Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13]([NH:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[C:22]2[S:27](Cl)(=[O:29])=[O:28])(=[O:15])[CH3:14].C(N(CC)CC)C.Cl>O1CCCC1>[C:1]1([CH2:11][NH:12][S:27]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:23]=2[CH:24]=[CH:25][CH:26]=[C:17]3[NH:16][C:13](=[O:15])[CH3:14])(=[O:29])=[O:28])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NCc1cccc2ccccc12
Reactant: CC(=O)Nc1cccc2c(S(=O)(=O)Cl)cccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc2c(S(=O)(=O)NCc3cccc4ccccc34)cccc12
Yield: 80.3 %

Procedure:
1-Naphthylmethylamine (174 mg, 1.1 mmol) was dissolved in tetrahydrofuran (10 ml), and 5-(acetylamino)-1-naphthalenesulfonyl chloride (284 mg, 1 mmol) was added under ice cooling and stirring. Then, triethylamine (0.17 mL, 1.2 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed successively with aqueous sodium hydrogen carbonate, water, and saturated brine, and after the layer was dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was crystallized by a mixed solvent of ethyl acetate/diisopropyl ether to give the title compound as a light brown crystal (325 mg, 80.4%).
Reaction SMILES: [CH2:1]([N:3](CC)CC)[CH3:2].ClC(OCC)=O.[OH:14][C@@H:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:16][CH2:17][C@@H:18]([O:27][CH2:28][CH:29]1[CH2:33][CH2:32][C:31](=[O:34])[NH:30]1)[C:19]1[S:23][C:22]([C:24]([OH:26])=O)=[CH:21][CH:20]=1.C(N)C>C(Cl)Cl>[CH2:1]([NH:3][C:24]([C:22]1[S:23][C:19]([C@H:18]([O:27][CH2:28][CH:29]2[CH2:33][CH2:32][C:31](=[O:34])[NH:30]2)[CH2:17][CH2:16][C@@H:15]([OH:14])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:20][CH:21]=1)=[O:26])[CH3:2]
Reactant: CCCCC[C@H](O)CC[C@@H](OCC1CCC(=O)N1)c1ccc(C(=O)O)s1
Reactant: CCN(CC)CC
Agent: CCN
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: CCCCC[C@H](O)CC[C@@H](OCC1CCC(=O)N1)c1ccc(C(=O)NCC)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.5 %

Procedure:
Triethylamine (9 mL, 0.065 mmol) and ethyl chloroformate (4.5 mL, 0.47 mmol) were added sequentially to a solution of acid 6 (12 mg, 0.031 mmol) in CH2Cl2 (0.2 mL) at 0° C., After 1 h at 0° C., ethylamine (2.0 M in THF, 0.15 mL, 0.30 mmol) was added and the mixture was allowed to warm to room temperature. After 18 h at room temperature, the reaction was quenched with 1.0 N HCl (5 mL) and extracted with EtOAc (3×10 mL). The combined extracts were washed with brine (5 mL), then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the crude residue by flash column chromatography on 4 g of silica gel (CH2Cl2→10% MeOH/CH2Cl2, gradient) afforded 7.7 mg (60%) of the title compound (8).
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]([F:15])([F:14])[S:10](Cl)(=[O:12])=[O:11]>N1C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([NH:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: NCc1ccco1
Solvent: c1ccncc1
Product: O=S(=O)(NCc1ccco1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a stirred solution of furfurylamine (0.899 g, 9.3 mmol) in pyridine (10 mL) at 0° C. was slowly added trifluoromethanesulfonyl chloride (1.300 g, 7.7 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hrs. The mixture was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% ethyl acetate/hexanes) to afford the product (1.5 g, 85%) as a yellowish oil. 1H NMR (300 MHz, CDCl3) δ 7.43 (dd, 1H, J=1.8, 0.9 Hz), 6.38 (dd, 1H, J=3.3, 1.8 Hz), 6.36 (d, 1H, J=3.3 Hz), 5.10 (br s, 1H), 4.48 (s, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][C@:9]12[CH2:17][CH2:16][C:15]3[C:18]4[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[CH:22][C:23]=4[CH2:24][CH2:25][C:14]=3[C:13]1=[CH:12][CH2:11][C:10]2=[O:28]>O1CCOCC1.[Ni]>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][C@:9]12[CH2:17][CH2:16][C:15]3[C:18]4[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[CH:22][C:23]=4[CH2:24][CH2:25][C:14]=3[C@@H:13]1[CH2:12][CH2:11][C:10]2=[O:28]
Reactant: COCCOCCC[C@]12CCC3=C(CCc4cc(OC)ccc43)C1=CCC2=O
Agent: [Ni]
Solvent: C1COCCO1
Product: COCCOCCC[C@]12CCC3=C(CCc4cc(OC)ccc43)[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 103.4 %

