Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[CH2:8]([O:10][C:11]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12])[CH3:9].C([N-]C(C)C)(C)C.[Li+:26].[I:27][CH2:28]I>O1CCCC1.Cl>[CH:1]([N-:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Li+:26].[CH2:8]([O:10][C:11]([C:13]1([CH2:28][I:27])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12])[CH3:9]
Reactant: CCOC(=O)C1CCOCC1
Reactant: ICI
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CI)CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Lithium diisopropylamide was prepared by the addition of 2.5M N-butyl lithium (5.6 mL, 13.9 mmol) in hexanes to a solution of diisopropylamine (1.95 mL, 13.9 mmmol) in tetrahydrofuran (30 mL) at 0° C. with stirring for 20 minutes. Then a solution of tetrahydropyran-4-carboxylic acid ethyl ester (2 g, 12.7 mmol) in tetrahydrofuran (8 mL) was added to the solution of lithium diisopropylamide at a temperature of -78° C. over 15 minutes. The resulting solution was stirred an additional 50 minutes, and diiodomethane (1.14 mL, 14.2 mmol) was added. The resulting mixture was stirred an additional 50 minutes, warmed to room temperature over 30 minutes, then recooled to 0° C. The mixture was diluted with 1M aqueous hydrochloric acid (25 ml), extracted with diethyl ether (2×100 mL), and washed with additional portions of diethyl ether (2×50 mL). The combined organic layers were washed once with 1M aqueous hydrochloric acid (100 mL), saturated aqueous sodium bisulfite (100 mL), saturated aqueous sodium bicarbonate (100 mL), and dried over magnesium sulfate, and concentrated in vacuo. The residue was filtered over a plug of silica gel, eluting successively with hexanes and ethyl acetate, removing excess alkylating agent with the hexane wash, to afford pure 4-(iodomethyl)tetrahydropyran-4-carboxylic acid ethyl ester as a pale yellow oil which was taken directly into the next reaction without further purification (3.20 g, 85%). IR (KBr) 1732 cm-1 ; 1HNMR (CDCl3) 1.31 (q, J=7.3 Hz, 3H), 1.56 (ddd, J=14.6, 10.9, 4.5, 2H), 2.17 (ddd, J=14.6, 5.7, 3.3, 2H), 3.31 (s, 2H), 3.51 (ddd, J=11.7, 11.1, 2.5 Hz, 2H), 3.51 (td, J=11.7, 4.3 Hz, 2H), 4.24 (q, J=7.1 Hz, 2H); 13CNMR (CDCl3) δ 14.33 (q) , 15.04 (t), 34.70 (t), 45.26 (s), 61.34 (t), 65.22 (t), 172.89 (s); EIHRMS Calcd. for C9H15IO3 (M+): 298.0066. Found: 298.0066. Anal. Calcd. for C9H15IO3 : C, 36.26; H, 5.07. Found: C, 36.56; H, 5.09.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C@@H:14]([C@@H:23]([CH2:25][O:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])=[O:31])[OH:24])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]([OH:13])=[CH:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)OO1.CC(C)=O.[CH2:43]([O:47][P:48]([O-:55])([O:50][CH2:51][CH2:52][CH2:53][CH3:54])=O)[CH2:44][CH2:45][CH3:46].[C:56](Cl)(=[O:61])[C:57]([CH3:60])([CH3:59])[CH3:58]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[P:48]([O:12][CH:11]1[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])=[O:31])[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:10]1[O:13][C:56](=[O:61])[C:57]([CH3:60])([CH3:59])[CH3:58])([O:47][CH2:43][CH2:44][CH2:45][CH3:46])([O:50][CH2:51][CH2:52][CH2:53][CH3:54])=[O:55]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(=O)CCC(=O)OC[C@@H](O)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)C(O)=CO
Reactant: CCCCOP(=O)([O-])OCCCC
Agent: CC1(C)OO1
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCCCOP(=O)(OCCCC)OC1O[C@H](COC(=O)CCC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
3,4-Di-O-benzyl-6-O-levulinoyl-D-arabino-hex-1-enitol (2.12 g, 5.0 mmol) was dissolved in CH2Cl2 (5 mL) and cooled to 0° C. A 0.08 M solution of dimethyldioxirane in acetone (75 mL, 6.0 mmol) was added and the reaction mixture was stirred for 15 min. After the solvent was removed in a stream of N2 and the remaining residue dried in vacuo for 15 min at 0° C., 20 mL CH2Cl2 were added. The solution was cooled to −78° C. for 15 min and dibutylphosphate (1.04 mL, 5.25 mmol) was then added dropwise over 5 min. After complete addition, the reaction mixture was warmed to 0° C. and DMAP (2.44 g, 20.0 mmol) and pivaloyl chloride (1.23 mL, 10.0 mmol) were added. The solution was warmed to room temperature over 1 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel to afford 3.29 g (90%) of 8 as a colorless oil. 1H NMR (500 MHz) δ 7.34–7.24 (m, 10H), 5.23 (app t, J=7.6, 7.9 Hz, 1H), 5.14 (app t, J=7.9, 9.2 Hz, 1H), 4.81 –4.78 (m, 2H), 4.72 (d, J=11.0 Hz, 1H), 4.57 (d, J=10.7 Hz, 1H), 4.39 (d, J=11.3 Hz, 1H), 4.23 (dd, J=4.0, 12.2 Hz, 1H), 3.67–3.66 (m, 2H), 2.76–2.70 (m, 2H), 2.57–2.54 (m, 2H), 2.19 (s, 3H), 1.67–1.60 (m, 4H), 1.41–1.35 (m, 4H), 1.20 (s, 9H), 0.96–0.90 (m, 6H); 13C NMR (125 MHz) δ 206.4, 177.0, 172.5, 137.9, 137.5, 128.7, 128.6, 128.4, 128.3, 128.2, 128.0, 127.5, 96.6, 96.6, 82.9, 75.3, 75.2, 73.8, 72.9, 68.2, 68.2, 68.0, 68.0, 62.7, 39.0, 38.0, 32.3, 32.3, 32.3, 32.2, 30.0, 27.9, 27.3, 18.8, 18.8, 13.8, 13.7; 31P NMR (120 MHz) δ-1.66.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:43][CH3:44])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[O:20][C@@H:21]1[CH2:25][N:24](C(OC(C)(C)C)=O)[C@H:23]([C:33](=[O:42])[N:34]([CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[CH2:41])[CH3:35])[CH2:22]1.C(Cl)(=O)C>CO>[ClH:1].[Cl:1][C:2]1[C:3]([O:43][CH3:44])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[O:20][C@@H:21]1[CH2:25][NH:24][C@H:23]([C:33]([N:34]([CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[CH2:41])[CH3:35])=[O:42])[CH2:22]1
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(C)C)cs3)nc3c(Cl)c(OC)ccc23)CN1C(=O)OC(C)(C)C
Solvent: CC(=O)Cl
Solvent: CO
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(C)C)cs3)nc3c(Cl)c(OC)ccc23)CN1
Product: Cl
Temperature: 40 °C

