Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:53])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4].[C:54]([O:58][C:59]([NH:61][CH2:62][C:63]([NH:65][CH2:66][C:67](O)=[O:68])=[O:64])=[O:60])([CH3:57])([CH3:56])[CH3:55]>ClCCl>[C:54]([O:58][C:59]([NH:61][CH2:62][C:63]([NH:65][CH2:66][C:67]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:53])[N:15]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4])=[O:68])=[O:64])=[O:60])([CH3:57])([CH3:56])[CH3:55]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Yield: 81 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-octadecyl-oleamide and N-tert-butyloxycarbonyl-glycyl-glycine. Yield 81%. [α]D =+15.0° (c=0.94, dichloromethane).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[CH:7][CH:8]=[CH:9][C:10]1[N:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[N:11]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C=CC=Cc1cc2ccccc2n1-c1cccnc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCCc1cc2ccccc2n1-c1cccnc1

Procedure:
A solution of 1.1 g of 2-[4-(ethoxycarbonyl)butadienyl)-N-(3-pyridyl)indole in 25 ml of 95% ethanol is hydrogenated at 3 atmospheres pressure with 0.2 g of 10% palladium on charcoal for 31/2 hours. The reaction mixture is filtered through celite and evaporated to yield 2-[4-(ethoxycarbonyl)butyl)-N-(3-pyridyl)indole as a yellow oil; Rf (15% ethyl acetate in toluene/silica gel)=0.65; IR (CH2Cl2) 1726 cm-1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[N:5]=[CH:4][N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:17]([N:19]1[CH2:24][CH2:23][NH:22][C:21](=[O:25])[CH2:20]1)=[O:18].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[N:5]=[CH:4][N:3]=2)[C:21](=[O:25])[CH2:20]1)=[O:18]
Reactant: CC(C)COc1cc(Cl)ncn1
Reactant: Cc1ccc(C(=O)N2CCNC(=O)C2)cc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)N2CCN(c3cc(OCC(C)C)ncn3)C(=O)C2)cc1F
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A mixture of 4-chloro-6-isobutoxypyrimidine (50 mg, 0.27 mmol), 4-(3-fluoro-4-methylbenzoyl)piperazin-2-one (76 mg, 0.32 mmol), tris(dibenzylideneacetone)dipalladium (12 mg, 0.013 mmol), Xantphos (23 mg, 0.040 mmol), and tripotassium phosphate (85 mg, 0.40 mmol) in dioxane (5 mL) was stirred at 100° C. for 12 h. After cooling to rt, the mixture was poured onto water, and the aqueous layer was extracted with dichloromethane (twice). The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 4.3 mg (4% yields) of the title compound.
Reaction SMILES: [CH2:1]([N:4]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH:27]([N:30]=[C:31]=[O:32])([CH3:29])[CH3:28]>O1CCCC1>[CH:27]([NH:30][C:31](=[O:32])[O:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([N:4]([CH2:1][CH2:2][CH3:3])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH:6]=[CH:7]2)([CH3:29])[CH3:28]
Reactant: CC(C)N=C=O
Reactant: CCCN(c1ccncc1)n1ccc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCN(c1ccncc1)n1ccc2cc(OC(=O)NC(C)C)ccc21
Reaction time: 4 h
Yield: 115.6 %

