Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:29](O)=[O:30])([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][C:3]=1[F:42].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:55][S:56]([NH2:59])(=[O:58])=[O:57].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH2:27][CH3:28])([CH2:25][CH3:26])[C:29]([NH:59][S:56]([CH3:55])(=[O:58])=[O:57])=[O:30])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][C:3]=1[F:42]
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)c(F)cc12)C(=O)O
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)c(F)cc12)C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
A solution of racemic (2′S,3S,4′R)-6-chloro-5-fluoro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-ethyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (100 mg, 0.16 mmol) and CDI (123 mg, 0.64 mmol) in DMF (3 mL) was heated at 75° C. for 3 h. Then to this solution was added a mixture of methanesulfonamide (144 mg, 1.5 mmol) and NaH (53 mg, 60%,1.3 mmol) in DMF (1.5 mL), which had been previously stirred at room temperature for 2 h. After the resulting mixture was stirred at room temperature for 20 mins, it was poured into water and the aqueous solution was acidified by diluted HCl solution. After the aqueous phase was extracted with EtOAc twice, the combined organic phases were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound (50 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH3:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCC1(C(=O)OCC)CCCC1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC1(C(=O)OCC)CCCC1OC(=O)c1ccccc1
Reaction time: 12 h
Yield: 109.7 %

Procedure:
Ethyl 2-hydroxy-1-n-propyl-cyclopentane carboxylate (6.00 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.67 ml) was slowly added, then benzoyl chloride (5.33 ml, 0.045 mol) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 10.00 g of yellow liquid, MS: m/e 305(M+″+1), 304(M+), 259, 230, 199, 182, 153, 105(base), 77.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])(O)[CH3:9].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.CCOCC>ClCCl.O>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])[CH3:9]
Reactant: CC(O)(c1ccccc1O)c1ccccc1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC(c1ccccc1O)c1ccccc1O
Temperature: 25 °C
Yield: 76.5 %

Procedure:
1,1-Bis(2-hydroxyphenyl)ethanol (8.57 g) dissolved in 40 ml of dichloromethane was cooled with an ice bath and to this was added sequentially with stirring 3.70 ml of trifluoroacetic acid in 20 ml of dichloromethane and (dropwise) 7.67 ml of triethylsilane in 20 ml of dichloromethane. The mixture was allowed to warm to room temperature and react for another 2 hours. Ether and water were added and the phases separated. The organic phase was extracted with several small portions of 2N sodium hydroxide and the extracts were combined and acidified with hydrochloric acid. The resulting mixture was extracted with ether and the ether extract was dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 6.10 g of the title compound as a brown oil.
Reaction SMILES: II.O[PH2]=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:13]([C:16]([C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH:25]=[CH:26][N:27]=4)[CH:24]=3)(O)[CH3:17])=[CH:14][N:15]=2)[N:12]=1.[OH-].[Na+]>C(O)(=O)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:13]([CH:16]([C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH:25]=[CH:26][N:27]=4)[CH:24]=3)[CH3:17])=[CH:14][N:15]=2)[N:12]=1
Reactant: CC(O)(c1ccc2nccn2c1)c1cnc2ccc(Cl)nn12
Agent: II
Agent: O=[PH2]O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(c1ccc2nccn2c1)c1cnc2ccc(Cl)nn12
Temperature: 150 °C

