50 ml of 1N sodium hydroxide and 250 ml of methylene chloride. The aqueous phase was decanted and was extracted again with methylene chloride. The organic phases were dried and evaporated to dryness to obtain 56.3 g of raw product which was rectified under reduced pressure to obtain 40 g of ethyl 2-[p-(4-tetrahydropyranyl)-phenoxy]-butanoate with a boiling point of 143° C. at 0.3 mm Hg.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30](=[O:31])[O:29]1>C(Cl)(Cl)Cl>[C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([O:18][CH:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:30](=[O:31])[O:29]2)=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C(=O)OC1OC(=O)c2ccccc21)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 79 %

Procedure:
To a solution of 7.6 g of 2-(3-benzoylphenyl)propionic acid in 30 ml of chloroform and 3.4 g of triethylamine is added a solution of 6.2 g of 3-bromophthalide in 20 ml of chloroform. The solution thus obtained is stirred 25 hours at room temperature, the organic phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally dried on anhydrous sodium sulfate and evaporated to dryness to give the phthalidyl 2-(3-benzoylphenyl)propionate; yield 79%.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:8]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.[N:35]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:39]2C=CC=CC=2N=N1.CN.O1CCCC1>CN(C)C=O.O>[CH:1]1([CH2:6][CH:7]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:8]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH:35][CH3:39])=[O:17])=[CH:13][N:12]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)nc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
A solution of 6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid (prepared in Example 46, 125 mg, 0.31 mmol), N)N-diisopropylethylamine (0.10 mL, 0.61 mmol), and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (142 mg, 0.32 mmol) in N,N-dimethylformamide (15 mL) at 25° C. was treated dropwise with a 2.0M solution of methylamine in tetrahydrofuran (0.16 mL, 0.32 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 6-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-N-methyl-nicotinamide (83 mg, 64%) as white solid: mp 229.1-231.7° C.; FAB-HRMS m/e calcd for C21H23Cl2N3O2 (M+H)+420.1245, found 420.1247.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:22]1[N:27]([CH3:28])[C:26](=[O:29])[CH:25]=[C:24]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[N:23]=1>O1CCCC1>[CH2:1]([C@@H:8]1[NH:9][CH2:10][CH2:11][N:12]([C:22]2[N:27]([CH3:28])[C:26](=[O:29])[CH:25]=[C:24]([C:30]3[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=3)[N:23]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C[C@H]2CNCCN2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCN[C@@H](Cc3ccccc3)C2)nc(-c2ccncc2)cc1=O
Yield: 81.4 %

Procedure:
To a solution of (S)-2-benzylpiperazine (48 mg, 0.27 mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.10 mL, 0.74 mmol) and then 2-chloro-3-methyl-6-(4-pyridyl)-3H-pyrimidin-4-one (55 mg, 0.248 mmol) at room temperature. After refluxing for 24 h, the resulting mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and saturated sodium bicarbonate aqueous solution, and the organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by a reverse phase chromatography eluting 0.05% TFA in water-acetonitrile to afford (S)-2-(3-benzylpiperazin-1-yl)-3-methyl-6-(4-pyridyl) pyrimidin-4-one (73 mg 81%), which was treated with 4 N hydrogen chloride in ethyl acetate to yield its dihydrochloride salt as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:32](S(C4C=CC(C)=CC=4)(=O)=O)[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH2:23][CH2:24][CH2:25][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:43][CH3:44].[OH-].[K+]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:32][C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH2:23][CH2:24][CH2:25][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:43][CH3:44]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CNCCCN4CCCCC4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNCCCN4CCCCC4)ccnc3[nH]1)cn2C
Yield: 32 %

Procedure:
The product is prepared by following the procedure described in example 34 stage (k), starting with 0.050 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-(3-piperidin-1-yl-propyl)amine instead of the cyclopropyl-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amine used in example 34 stage (k) and 0.324 cm3 of 5N potassium hydroxide. 0.012 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-(3-piperidin-1-yl-propyl)amine is obtained with the following characteristics:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[N:9][CH:10]=1)=[O:4].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:7][CH:6]=1)=[O:4].[C:26]([OH:28])([C:25]([F:30])([F:29])[F:24])=[O:27]
Reactant: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCNCC2)nc1
Reaction time: 2 h