Procedure:
A mixture of 49 (9.7 g, 24.4 mmol) and Raney® nickel (26 mL) in dioxane (220 mL) was stirred under H2 (g) (1 atm) at room temperature for 25 min. The mixture was filtered through Celite pad and washed several times with ethyl acetate. The solvents were removed by evaporation to give quantitatively (9.7 g) the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC>CN(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>[CH:13]([C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2)=[CH2:14]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1CCc2cc(Br)cnc2N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1cnc2c(c1)CCC(=O)N2
Temperature: 105 °C
Yield: 59.4 %

Procedure:
6-Bromo-3,4-dihydro-1H-[1,8]naphthyridin-2-one (113e) (4.6 g, 20.3 mmole) and tributyl(vinyl)tin (7.7 g, 24.4 mmole) were dissolved in DMF (200 mL) and the solution was degassed with nitrogen. (Ph3P)4Pd (590 mg, 0.5 mmole) was added to the solution. The reaction was heated to 105° C. under nitrogen overnight, then was cooled to room temperature and filtered through a sintered glass funnel. The filtrate was washed with NH4OH and extracted with EtOAc (2×150 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound (2.1 g, 60%) as an off white solid: MS (ES) m/e 175 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[CH3:11][C:12]([S:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])/[CH:5]=[N:17]/[S:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)S(N)=O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)/N=C/c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 1-L round-bottomed flask was charged with 3,4-dichlorobenzaldehyde (25.0 g, 143 mmol), 2-methylpropane-2-sulfinamide (17.3 g, 143 mmol), and 200 mL of THF. To this was added Ti(OEt)4 (65.2 g, 286 mmol) over 5 min. The reaction was stirred at rt for 5 h and then poured onto brine. The resulting white precipitate was removed by filtration, and the filter cake was washed with EtOAc. The filtrate was transferred to a separatory funnel and the layers were separated. The organic layers were combined and dried (MgSO4), filtered, and concentrated to give (E)-N-(3,4-dichlorobenzylidene)-2-methylpropane-2-sulfinamide as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[CH:22][C:21]=2[OH:28])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC(C)=O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([O:27][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:22][C:21]=2[O:28][CH2:17][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(F)c(O)cc2O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(F)c(OCc3ccccc3)cc2OCc2ccccc2)CC1
Temperature: 50 °C

Procedure:
241 mg (1.74 mmol, 3 eq) of potassium carbonate (325 mesh) are added to a solution of 181 mg (0.58 mmol, 1 eq) of 4-(5-fluoro-2,4-dihydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester in 3 ml of acetone. 152 μl (1.28 mmol, 2.2 eq) of benzyl bromide are added dropwise. The reaction medium is heated at 50° C. for 20 hours. The solvent is evaporated off and then the residue is taken up with a water/ethyl acetate mixture. The aqueous phase is extracted with ethyl acetate, and the organic phases are combined, washed with a solution of sodium hydrogen carbonate and then with a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and evaporated. The residue is chromatographed on silica gel, elution being carried out with 85/15 heptane/ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:11](O)[CH2:12][CH2:13][CH3:14])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[SH:16][CH2:17][C:18]([OH:20])=[O:19].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C(OCC)(=O)C>C1C=CC=CC=1>[CH3:1][C:2]1[C:3]([CH:11]([S:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:12][CH2:13][CH3:14])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CCCC(O)c1cc2c(cc1C)OCO2
Reactant: O=C(O)CS
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCCC(SCC(=O)O)c1cc2c(cc1C)OCO2
Yield: 54 %