Procedure:
Compound 134 (20.37 g) was suspended in anhydrous methanol (120 mL) under argon at room temperature. Separately acetyl chloride (3 eq.) was added to anhydrous methanol (70 mL) at 10-20° C. This solution was added to the compound 134 solution at 5° C. The reaction mixture was heated at 40° C. for 3-4 hrs. After the completion of the reaction, the reaction mixture was concentrated under vacuum and then co-evaporated with 100 mL of anhydrous dichloromethane. The product was then dried in a vacuum oven at 40-45° C. Compound 135 (19.81 g) was recovered as a yellow foam in quantitative yield and 100% purity (HPLC).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH2:11][Cl:12])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O>C(#N)C>[Br:13][C:8]1[N:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]2=[N:10][C:9]=1[CH2:11][Cl:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: ClCc1cn2cccc(Cl)c2n1
Solvent: CC#N
Product: ClCc1nc2c(Cl)cccn2c1Br
Temperature: 25 °C

Procedure:
Acetonitrile (8.5 ml) was added to 8-chloro-2-(chloromethyl)imidazo[1,2-a]-pyridine (341 mg, 1.7 mmol). N-bromosuccinimide (302 mg, 1.7 mL) was added and the mixture was stirred at rt until complete. The reaction mixture was partitioned with EtOAc and satd. aq. NaHCO3 solution. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was taken up in DCM and purified by chromatography on a 23 g silica gel column using 0 to 70% gradient of EtOAc in hexane. The desired fractions were combined and concentrated under reduced pressure to give 3-bromo-8-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][Br:12])=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1nc2cc(Cl)ccc2o1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2oc(CBr)nc2c1
Reaction time: 24 h