Procedure:
Iodine (4.8 g, 18.91 mmol) and H3PO2 (5.1 mL of a 50% aqueous solution, 46.8 mmol) were added to a solution of (rac)-1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(imidazo[1,2-a]pyridin-6-yl)ethanol (Stage 292.1, 1.85 g, 5.90 mmol) in acetic acid (50 mL). The RM was portion wise in 3 different microwave reactors and was heated at 150° C. for 5 min under microwave irradiations. It was basified with 2.5 N NaOH solution and then it was extracted twice with EtOAc/MeOH (9:1) twice. Combined organic layers was washed with brine and dried over Na2SO4, filtered and concentrated to give the title compound as a brown solid (tR 0.5 min (conditions 2), MH+=298)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]2=3)[CH2:3][CH2:2]1.[CH2:17]1[O:27][C:20]2([CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]2)[O:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:19]1[C:20]2([CH2:25][CH2:24][CH:23]([N:1]3[CH2:2][CH2:3][C:4]4([O:11][C:10](=[O:12])[NH:9][C:8]5[CH:13]=[CH:14][CH:15]=[CH:16][C:7]4=5)[CH2:5][CH2:6]3)[CH2:22][CH2:21]2)[O:27][CH2:17][CH2:18]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: O=C1Nc2ccccc2C2(CCNCC2)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2C2(CCN(C3CCC4(CC3)OCCO4)CC2)O1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Spiro[4H-3,1-benzoxazine-4,4′-piperidin]-2(1H)-one (A4) (400 mg, 1.83 mmol) was suspended in anhydrous 1,2-dichloroethane (8.0 mL) and treated with 1,4-cyclohexanedione mono-ethylene ketal (viia) (429 mg, 2.75 mmol), glacial acetic acid (220 mg, 3.66 mmol), and sodium triacetoxyborohydride (776 mg, 3.66 mmol). The reaction flask was flushed with nitrogen and stirred for 60 hours at room temperature. The reaction was diluted with dichloromethane (25 mL), quenched with 1.0 N NaOH (10 mL), and stirred at room temperature vigorously for 30 minutes. The layers were separated and the aqueous layer was extracted once with dichloromethane (10 mL). The pooled organic layers were washed with water (1×25 mL) and saturated brine (1×25 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford crude 1′-(1,4-dioxaspiro[4.5]decan-8-yl)spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one (viiib) as a white solid. LC/MS m/z 359.2 [M+H]+, retention time 1.61 min (RP-C18, 10-99% CH3CN/0.05% TFA).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8]N(CC)CC)=[CH:6][C:5]([CH3:14])=[CH:4][C:3]=1[N:15]1[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=[N:16]1.[OH:24][C:25]1[CH:38]=[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH:36]=[CH:35][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28]>>[N:19]1[N:15]([C:3]2[CH:4]=[C:5]([CH3:14])[CH:6]=[C:7]([CH2:8][C:38]3[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:36][CH:35]=[C:26]([C:27](=[O:28])[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:25]=3[OH:24])[C:2]=2[OH:1])[N:16]=[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=12
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: CCN(CC)Cc1cc(C)cc(-n2nc3ccccc3n2)c1O
Product: CCCCCCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1Cc1cc(C)cc(-n2nc3ccccc3n2)c1O

Procedure:
Following the general procedure of Example 5 using the Mannich intermediate of Example 1 and 2-hydroxy-4-dodecyloxybenzophenone, the title compound is obtained as a yellow crystalline solid melting at 100°-105° C.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[CH:11]=[C:10]([Cl:16])[CH:9]=2)([O:3][CH2:4][CH3:5])=[O:2].CN(C)[CH:19]=[O:20].P(Cl)(Cl)(Cl)=O>ClC(Cl)C>[CH:19]([C:14]1[C:13]2[C:8](=[CH:9][C:10]([Cl:16])=[CH:11][C:12]=2[Cl:15])[NH:7][C:6]=1[C:1]([O:3][CH2:4][CH3:5])=[O:2])=[O:20]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2[nH]1
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Combine 2-carboethoxy-4,6-dichloroindole (20.0 g, 0.077 mol), and dimethylformamide (9.0 mL, 0.117 mol) in dichloroethane (100 mL). Add phosphoryl chloride (18.0 g, 0.117 mmol). Heat to reflux. After 3.5 hours, cool the reaction mixture to ambient temperature to obtain a solid. Collect the solid by filtration, rinse with water. Combine the solid with aqueous 1 M sodium acetate solution and stir. After 1 hour, filter, rinse with water, and dry to give 3-formyl-2-carboethoxy-4,6-dichloroindole.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.Cl.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH2:22][C:23]([O:25][CH3:26])=[O:24].C(N(CC)CC)C.Cl>ClCCl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][C:23]([O:25][CH3:26])=[O:24])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CC1CCCCN1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
A solution of 3-(trifluoromethyl)benzenesulfonyl chloride (1 eq) in dichloromethane (1.6 ml/mmol) was added dropwise to a cooled solution (0° C.) of methyl 2-(piperidin-2-yl)acetate hydrochloride (1.1 eq) in dichloromethane (40 ml/mmol) and triethylamine (2.5 eq). The mixture was stirred for 90 min at 25° C., after which the reaction was completed (thin-layer chromatographic analysis). Hydrogen chloride solution (0.5 mol/l, 2 ml/mmol) was added and the mixture was stirred for 15 min. The organic phase was separated off, washed with water, dried over sodium sulfate and concentrated to small volume under vacuum. Yield: 80%
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[CH2:11][C@:10]1([C:41]1[CH:46]=[C:45]([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([CH2:54][CH3:55])=[CH:50][CH:49]=2)[CH:44]=[CH:43][C:42]=1[F:56])[OH:40])C1C=CC=CC=1>CO.C1COCC1.[OH-].[Pd+2].[OH-]>[CH2:54]([C:51]1[CH:50]=[CH:49][C:48]([CH2:47][C:45]2[CH:44]=[CH:43][C:42]([F:56])=[C:41]([C@:10]3([OH:40])[CH2:11][C@H:12]([CH2:31][OH:32])[C@@H:13]([OH:23])[C@H:14]([OH:15])[C@H:9]3[OH:8])[CH:46]=2)=[CH:53][CH:52]=1)[CH3:55]
Reactant: CCc1ccc(Cc2ccc(F)c([C@]3(O)C[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Cc2ccc(F)c([C@]3(O)C[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c2)cc1
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
To a mixture solution of (1R,2R,3S,4R,5R)-2,3,4-trisbenzyloxy-5-benzyloxymethyl-1-[5-(4-ethylbenzyl)-2-fluorophenyl]cyclohexanol (271 mg, 0.361 mmol) in methanol-THF (1:1) mixed solvent (20 mL), a 20% palladium hydroxide catalyst (40 mg) was added thereto. The mixture was stirred under a hydrogen atmosphere for 30 minutes, and then the catalyst was filtered off. The solvent was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography [developing solution=methanol:methylene chloride (1:10)] to obtain the title compound (44.6 mg, 31.6%).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+:14]>O>[C:1]([O-:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[K+:14].[K+:14]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1ccc(C(=O)[O-])cc1