Procedure:
A solution of 5.6 g of (6-methyl-1,3-benzodioxol-5-yl)butan-1-ol, 4.8 g of mercaptoacetic acid and a catalytic amount of D-10-camphorsulfonic acid in 60 ml of benzene was heated under reflux for 3 hours, followed by the addition of ethyl acetate. The obtained mixture was washed with water and extracted with a 1N aqueous solution of sodium hydroxide. The aqueous layer was washed with ethyl acetate, acidified with 1N hydrochloric acid and extracted with chloroform. The organic layer was dried over magnesium sulfate and distilled to remove the solvent. The obtained residue was chromatographed over silica gel column and eluted with chloroform to obtain a colorless crystal. This crystal was recrystallized from isopropyl ether/hexane to obtain 4.1 g of the title compound as a colorless prismatic crystal.
Reaction SMILES: C(C1COC(=O)C1)CCC.OC1C=CC=CN=1.C1([C@@H](N)C)C=CC=CC=1.[C:27]1([C@@H:33]([NH:35][C:36](=[O:45])[CH2:37][C@@H:38]([CH2:43][OH:44])[CH2:39][CH2:40][CH2:41][CH3:42])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:27]1([C@@H:33]([NH:35][C:36](=[O:45])[CH2:37][C@H:38]([CH2:43][OH:44])[CH2:39][CH2:40][CH2:41][CH3:42])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCC[C@H](CO)CC(=O)N[C@@H](C)c1ccccc1
Agent: CCCCC1COC(=O)C1
Agent: C[C@H](N)c1ccccc1
Agent: Oc1ccccn1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCC[C@@H](CO)CC(=O)N[C@@H](C)c1ccccc1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
A mixture of (+/−)-4-butyldihydrofuran-2-one (3.9 g, 27.4 mmol), 2-hydroxypyridine (3.1 g, 32.9 mmol) and (S)-1-phenylethyl amine (7.8 mL, 60.3 mmol) in dry toluene (50 mL) was heated to reflux overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL), washed with 1 N HCl (2×50 mL) and brine (50 mL), dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography (silica gel, 8:2 EtOAc/hexanes) to afford two compounds as white solids. The first eluted fraction was (S)-3-hydroxymethylheptanoic acid, (S)-1-phenyl-ethylamide (2.8 g, 39%) which is used in Example 3. 1H NMR (CDCl3) δ 7.33 (m, 5H), 6.07 (bs, 1H), 5.11 (q, 1H), 3.63 (m, 1H), 3.48 (m, 1H), 3.29 (bs, 1H), 2.29 (m, 2H), 1.95 (m, 1H), 1.50 (d, 2H), 1.28 (m, 6H), 0.88 (t, 3H). MS(ES) m/e 264 [M+H]+. The second eluted fraction was the title compound (2.6 g, 36%). 1H NMR (CDCl3) δ 7.29 (m, 5H), 6.34 (bs, 1H), 5.09 (q, 1H), 3.64 (m, 1H), 3.57 (bs, 1H), 3.48 (m, 1H), 2.28 (m, 2H), 1.93 (m, 1H), 1.48 (d, 2H), 1.28 (m, 6H), 0.88 (t, 3H). MS(ES) m/e 264 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[C:10]([C:18]([O:20]C)=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH3:17][O:16][C:14]([C:12]1[CH:11]=[C:10]([C:18]([OH:20])=[O:19])[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:13]=1)=[O:15]
Reactant: COC(=O)c1cc(C(=O)OC)cc(-c2ccc(C)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Temperature: 60 °C

Procedure:
A mixture of dimethyl 4′-methylbiphenyl-3,5-dicarboxylate (1.70 g, 5.98 mmol), MeOH (100 mL) and 2N aq. NaOH (8 mL) was stirred at 60° C. until LC-MS indicated the diester was almost completely consumed. After cooling, the mixture was concentrated in vacuo and acidified with 1N aq. HCl to pH<4 and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to yield a white solid (contained some dicarboxylic acid).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1.C(N(CC)CC)C.[C:27]([N:31]=[C:32]=[O:33])([CH3:30])([CH3:29])[CH3:28].CN(C)C=O>O>[C:27]([NH:31][C:32](=[O:33])[NH:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12