Procedure:
A solution of the benzoxazole (1.3 g) (Step 2) in CCl4 (15 mL) was treated with N-bromo-succinimide (NBS) (1.5 g) and benzoyl peroxide (38 mg) at reflux using a U.V. lamp for 24 hours. Filtration, evaporation, and flash chromatography of the residue using 1:1 hexane/toluene afforded the title compound which was used as such for the next step.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].O[NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=[NH:15].N1C=CC=CC=1>O1CCOCC1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]2[O:8][N:15]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:24][CH:23]=4)=[CH:20][CH:21]=3)[N:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N=C(NO)c1ccc(-c2ccc(OCCCC(=O)O)cc2)cc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2nc(-c3ccc(-c4ccc(OCCCC(=O)O)cc4)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
A solution of 4-cyanobenzoyl chloride (2.29 g, 13.8 mmol) in dioxane (10 ml) was added to a suspension of 4-(4′-(N-hydroxycarbamimidoyl)biphenyl-4-yloxy)butyric acid (3.23 g, 9.6 mmol) in dioxane (50 ml) and pyridine (2.5 ml, 31.6 mmol). The mixture was stirred at room temperature for 4 h, and then heated to 100° C. for 22 h. The mixture was concentrated to ½ of its original volume, diluted with water (100 ml), and acidified by addition of concentrated hydrochloric acid (3 ml). The product was isolated by filtration and washed with water (50 ml). The solid was suspended in MeCN (70 ml), heated to reflux, allowed to cool, filtered off, and dried under reduced pressure to yield 3.17 g (54%) of 4-(4′-{5-[4-cyanophenyl]-[1,2,4]oxadiazol-3-yl}biphenyl-4-yloxy)butyric acid as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.Cl.[CH2:26]([O:28][C:29](=[O:33])[C@H:30]([CH3:32])[NH2:31])C.O.[OH:35]C1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:26][O:28][C:29](=[O:33])[CH:30]([NH:31][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][C:12]([S:9](=[O:10])(=[O:11])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[C:21]([F:22])([F:23])[F:24])=[CH:13][CH:14]=1)[CH2:32][OH:35]
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)cc1
Reactant: CCOC(=O)[C@H](C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C(CO)NC(=O)c1ccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)cc1

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 4-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.536 g (10 mmol) of L-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[H][H]>C(O)C>[Cl:1][CH2:2][C@@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: [H][H]
Solvent: CCO
Product: CCOC(=O)C[C@H](O)CCl

Procedure:
In a stainless steel autoclave, 12.4 mg (0.008 mmol) of Ru2Cl4 ((R)-BIPHEMP)2NEt3 was charged, and the air in the autoclave was replaced with nitrogen. Further, 6.6 ml of ethanol and 2.7 ml (20 mmol) of ethyl 4-chloroacetoacetate were added, and the nitrogen in the autoclave was replaced with hydrogen. At a hydrogen pressure of 10 kgf/cm2, it was stirred for 2 hours at 100° C. After termination of the reaction, the conversion ratio, selectivity and optical purity were measured under the same chromatography conditions as in Example 5. At a conversion ratio of 95.5%, selectivity of 93.9% and optical purity of 95.7%ee, ethyl 4-chloro-(S)-3-hydroxybutyrate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH:25]12[CH2:31][CH:28]([NH:29][CH2:30]1)[CH2:27][N:26]2C(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>CO.O1CCOCC1.ClCCCl>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:26]2[CH2:27][CH:28]3[CH2:31][CH:25]2[CH2:30][NH:29]3)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: O=CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Solvent: C1COCCO1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCN2CC3CC2CN3)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 106.2 %

Procedure:
Prepared according to the method described in Example 66c from 2-chloro-5-(2-oxoethyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.094 g, Example 66b), 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid, 1,1-dimethylethyl ester (0.108 g), sodium triacetoxyborohydride (0.081 g) and 1,2-dichloroethane (2 ml). After work-up, the residue was purified by HPLC eluting with a gradient of 0-5% ethanol in dichloromethane. The white powder obtained was dissolved in methanol (2 ml) and a solution of hydrochloric acid in dioxane (4N, 1 ml) was added. The mixture was stirred for 14 h at room temperature. Solvents were then removed under reduced pressure and the product obtained was triturated with diethyl ether to afford the title compound as a white powder (0.067 g).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]2[O:9][CH2:10][C:11](=[O:20])[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C=O.[C:23]([BH3-])#[N:24].[Na+].[C:27](O)(=O)C>C(#N)C.C(OCC)(=O)C>[CH3:27][N:24]([CH3:23])[C:2]1[CH:3]=[C:4]([C:8]2[O:9][CH2:10][C:11](=[O:20])[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Nc1cccc(C2=NN(c3ccccc3)C(=O)CO2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(C)c1cccc(C2=NN(c3ccccc3)C(=O)CO2)c1
Reaction time: 0.08 h
Yield: 97 %