Procedure:
To a solution of 1-(propyl-4-pyridinylamino)-1H-indol-5-ol (2.1 g) in 50 ml of tetrahydrofuran was added potassium carbonate (milled, 1.3 g). Then isopropyl isocyanate (0.67 g) was added and the reaction mixture was stirred for 4 hours. The mixture was filtered and the filtrate was concentrated to yield a solid (3.2 g), which was eluted with 5% methanol/dichloromethane on a silica gel column via HPLC. The desired fractions were concentrated to yield an oil which solidified on standing (2.75 g), m.p. 131°-133° C.
Reaction SMILES: CO.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:12]([N+:23]([O-])=O)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1>[C].[Pd].C(OCC)(=O)C>[NH2:23][C:12]1[CH:11]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=2)[CH:22]=[CH:21][C:13]=1[C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.33 g of 10% palladium-carbon was added to a mixed solution of 11 mL of methanol and 11 mL of ethyl acetate containing 1.1 g of tert-butyl 4-(3-chlorophenyl)-2-nitrobenzoate and stirred under hydrogen atmosphere at room temperature for 3 hours. After insoluble were removed by filtration, the solvent was evaporated under reduced pressure. 11 mL of acetic acid, 11 mL of methanol and 0.33 g of 10% palladium-carbon were added to the obtained residue sequentially and stirred under hydrogen atmosphere at room temperature for 2 hours. After insoluble were removed by filtration, the solvent was evaporated under reduced pressure to obtain 0.70 g of tert-butyl 2-amino-4-(3-chlorophenyl)benzoate as white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=[O:12])=[N:8][C:6]=2[N:7]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][OH:12])=[N:8][C:6]=2[N:7]=1
Reactant: O=Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 5-chloro-7-morpholinothiazolo[4,5-d]pyrimidine-2-carbaldehyde 43 (1.0 g, 3.5 mmol) in MeOH (30 mL) at 0° C. was treated with NaBH4(0.1 g, 3.5 mmol). The solution was allowed to warm to room temperature and stirred 15 min. The reaction mixture was quenched with a mixture of a saturated solution of sodium bicarbonate and water (1:1, v/v). The aqueous solution was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude (5-chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)methanol 56 required no further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1C(O)=O.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(O)c(C(=O)O)cnc2c1
Solvent: CCOC(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc2c(O)ccnc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
4-Hydroxy-7-methoxy-3-quinolinecarboxylic acid (21.4 g, 0.1 mol) was added with diphenyl ether (150 ml) and decarboxylated at 250° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and added with ethyl acetate (300 ml). The resulting precipitates were collected by filtration to obtain crude 4-hydroxy-7-methoxyquinoline (15.0 g). This was recrystallized from water (about 300 ml) to obtain 14.8 g (86%) of 4-hydroxy-7-methoxyquinoline.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28](O)(=[O:33])[CH2:29]/[CH:30]=[CH:31]/[CH3:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:33])[CH2:29]/[CH:30]=[CH:31]/[CH3:32])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: C/C=C/CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: C/C=C/CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (92 mg, 89%), MS (ISP) m/z=413.4 [(M+H)+], mp 170° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and (E)-pent-3-enoic acid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[C:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:27][CH2:28][CH2:29][CH2:30]CS([O-])(=O)=O)=[CH:22][CH:21]=1)(=[O:18])[CH3:17]>>[C:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:27][CH2:28][CH2:29][CH2:30][O:1][C:2]2[C:3]([CH3:15])=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=3[CH:14]=2)=[CH:22][CH:21]=1)(=[O:18])[CH3:17]
Reactant: Cc1cc2c(cc1O)C(C)(C)OC(=O)N2
Reactant: CC(=O)Nc1ccc(SCCCCCS(=O)(=O)[O-])cc1
Product: CC(=O)Nc1ccc(SCCCCOc2cc3c(cc2C)NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 4 from 6-hydroxy-4,4,7-trimethyl-4H-3,1-benzoxazin-2-one and 4-(4-acetamidophenylmercapto)-butylmesylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27](O)=[O:28])[CH:5]=[N:6][C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:24])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:11][CH2:10]1.[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:36][NH2:37].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O.O>[Cl:1][C:2]1[C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)=[O:24])[CH2:11][CH2:10]2)=[N:6][CH:5]=[C:4](/[CH:25]=[CH:26]/[C:27](=[O:28])[NH:37][O:36][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][O:30]2)[CH:3]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)C=Cc1cnc(NC2CCN(C(=O)Nc3ccc(Cl)cc3)CC2)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(/C=C/c1cnc(NC2CCN(C(=O)Nc3ccc(Cl)cc3)CC2)c(Cl)c1)NOC1CCCCO1
Temperature: 23 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a suspension of crude 3-{5-Chloro-6-[1-(4-chlorophenylcarbamoyl)-piperidin-4-ylamino]-pyridin-3-yl}-acrylic acid (247 mg) in DMF (3 ml) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (73.1 mg), EDCI (96.9 mg), HOBt (84.3 mg,), the mixture was stirred at 23° C. for 8 hours. The mixed solution was poured into a mixture of water (20 ml) and AcOEt (20 ml). The organic layer was separated, washed with water twice and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with 5% MeOH in dichloromethane to give 4-[(3-chloro-5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)amino]-N-(4-chlorophenyl)-1-piperidinecarboxamide (246 mg).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Mg+2].[Cl-].[Cl-].[Cl:15][C:16]1[CH:17]=[C:18]([C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24])[CH:19]=[CH:20][CH:21]=1.C([O-])(=O)CC([O-])=O>C(#N)C>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]([CH3:27])([CH3:26])[C:23]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:24])[CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C(=O)Cl)c1cccc(Cl)c1
Agent: O=C([O-])CC(=O)[O-]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 104.5 %