Procedure:
The preparation is carried out as in Example 7, from 1.2 g of 8-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one hydrochloride, 1.8 ml of triethylamine, 2 times 0.6 ml of tert-butyl isocyanate and 25 ml of dimethylformamide. After addition of 100 ml of distilled water to the reaction mixture, the precipitate formed is filtered and recrystallized from dimethylformamide. The solid thus obtained is washed with water, then with ethyl ether and dried under reduced pressure (1 mm Hg, 0.13 kPa) at 80° C. There is obtained 0.31 g of 8-(3-tert-butylureido)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one in the form of a brown solid, the melting point of which is greater than 260° C. (Analysis C18H19N5O2 0.83H2 0.0.03DMF, % calculated C: 64.08, H: 5.68, N: 20.76, % found C: 63.7, H: 5.9, N: 20.6).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:47]2[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=2)[CH2:10][NH:11][C:12]2[N:20]=[C:19]([N:21]3[CH2:25][CH2:24][C@@H:23]([NH:26][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:22]3)[N:18]=[C:17]3[C:13]=2[N:14]=[CH:15][N:16]3[C@@H:35]2[CH2:39][C@H:38]([NH:40][C:41](=[O:44])[CH2:42][CH3:43])[C@@H:37]([OH:45])[C@H:36]2[OH:46])=[CH:5][CH:4]=1.[CH3:54][N:55]1[C:59]2C=CC(C([Cl:66])=O)=CC=2N=[N:56]1>>[ClH:66].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:47]2[CH:48]=[CH:49][C:50]([OH:53])=[CH:51][CH:52]=2)[CH2:10][NH:11][C:12]2[N:20]=[C:19]([N:21]3[CH2:25][CH2:24][C@@H:23]([NH:26][C:27]([C:28]4[CH:33]=[CH:32][C:54]5[N:55]([CH3:59])[N:56]=[N:31][C:30]=5[CH:29]=4)=[O:34])[CH2:22]3)[N:18]=[C:17]3[C:13]=2[N:14]=[CH:15][N:16]3[C@@H:35]2[CH2:39][C@H:38]([NH:40][C:41](=[O:44])[CH2:42][CH3:43])[C@@H:37]([OH:45])[C@H:36]2[OH:46])=[CH:5][CH:4]=1
Reactant: Cn1nnc2cc(C(=O)Cl)ccc21
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(N4CC[C@@H](NC(=O)c5ccncc5)C4)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(N4CC[C@@H](NC(=O)c5ccc6c(c5)nnn6C)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to N-{(R)-1-[6-[2,2-Bis-(4-hydroxy-phenyl)-ethylamino]-9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-9H-purin-2-yl]-pyrrolidin-3-yl}-isonicotinamide hydrochloride (Example 158) by replacing isonicotinoyl chloride hydrochloride with 1-methyl-1H-1,2,3-benzotriazole-5-carbonyl chloride. (MH+ 762.4)
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:3]=1[O:4][CH:5]([C:9](O)=[O:10])[C:6](O)=[O:7].Cl.[CH:19]([NH2:21])=[NH:20]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:3]=1[O:4][C:5]1[C:9]([OH:10])=[N:20][CH:19]=[N:21][C:6]=1[OH:7]
Reactant: N=CN
Reactant: COc1ccc(Cl)c(OC(C(=O)O)C(=O)O)c1
Agent: Cl
Product: COc1ccc(Cl)c(Oc2c(O)ncnc2O)c1

Procedure:
5-(2-Chloro-5-methoxy-phenoxy)-pyrimidine-4,6-diol was prepared from 2-(2-chloro-5-methoxy-phenoxy)-malonic acid dimnethyl ster and formamidine hydrochloride according to the procedure described in Referential Example 1c.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[C:40]2[S:41][C:42]([Sn](CCCC)(CCCC)CCCC)=[CH:43][C:39]=2[C:38]([CH3:57])=[N:37]1>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:42]3[S:41][C:40]4[N:36]([CH3:35])[N:37]=[C:38]([CH3:57])[C:39]=4[CH:43]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(C)nn(C)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1nn(C)c2sc(-c3nc(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)cc12
Temperature: 120 °C

Procedure:
A mixture of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (200 mg, 0.399 mmol), 1,3-dimethyl-5-(tributylstannyl)-1H-thieno[2,3-c]pyrazole (352 mg, 0.798 mmol) and tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.200 mmol) in toluene (3 mL) was heated to 120° C. in a Biotage Initiator microwave for 30 minutes. The mixture was concentrated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(1,3-dimethyl-1H-thieno[2,3-c]pyrazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was subsequently dissolved in DCM (5 mL) and TFA (5 mL). The resulting solution was stirred at room temperature for 20 minutes, concentrated, and purified by preparatory HPLC, eluting with a gradient of 10-30% ACN (0.035% TFA) and water (0.05% TFA). The collected fractions were combined and dried to give a TFA salt of the title compound as a white solid (85 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79-1.81 (m, 1H), 2.13-2.14 (m, 1H), 2.53 (s, 3H), 3.61-3.63 (m, 1H), 3.85-3.87 (m, 2H), 3.87 (s, 3H), 4.01-4.07 (m, 2H), 4.33-4.35 (m, 1H), 4.44 (d, J=7.80 Hz, 2H), 7.33-47.34 (m, 1H), 8.01-8.02 (m, 2H), 8.53 (s, 1H), 9.16 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C19H21FN6O2S, 417. found, 417.
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=O>C1C=CC=CC=1>[C:6]([Cl:3])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCC(=O)O
Solvent: c1ccccc1
Product: CCCCCCCCCC(=O)Cl