Procedure:
The procedure of Example 1 was employed with the following exceptions. 24.75 grams of terephthalic acid were added to a solution of 18.89 grams of potassium hydroxide in 200 grams of distilled water, slowly and with heating and stirring to form potassium terephthalate, and then 41.17 grams of potassium carbonate were dissolved in the solution. 6.16 grams of potassium dichromate were dissolved in 100 grams of water, and this solution was added to the solution of potassium terephthalate to form the solution for spray drying. 50 grams of the resulting co-crystallite powder from the spray drying step was then dry blended with 31.7 grams of 90 percent potassium hydroxide powder in the Waring blender. The resulting dry pyrolysis product weighed 5.7 grams, had a BET surface area of 1680 square meters per gram, and contained 30 percent of chromia (Cr2O3) by weight, based on the weight of the pyrolysis product. Two percent of the chromia had an average crystallite size of 80 Å, with the remainder having an average crystallite size below 35 Å.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.[ClH:11]>>[Cl:11][C:6](=[N:7][OH:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(C=NO)cc1
Reactant: Cl
Product: Cc1ccc(C(Cl)=NO)cc1

Procedure:
27 g (0.2 mol) of 4-methylbenzaldoxime was chlorinated in the same manner as described in Example 9 (A) in 150 ml of 8N hydrochloric acid to give 28 g of the product as white crystals having a melting point of 60°-70°C. Yield, about 82%.
Reaction SMILES: [OH:1][CH:2]([CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][CH3:29])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([C:14]([OH:16])=[O:15])=[CH:11][C:10](=[O:17])[C:9]=2[CH:18]=1.C(=O)(O)[O-].[Na+:34]>O>[OH2:1].[OH:1][CH:2]([CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][CH3:29])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([C:14]([O-:16])=[O:15])=[CH:11][C:10](=[O:17])[C:9]=2[CH:18]=1.[Na+:34].[Na+:34].[OH:1][CH:2]([CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][CH3:29])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([C:14]([O-:16])=[O:15])=[CH:11][C:10](=[O:17])[C:9]=2[CH:18]=1
Reactant: CCCc1ccccc1OCC(O)COc1ccc2oc(C(=O)O)cc(=O)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCc1ccccc1OCC(O)COc1ccc2oc(C(=O)[O-])cc(=O)c2c1