Procedure:
Diethyl malonate (3.72 mL, 24.6 mmol) in ACN (50 mL) was cooled to 0° C. MgCl2 (2.34 g, 24.6 mmol) was added, followed by addition of TEA (7.18 mL, 51.7 mmol) slowly via syringe. The mixture was stirred at 0° C. for 15 minutes before being brought to room temperature and stirred for 2.5 hours. 2-(3-Chlorophenyl)-2-methylpropanoyl chloride (5.69 g, 24.6 mmol) was dissolved in ACN (20 mL) and added to the malonate solution. The reaction mixture was then stirred at 50° C. for 16 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, and partitioned between 1M HCl and EtOAc. The aqueous layer was separated and extracted with EtOAc (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give the desired compound as a brown oil (8.76 g). MS (m/e)=341.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:23]([O:25]C)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>CO.[OH-].[Na+]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][C:17]2([C:23]([OH:25])=[O:24])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(CN2CCC(CNC(=O)OC(C)(C)C)CC2)CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCN(CC2(C(=O)O)CCOCC2)CC1
Temperature: 60 °C
Reaction time: 7 h
Yield: 65.7 %

Procedure:
To a solution of methyl 4-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidine-1-yl)methyl]tetrahydro-2H-pyran-4-carboxylate (6.47 g, 17.5 mmol, step 3 of Example 8) in methanol (32 mL), 5 N NaOH aq (10 mL) was added at room temperature (exothermic). The resulting solution was stirred at 60° C. for 7 h, then cooled to 5˜10° C. in ice-cold bath. To this solution, 5 N HCl aq (10 added and the resulting solution (pH value was ca. 6) was concentrated. To the residue, 2-propanol (80 mL) was added. This solution was concentrated. To the residue, 2-propanol (80 mL) was added and it was concentrated again. The residue was diluted with ethanol (80 mL) and the mixture was stirred at room temperature for 2 h. It was filtered through a Celite pad (5.0 g) to remove NaCl. The Celite pad was washed with ethanol (20 mL) and the combined filtrate was concentrated. To the residue, CH3CN (40 mL) was added and it was concentrated. During this procedure, the formation of white precipitate was noticed. To the residue, CH3CN (40 mL) was added and the resulting suspension was stirred at room temperature for 2 h. This mixture was filtered and obtained solid was washed with CH3CN (10 mL), then dried under reduced pressure to give 4.1 g (65%) of the titled compound as white powder.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3](=O)[CH2:4][C:5](=O)[CH3:6].[CH3:11][NH:12][NH2:13]>C(O)C>[CH3:11][N:12]1[C:5]([CH3:6])=[CH:4][C:3]([C:2]([F:10])([F:9])[F:1])=[N:13]1
Reactant: CNN
Reactant: CC(=O)CC(=O)C(F)(F)F
Solvent: CCO
Product: Cc1cc(C(F)(F)F)nn1C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution 25.0 grams of 1,1,1-trifluoro-2,4-pentanedione in 150 ml of ethanol (anhydrous, 5% methanol) at 10° C. was added dropwise over 35 minutes a solution 8.3 grams of methyl hydrazine in 25 ml of ethanol. The reaction temperature did not exceed 20° C. After an additional 30 minutes of stirring, the cooling bath was removed and the reaction was allowed to stir for one hour. Then five ml of glacial acetic acid was added and the reaction was refluxed for four hours. The reaction was then concentrated under reduced pressure and 100 ml of toluene was added to help azeotrope the residual acetic acid during a second concentration under reduced pressure. High vacuum was pulled on the sample for one hour at 50° C. to yield 25.3 g of the desired product as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[Cl:15][CH2:16][C:17]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:13][CH:14]=1)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(C(=O)CCC(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)CCl)cc1
Yield: 90.4 %

Procedure:
20 g (103 millimoles) of β-(p-aminobenzoyl)-propionic acid and 12.9 g (114 millimoles) of chloroacetyl chloride, together with 200 ml of absolute toluene, are kept for 4 hours at 80° C. The product is filtered off at 10° C., washed with water and dried under reduced pressure at 50° C. 25.1 g (90% of theory) of β-(p-chloroacetylaminobenzoyl)-propionic acid are isolated as light brown crystals which, after recrystallization from acetone, melt at 184°-185° C.
Reaction SMILES: [I:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[C@H:26]2[CH2:31][CH2:30][C@H:29]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:28][CH2:27]2)(=O)=O)=CC=1>CN(C=O)C>[Si:33]([O:32][C@@H:29]1[CH2:28][CH2:27][C@H:26]([N:4]2[C:5]3[CH:10]=[CH:9][N:8]=[C:7]([O:11][CH3:12])[C:6]=3[C:2]([I:1])=[CH:3]2)[CH2:31][CH2:30]1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)cc1
Reactant: COc1nccc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c1c(I)cn2[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine (0.100 g) in DMF (5 mL) was added sodium hydride (60% dispersion in mineral oil, 36.5 mg), and the mixture was stirred at room temperature for 1 hr. trans-4-((tert-Butyl(dimethyl)silyl)oxy)cyclohexyl 4-methylbenzenesulfonate (351 mg) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (100 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:30])[C:12]3[S:19][C:18]([CH:20]=[O:21])=[C:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:30])[C:12]3[S:19][C:18]([CH2:20][OH:21])=[C:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:31][CH:32]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(C=O)c(COCC[Si](C)(C)C)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CO)c(COCC[Si](C)(C)C)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.7 %