Procedure:
2-(3-Aminophenyl)-4-phenyl-4H-1,3,4-oxadiazine-5(6H)-one (200 mg) obtained in Example 78 was dissolved in acetonitrile (5 ml), and 37% aqueous formaldehyde (1 ml) and sodium cyanoborohydride (250 mg) were added thereto, and acetic acid (0.15 ml) was added dropwise thereto over 5 minute, and mixed at room temperature for 6 hours. The reaction solution was diluted with ethyl acetate, washed with an aqueous saturated sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the filtrate was evaporated and purified by silica gel chromatography (hexane/ethyl acetate system), to give the title compound (215 mg, 97%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][OH:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>N1C=CC=CC=1>[C:11]([O:10][CH2:9][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)(=[O:13])[CH3:12]
Reactant: OCCCc1ccccn1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCCc1ccccn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.4 %

Procedure:
2-Pyridinepropanol (2.0 g, 14.6 mmol) was dissolved in pyridine (5 ml), and acetic anhydride (3.0 g, 29.2 mmol) was added thereto. The reaction mixture was stirred at room temperature for 2.5 hrs, and subjected to a silica gel (75 g) column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected and concentrated to give the titled compound (2.6 g, 99%).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[C:16](Br)=[N:15][C:14]=2[N:13]([CH3:26])[C:11]1=[O:12])(=[O:3])[CH3:2].[S-2:28].[Na+].[Na+]>C(O)C>[C:1]([O:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[C:16]([SH:28])=[N:15][C:14]=2[N:13]([CH3:26])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: CCOCn1c(Br)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Reactant: [S-2]
Agent: [Na+]
Solvent: CCO
Product: CCOCn1c(S)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a stirring solution of (R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (prepared as described above for CT12440) (1.77 g, 4.0 mmol) in ethanol (100 ml) was added sodium sulfide (4.48 g, 80 mmol). The reaction mixture was stirred at 90° C. for 1 hour. After evaporation of the solvent under reduced pressure, the crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-methanol (7:1) to provide (R)-1-(5-acetoxyhexyl)-7-ethoxymethyl-8-mercapto-3-methylxanthine. This product was dissolved in methanol (100 ml). A solution of hydrogen chloride in ether (1.0 M, 1 .0 ml) was added and stirred at room temperature for 24 hours. After evaporation of the solvent under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-methanol (4:1) to provide (R)-1-(5-hydroxyhexyl)-7-ethoxymethyl-8-mercapto-3-methylxanthine (610 mg, 51% yield) as a white solid.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][I:21])[OH:19])[CH3:9].CN(C1C=CC=CN=1)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>ClCCl.C(OCC)(=O)C>[C:31]([O:18][CH:14]1[CH2:13][CH2:12][C:11]([CH2:20][I:21])([OH:19])[CH:10]([C:2]2([CH3:9])[O:1][CH:3]2[CH2:4][CH:5]=[C:6]([CH3:7])[CH3:8])[CH:15]1[O:16][CH3:17])(=[O:33])[CH3:32]
Reactant: COC1C(O)CCC(O)(CI)C1C1(C)OC1CC=C(C)C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC1C(OC(C)=O)CCC(O)(CI)C1C1(C)OC1CC=C(C)C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
In dichloromethane (5 ml) was dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-iodomethyl-1,4-cyclohexanediol (2.08 g). To the solution were added dimethylaminopyridine (0.74 g) and acetic anhydride (0.58 ml). The mixture was stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 ml), which was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the solvent was purified by means of a silica gel column chromatography (carrier 100 g, developing solvent: ethyl acetate - hexane=1:3) to afford 4-O-acetyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-iodomethyl-3-methoxy-1,4-cyclohexanediol (2.19 g: yield 95%) as a colorless oily product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:31])[C:24]([NH:26][C:27](=[O:30])[CH2:28]Br)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:31])[C:24]([NH:26][C:27](=[O:30])[CH2:28][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(NC(=O)CBr)c(Cl)cc3n2COCCOC)c1
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2nc3cc(NC(=O)CN4CCOCC4)c(Cl)cc3n2COCCOC)c1
Temperature: 23 °C
Reaction time: 0.83 h
Yield: 96 %