Procedure:
A mixture of 7.31 parts of 6-[2-hydroxy-3-(2-propylphenoxy)propoxy]-4-oxo-4H-1-benzopyran-2-carboxylic acid and 1.54 parts of sodium bicarbonate in 100 parts of water, was heated to effect solution. The solution was filtered and freeze dried to yield 7.5 parts of sodium 6-[2-hydroxy-3-(2-propylphenoxy)propoxy]-4-oxo-4H-1-benzopyran-2-carboxylate, hemihydrate.
Reaction SMILES: [Si](OC(COC1C=CC=CC=1)/C=C/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14][CH:15]([CH:21]([OH:29])[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:16]2=[O:20])(C(C)(C)C)(C)C.[Si](OC(COC1C=CC=CC=1)/C=C/C1CCC2C1C/C(=C\CCCC(OC)=O)/C2=O)(C(C)(C)C)(C)C.COC(CCC/C=C1/C(=O)C2C(C/1)CCC2)=O>>[OH:29][CH:21]([CH:15]1[CH2:14][CH:13]2[CH:17]([CH2:18][CH2:19][CH2:12]2)[C:16]1=[O:20])[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)CCCC(O)C1CC2C(/C=C/C(COc3ccccc3)O[Si](C)(C)C(C)(C)C)CCC2C1=O
Agent: COC(=O)CCC/C=C1\CC2C(/C=C/C(COc3ccccc3)O[Si](C)(C)C(C)(C)C)CCC2C1=O
Agent: COC(=O)CCC/C=C1\CC2CCCC2C1=O
Product: COC(=O)CCCC(O)C1CC2CCCC2C1=O

Procedure:
By proceeding in a manner similar to that described in Reference Example 48, but replacing the starting material by the appropriate quantity of 6-[(E)-3-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl]-3-(1-hydroxy-4-methoxycarbonylbut-1-yl)bicyclo[3,3,0]octan-2-one, prepared as described in Reference Example 53, and in the form of (±)-6β-[(E)-(mixture of 3α and 3β)-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl]-3-(1-hydroxy-methoxycarbonylbut-1-yl)bicyclo[3,3,0]octan-2-one, there was prepared 6-[(E)-3-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one, in the form of (±)-6β-[(E)-(mixture of 3α and 3β)-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one, otherwise known as (±)-methyl (5E,13E)-(9S), [mixture of (15R) and (15S)]-6a-oxo-6,9-methano-15-tert-butyldimethylsilyloxy-16-phenoxy-17,18,19,20-tetranorprosta-5,13-dienoate.
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[CH2:3][CH2:4][OH:5].[F:8][C:9]([F:21])([F:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17].C(OCC)(=O)C>C(Cl)Cl>[F:21][C:9]([F:8])([F:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([O:5][CH2:4][CH2:3][C:2]([OH:7])([CH3:6])[CH3:1])(=[O:17])=[O:18]
Reactant: CC(C)(O)CCO
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(O)CCOS(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 7 h
Yield: 66.7 %

Procedure:
To a solution of 3-methyl-1,3-butane diol (2.5 g, 21 mmol) and TEA (1.63 g, 16 mmol) in CH2Cl2 (15 mL) was added o-(trifluoromethyl)benzenesulfonyl chloride (2.03 g, 8.3 mmol) dissolved in CH2Cl2 (20 mL). The solution was stirred at rt for 7 h. The reaction mixture was diluted with CH2Cl2 (75 mL) and washed with 1 M HCl (2×25 mL), saturated aqueous NaHCO3 (1×25 mL) and saturated aqueous NaCl (1×25 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography with ethyl acetate in hexanes yielded the desired product (1.73 g, 66%). 1H NMR (400 MHz CDCl3) δ 8.23 (m, 1H), 7.91 (m, 1H), 7.75 (m, 2H), 4.32 (t, 2H, J=7.0 Hz), 1.91 (t, 2H, J=7.0 Hz) 1.22 (s, 6H). Anal. Calcd. For C12H15F3O4S: C, 46.15; H, 4.84. Found: C, 45.73; H, 4.88.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9](=O)[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12](=[NH:19])(OCC)[CH2:13][CH2:14][CH3:15]>C(O)C>[CH3:10][C:9]1[N:19]=[C:12]([CH2:13][CH2:14][CH3:15])[NH:2][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(N)C(C)=O
Reactant: CCCC(=N)OCC
Agent: Cl
Solvent: CCO
Product: CCCc1nc(C)c(C(=O)OCC)[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.5 %