Procedure:
2-(4-tert-Butoxycarbonyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid methyl ester (140 mg, 0.434 mmol) is dissolved in dichloromethane (3.0 mL) under N2. Trifluoroacetic acid (0.83 ml, 10.85 mmol) is added and the reaction mixture is stirred for 2 h. The reaction mixture is concentrated under reduced pressure and co-evaporated several times with dichloromethane. It is dried under high vacuum to afford the title compound as a TFA salt (130 mg, 90% yield).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.O=P(Cl)(Cl)Cl.[I:11][C:12]1[N:13]=[C:14]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:23]2)[N:15]2[C:20]=1C(=O)NC=N2>N1C=CC=CC=1>[NH2:1][C:5]1[C:20]2=[C:12]([I:11])[N:13]=[C:14]([C@H:22]3[CH2:23][CH2:24][C@H:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:26][CH2:27]3)[N:15]2[N:2]=[CH:3][N:4]=1
Reactant: c1nc[nH]n1
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(=O)[nH]cnn32)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CC[C@H](c2nc(I)c3c(N)ncnn32)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1H-1,2,4-triazole (0.881 g, 0.0128 mol) in pyridine (3.00 mL) was charged with POCl3 (0.396 mL, 0.00425 mol) and stirred at rt for 15 min. To this mixture was drop wise added methyl trans-4-(5-iodo-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-7-yl)cyclohexanecarboxylate (0.570 g, 0.00142 mol) in pyridine (6.00 mL) and stirred at rt for an additional 2.45 h. The reaction was quenched with excess 2 M of NH3 in i-PrOH (40.00 mL) at 0° C. and allowed to stir at rt for an additional 3 h. The reaction was concentrated in vacuo and partitioned between EtOAc and sat. NaHCO3 and separated. The aqueous was washed with EtOAc (3×) and the combined organic fractions were washed with brine (1×). The aqueous was re-extracted with CHCl3 (3×) and the organic was added to the EtOAc fractions. The combined organic fractions were dried over Na2SO4, filtered and concentrated in vacuo. The crude brown/red solid was purified by chromatography over silica gel [eluting with 5% MeOH in CHCl3] resulting in 438 mg, (76% yield) of the title compound as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39-1.54 (m, 2H), 1.55-1.71 (m, 2H), 1.92-2.07 (m, 4H), 2.35-2.46 (m, 1H), 3.06-3.19 (m, 1H), 3.61 (s, 3H), 6.77 (br. s., 1H) 7.86 (s, 1H) and 8.44 (br. s., 1H); MS (ES+): m/z 401.85 [MH+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH:9]1([CH2:12][OH:13])[CH2:11][CH2:10]1>>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:13][CH2:12][CH:9]2[CH2:11][CH2:10]2)[N:3]=1
Reactant: OCC1CC1
Reactant: Brc1cccc(Br)n1
Product: Brc1cccc(OCC2CC2)n1

Procedure:
Prepared according to the procedure described in Example 139, Step 1, using 2,6-dibromo-pyridine and cyclopropyl-methanol.
Reaction SMILES: [C:1]1([CH:7]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:24]2[C@@H:28]3[O:29][C:30]([CH3:33])([CH3:32])[O:31][C@@H:27]3[C@@H:26]([C:34](O)=[O:35])[O:25]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)([N:45]1[CH:49]=[CH:48]N=C1)=O.C(N)C.O>O1CCCC1>[CH2:49]([NH:45][C:34]([C@@H:26]1[C@H:27]2[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@H:28]2[C@H:24]([N:14]2[CH:13]=[N:12][C:11]3[C:15]2=[N:16][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:18][C:10]=3[NH:9][CH2:8][CH:7]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:25]1)=[O:35])[CH3:48]
Reactant: CCOC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](C(=O)O)[C@H]4OC(C)(C)O[C@H]43)c2n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CCN
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OCC)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 15 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a solution of (3aS,4S,6R,6aR)-6-[6-[(2,2-diphenylethyl)amino]-2-(ethoxycarbonyl)-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid (Preparations 67 and 68) (20.0 g, 0.0349 moles) in anhydrous tetrahydrofuran (100 ml) under an atmosphere of nitrogen was added 1,1′-carbonyldiimidazole (6.80 g, 0.0418 moles) and the resultant mixture was stirred at ambient temperature for 1.5 hours. To this solution was then added a solution of ethylamine in tetrahydrofuran (24.4 ml of a 2M solution, 0.0488 moles) with cooling at 15° C., and the resultant mixture was then stirred at ambient temperature for 2 hours. To the mixture was added more of a solution of ethylamine in tetrahydrofuran (3.5 ml of a 2M solution, 0.0007 moles) and stirring was continued for an additional 2 hours after which time deionised water (10 ml) was added. The resultant mixture was concentrated in vacuo and the residue was then partitioned between ethyl acetate (200 ml) and aqueous citric acid (200 ml of a 0.5M solution). The layers were separated and the aqueous phase was extracted with ethyl acetate (50 ml). The organic phases were combined and were washed successively with deionised water (200 ml), saturated aqueous sodium bicarbonate solution (200 ml) and saturated brine (200 ml), and were subsequently dried over anhydrous magnesium sulphate and concentrated in vacuo to give the crude product as a cream coloured foam (20.22 g). The crude product was purified by flash chromatography on silica gel (700 g) eluting with a gradient system of 65% v/v ethyl acetate in heptane changing to 80% v/v ethyl acetate in heptane changing to ethyl acetate, to give the title compound (16.55 g) as a colourless foam.