Procedure:
To a cold (0° C.), stirred solution of 1.56 g of N-(4-chlorobenzyl)-2-formyl-4-methyl-7-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide And 0.91 mL of acetic acid in 32 mL of CH2Cl2 is added 1.7 g of sodium triacetoxyborohydride. The ice bath is removed and the reaction allowed to stir at room temperature for 4 h, then partitioned between chloroform and aq. NaHCO3. The organic phase is dried (Na2SO4) and concentrated under reduced pressure, and the residue flash chromatographed on silica using 2% MeOH in CH2Cl2 to provide 1.53 g of the title compound as a pale yellow solid. Recrystallization from acetonitrile furnishes white platelets.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5]>CO>[OH:1][C@@H:2]([CH2:8][CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCC(=O)CC(=O)OC
Solvent: CO
Product: CCC[C@H](O)CC(=O)OC
Temperature: 30 °C
Reaction time: 66 h
Yield: 77 %

Procedure:
To a solution of 2.88 g (20 mmol) of methyl 3-ketohexanoate in 10 ml methanol, 36 mg (0.004 mmol) RuCl2(R)-binap was added and stirred in an autoclave under a hydrogen pressure of 100 atm at 30° C. for 66 hours. After concentration and distillation, 2.24 g (15.4 mmol, 99% ee) of methyl (S)-3-hydroxyhexanoate was obtained. The condition of chiral HPLC is the following. Column, CHIRALPAK OD-H manufactured by Daicel Chemical Industries, Ltd.; Eluate, Hexane:2-propanol=90:10; flow rate, 1.0 mL/min; Wavelength of detection, 210 nm; Temperature, 25° C.; Retention time, 5 min (R) and 7 min (S).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:37]=[CH:36][C:11]2[NH:12][C:13]([C:18]3[C:27](=[O:28])[C@:26]([CH3:34])([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]=3[OH:35])=[N:14][S:15](=[O:17])(=[O:16])[C:10]=2[CH:9]=1)(C)(C)C.[ClH:39]>O1CCOCC1>[ClH:39].[NH2:7][C:8]1[CH:37]=[CH:36][C:11]2[NH:12][C:13]([C:18]3[C:27](=[O:28])[C@:26]([CH3:34])([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[C:25]4[C:20]([C:19]=3[OH:35])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[N:14][S:15](=[O:17])(=[O:16])[C:10]=2[CH:9]=1
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Yield: 85 %

Procedure:
A solution of Example 39G (0.713 g, 1.32 mmol) in 4M hydrochloric acid in 1,4-dioxane (10 mL) was stirred at 25° C. for 1 hour. The solution was concentrated in vacuo and the residue was triturated in diethyl ether to give the title compound (0.537 g, 85%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.42 m, 1 H) 0.74 m, 7 H) 1.32 m, 1 H) 1.58 (m, 3 H) 2.15 m, 2 H) 7.07 m, 2 H) 7.51 m, 2 H) 7.77 m, 2 H) 8.16 m, 1 H) 13.57 (m, 1 H). MS (ESI−) m/z 438 (M−H)−.
Reaction SMILES: C(OCC)(=O)C=C.ON1C(=O)C2=CC=CC=C2C1=O.O=O.[OH:22][CH:23]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[C:24]([O:26]CC)=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(#N)C.CC(O)C>[OH:22][CH:23]1[CH2:29][C:30]([CH3:31])([CH3:32])[O:33][C:24]1=[O:26]
Reactant: CCOC(=O)C(O)CC(C)(C)O
Agent: [Co+2]
Agent: C=CC(=O)OCC
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CC(C)O
Product: CC1(C)CC(O)C(=O)O1

Procedure:
A mixture of 3 mmol of ethyl acrylate, 1 ml of 2-propanol, 0.6 mmol of N-hydroxyphthalimide, 0.06 mmol of cobalt(II) acetate, and 1 ml of acetonitrile was stirred at 60° C. in an oxygen atmosphere (1 atm) for 5 hours. A gas chromatographic analysis of products in a reaction mixture revealed that ethyl 2,4-dihydroxy-4-methylpentanoate and α-hydroxy-γ,γ-dimethyl-γ-butyrolactone were formed in yields of 1% and 43%, respectively. The conversion rate from ethyl acrylate was 53%.