Procedure:
Ethyl 2-amino-3-oxobutanoate hydrochloride (10 g) was added to a stirring solution of ethyl butaneimidate (83.5 g) in ethanol (800 ml, freshly distilled from magnesium ethoxide) and triethylamine (85 ml) and the resultant yellow mixture stirred at room temperature for 48 h. The solvent was removed in vacuo and the residue diluted with water (500 ml) and extracted into ethyl acetate (3×200 ml). The combined organic extracts were washed with water (2×100 ml), dried and concentrated in vacuo. The resultant residue was purified by trituration with ether (5×50 ml) and the residual buff solid dried to afford the title compound (4.05 g)
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([N:15]3C(=O)C4C(=CC=CC=4)C3=O)[CH:12]=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.CNN>ClCCl>[F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(F)c(-c2cc(N3C(=O)c4ccccc4C3=O)ccn2)n1
Agent: CNN
Solvent: ClCCl
Product: Cc1ccc(F)c(-c2cc(N)ccn2)n1
Temperature: 25 °C

Procedure:
2-(3′-fluoro-6′-methyl-2,2′-bipyridin-4-yl)isoindoline-1,3-dione (65 mg, 0.195 mmol) was suspended in dichloromethane (3 mL); methylhydrazine (0.205 mL, 3.90 mmol) was added and the mixture was stirred at room temperature over night. The reaction was filtered thru Celite® and the filtrate was concentrated to give the title compound as a clear yellow film which was used without further purification. ESI-MS: m/z 204.1 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:21]=[C:9]2[C:10]([NH2:20])=[N:11][C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:13][N:8]2[N:7]=1.[Cl:22][C:23]1[N:27]([CH3:28])[N:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:24]=1[CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[Cl:22][C:23]1[N:27]([CH3:28])[N:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:24]=1[CH2:33][N:17]1[CH2:18][CH2:19][N:14]([C:12]2[N:11]=[C:10]([NH2:20])[C:9]3[N:8]([N:7]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[N:21]=3)[CH:13]=2)[CH2:15][CH2:16]1
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1Cl
Reactant: Nc1nc(N2CCNCC2)cn2nc(-c3ccco3)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1nc(C(F)(F)F)c(CN2CCN(c3cn4nc(-c5ccco5)nc4c(N)n3)CC2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
To a solution of 2-furan-2-yl-6-piperazin-1-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine in methylene chloride (see Example 16 above) was added 5-chloro-1-methyl-3-(trifluoromethyl)pyrazole-4-carboxaldehyde (45 mg, 0.21 mmol), sodium triacetoxyborohydride (65 mg, 0.31 mmol) and acetic acid (12 μL, 0.2 mmol). The reaction was stirred at room temperature overnight. After the solvent was removed, the residue was subjected to flash chromatography (ethyl acetate/hexanes=40:60) to afford 6-[4-(5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)-piperazin-1-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine as a white solid (9 mg, 13%).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([CH2:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])=[N:13][N:12]=1)[CH3:2].[NH:28]1[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C.ClCCl.O>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:15][C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:28]4[CH2:33][CH2:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][CH2:29]4)[CH:7]=[CH:6][CH:5]=3)=[N:12][N:13]=2)[CH:17]=[CH:18][C:19]=1[CH2:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCc1c(C=O)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1CCN(Cc2cccc(-c3nnc(-c4ccc(CC(C)C)c(C#N)c4)s3)c2CC)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a solution of 5-[5-(2-ethyl-3-formylphenyl)-1,3,4-thiadiazol-2-yl]-2-(2-methylpropyl)benzonitrile (D27) (31 mg) and ethyl 4-piperidinecarboxylate (64.9 mg) in ethanol (10 mL) stirred at room temperature was added AcOH (0.15 mL). The reaction mixture was stirred at room temperature for 10 min. The residue was dissolved in dichloromethane (DCM) (10 mL), and sodium triacetoxyborohydride (52.5 mg) was added. Stirring continued for overnight. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated to give ethyl 1-[(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-ethylphenyl)methyl]-4-piperidinecarboxylate (D28) (38.4 mg). MS (ES): C30H36N4O2S requires 516. found 517.3 (M+H+).