Procedure:
A mixture of 0.5 ml of thionyl chloride, 934 mg of capric acid and 4 ml of benzene was refluxed for 2 hours and then was evaporated to dryness to obtain capric acid chloride. The raw acid chloride was taken up in 5 ml of benzene and 1 ml of pyridine was added thereto. Then, a solution of 728 mg of ethyl 3'-(3'-α-hydroxy trans-1'-octenyl)-cyclopentane-2-carboxylate in 5 ml of benzene was slowly added to the mixture and after the addition of 66 mg of 4-dimethylaminopyridine, the mixture was stirred for 17 hours at 20° C. The mixture was poured into 1N hydrochloric acid and the mixture was extracted with ether. The ether extracts were washed with water, and aqueous sodium bicarbonate solution, dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture containing 0.1% of triethylamine to obtain 710 mg of ethyl (1RS, 5RS, 3'SR) (1'E) 2-oxo-5-(3'-decanoyloxy-1'-octenyl)-cyclopentanecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[CH2:14](I)[CH2:15][CH3:16]>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:14][CH2:15][CH3:16])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: CCCI
Product: CCCn1ccc2ccc(C(=O)OC)cc21

Procedure:
This compound was prepared from methyl-6-indolecarboxylate and propyliodide by the method described in Example 10, part i. The reaction mixture was worked up by removal of the dimethylformamide in vacuo and the residue partitioned between diethyl ether and water. The organic phase was further washed with water and brine, dried and evaporated. The resulting oil was purified by chromatography on flash silica eluting with petroleum spirit 40°-60° C.-diethyl ether (9:1) to give the product as a colourless oil.
Reaction SMILES: B(Br)(Br)Br.[NH:5]1[CH:9]=[C:8]([CH2:10][CH:11]2[C:19]3[C:14](=[CH:15][C:16]([O:22]C)=[C:17]([CH:20]=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)[N:7]=[CH:6]1.O.[OH-].[NH4+]>C(Cl)Cl>[OH:22][C:16]1[CH:15]=[C:14]2[C:19]([CH:11]([CH2:10][C:8]3[N:7]=[CH:6][NH:5][CH:9]=3)[CH2:12][CH2:13]2)=[CH:18][C:17]=1[CH:20]=[O:21]
Reactant: COc1cc2c(cc1C=O)C(Cc1c[nH]cn1)CC2
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=Cc1cc2c(cc1O)CCC2Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Boron tribromide 1.0 M solution in methylene chloride (3.9 ml) is added dropwise to a stirred solution of 3-(1H-imidazol-4-ylmethyl)-6-methoxyindan-5-carbaldehyde (318 mg) in methylene chloride (15 ml) at −70° C. under a nitrogen atmosphere. After the addition the mixture is allowed to warm to room temperature and is stirred for 3 hours. The mixture is then poured into cold water and is made basic with ammonium hydroxide solution. Work-up of the mixture gives the crude product which is purified by flash chromatography and recrystallized from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].[CH3:22][N:23]1[C:27]([C:28]2([C:31](=N)OCC)[CH2:30][CH2:29]2)=[N:26][CH:25]=[N:24]1.[S].C(O)(=O)C>C(O)C>[CH3:22][N:23]1[C:27]([C:28]2([C:31]3[NH:8][C:7]4=[N:6][C:5]([N:9]5[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]6[CH2:21][CH2:20][CH2:19][CH2:18]6)=[O:16])[CH2:10]5)=[CH:4][CH:3]=[C:2]4[N:1]=3)[CH2:30][CH2:29]2)=[N:26][CH:25]=[N:24]1
Reactant: CCOC(=N)C1(c2ncnn2C)CC1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: [S]
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1ncnc1C1(c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)CC1
Temperature: 80 °C
Yield: 18 %

Procedure:
(R)-(1-(5,6-Diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone, prepared during the previous step, was added to a suspension of ethyl 1-(1-methyl-1H-1,2,4-triazol-5-yl)cyclopropanecarbimidate (0.39 g, 2.0 mmol), sulfur (20 mg, 0.31 mmol) and acetic acid (0.96 mL, 15.5 mmol) in ethanol (10 mL) at room temperature. The reaction mixture was heated to 80° C. for 16 h. The mixture was concentrated under reduced pressure and the resulting crude was dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting crude was purified via preparative TLC to afford the title compound (120 mg, 18%). MS (ES+APCI) (M+H) 421.2; LCMS retention time: 3.311 min (Method Y1).