Procedure:
To a suspension of 1-[5-(2-bromo-acetylamino)-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.100 g, 0.194 mmol) and dichloromethane (1 mL) was added morpholine (51.0 μL, 0.580 mmol). The reaction mixture was stirred at 23° C. for 50 min. The reaction mixture was partitioned between EtOAc (15 mL) and water (10 mL), and the aqueous layer was further extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine (15 mL), dried, filtered, and concentrated under reduced pressure, to yield the titled compound (97 mg, 96% yield) as a 3:1 mixture of regioisomers. MS (ESI/CI): mass calcd. for C23H29ClN6O6, 520.2; m/z found, 521.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 10.00 (s, 1H), 8.89 (s, 1H), 8.85 (s, 1H), 8.18 (s, 1H), 7.68 (s, 1H), 6.12 (s, 2H), 4.36 (q, J=7.1 Hz, 2H), 3.87-3.80 (m, 4H), 3.67-3.60 (m, 2H), 3.48-3.42 (m, 2H), 3.32 (s, 2H), 3.24 (s, 3H), 2.73-2.67 (m, 4H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8](O)[C:7]([CH3:12])([CH3:11])[C:6]=2[CH:13]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:12])[C:6]=2[CH:13]=1
Reactant: CC1(C)c2cc(Br)ccc2OC1O
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC1(C)COc2ccc(Br)cc21

Procedure:
A solution of 5-Bromo-3,3-dimethyl-2,3-dihydro-benzofuran-2-ol (813 mg, 3.36 mmol), Triethylsilane (805 □L, 5.04 mmol), and 30% TFA/CH2Cl2 (15 mL), were stirred at room temperature for 1 h. The solution was then diluted with Toluene (15 mL), stripped of all solvents, and chromatographed on silica eluted with a gradient 5–25% Ethyl acetate/Hexanes. Yield 549 mg, 72%.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([CH2:15][C:16]([OH:18])=O)[C:13]=3[CH2:14][C:5]=2[N:4]2[CH:19]=[CH:20][N:21]=[C:3]12.[CH3:22][NH2:23]>C(O)C.CO.CC(C)=O>[CH3:22][NH:23][C:16](=[O:18])[CH2:15][C:12]1[C:13]2[CH2:14][C:5]3[N:4]4[CH:19]=[CH:20][N:21]=[C:3]4[C:2](=[O:1])[NH:7][C:6]=3[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CN
Reactant: O=C(O)Cc1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Solvent: CC(C)=O
Solvent: CO
Solvent: CCO
Product: CNC(=O)Cc1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Reaction time: 0.25 h

Procedure:
A solution of 0.93 g of the ethyl ester of (4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-9-yl)acetic acid, 20 ml of methylamine as a 33% solution in ethanol and 20 ml of methanol under an argon atmosphere is stirred at a temperature in the region of 20° C. for 18 hours. The reaction mixture is filtered. The precipitate obtained is washed successively with three times 40 ml of ethanol and three times 40 ml of methyl-tert-butyl ether and dried under reduced pressure (15 mm Hg; 2 kPa) at 20° C. The solid obtained is suspended in a mixture of acetone (25 ml) and methanol (5 ml) and stirred for 15 minutes and then filtered, washed with 10 ml of acetone and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 60° C. 0.32 g of N-methyl-2-(4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-9-yl)acetamide is obtained in the form of a white solid, the melting point of which is greater than 260° C (Analysis C16H14N4O2; % Calculated C: 65.30, H: 4.79, N: 19.04; % Found C: 65.00, H: 4.50, N: 18.80).
Reaction SMILES: [CH2:1]([O:8][CH:9]([OH:14])[CH2:10][CH2:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](Br)[CH3:18].O>O1CCCC1>[CH2:17]([O:14][CH:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH3:13])[CH3:18]
Reactant: CCBr
Reactant: CCCCC(O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC(OCC)OCc1ccccc1
Yield: 86.4 %

Procedure:
A solution of 194 g (1 mol) of pentanediol monobenzyl ether in 1 L of tetrahydrofuran (hereinafter referred to THF) was added to a solution of 48 g (2 mol) of sodium hydride in 100 ml of THF under cooling. Then, the mixture was heated under reflux for 2 hours and cooled to the room temperature before 140 g (1.3 mol) of ethyl bromide in 300 ml of THF was added dropwise. The mixture was heated under reflux for 6 hours. 500 ml of water was added and extraction was carried out with 500 ml of diethyl ether. After the organic layer was neutralized and washed with water and dried over anhydrous magnesium sulfate and concentrated. The oily residue was purified by distillation under the reduced pressure, to obtain 192 g of pentanediol benzyl ethyl ether. Boiling point; 110-117° C. (1 mmHg).