Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[I:15]I>O1CCCC1>[I:15][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: II
Reactant: c1ccc2sccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Ic1cc2ccccc2s1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 39.1 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 25.0 grams (0.186 mole) of benzothiophene in 250 ml of dry tetrahydrofuran was cooled to -65° C., and 69.8 ml (0.186 mole) of n-butyllithium (2.7M in hexane) was added dropwise keeping the reaction mixture temperature below -60° C. Upon completion of addition, the reaction mixture was stirred for five minutes and then was allowed to warm to 0° C. After this time a solution of 50.8 grams (0.200 mole) of iodine in 180 ml of tetrahydrofuran was added dropwise keeping the reaction mixture temperature below 10° C. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it was quenched with an aqueous solution saturated with sodium metabisulfite. The reaction mixture was placed in a separatory funnel, and the organic layer was separated. The organic layer was washed with one portion of an aqueous solution saturated with sodium metabisulfite and with one portion of an aqueous solution saturated with sodium chloride. The aqueous layers were combined and washed with diethyl ether. The ether washes were combined with the organic layer, and the combination was dried with sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in diethyl ether and reconcentrated under reduced pressure to a residue. The residue was dissolved in warm hexane and eluted through a column of silica gel. The eluate was concentrated under reduced pressure to a volume of approximately 100 ml, and a solid crystallized from the solution. The mixture was cooled, and the solid was collected by filtration, yielding in two crops 18.9 grams of 2-iodobenzothiophene.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH3:15])[C:12]([OH:14])=O.[CH2:16]([O:18][C:19]([N:21]1[C:25]2[CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][C:24]=2[C:23]([NH2:36])=[N:22]1)=[O:20])[CH3:17].CCN(C(C)C)C(C)C.C(OCC)(=O)C.C1CCCCC1>C(Cl)Cl.CN(C=O)C.C1COCC1>[CH2:16]([O:18][C:19]([N:21]1[C:25]2[CH2:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][C:24]=2[C:23]([NH:36][C:12](=[O:14])[CH:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH3:15])=[N:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)n1nc(N)c2c1CN(C(=O)OC(C)(C)C)C2
Reactant: CC(C(=O)O)c1ccc2ccccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: CCOC(=O)n1nc(NC(=O)C(C)c2ccc3ccccc3c2)c2c1CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of 2-naphthalen-2-yl-propionic acid (1.48 g. 7.4 mmol) in DCM (40 ml) and DMF cat., (COCl) 2 (0.83 ml, 9.65 mmol) in DCM (10 ml) was added dropwise. The mixture was stirred at r.t. for 30 min. The reaction mixture was concentrated under vacuum, reconstituted twice with toluene and concentrated. A solution of the obtained acyl-chloride in THF (40 ml) was added slowly to a mixture of 3-amino-4,6-dihydro-pyrrolo[3,4-c]pyrazole-1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester (2.0 g, 6.75 mmol) and DIEA (5.8 ml, 33.3 mmol) in THF (40 ml) at 0-5° C. The reaction was allowed to reach r.t. and stirred overnight. The mixture was filtered and the solution evaporated to dryness under vacuum. The resulting residue was dissolved in DCM and the obtained solution was washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified by flash-chromatography (eluent: ethyl acetate/cyclohexane 3/7 then 4/6) to give 3.0 g (93% yield) of the title compound as a white solid.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][OH:6].[C:7]([C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[N:13][CH:14]=1)#[N:8]>CO>[Cl:15][C:12]1[N:13]=[CH:14][C:9]([C:7](=[N:5][OH:6])[NH2:8])=[CH:10][CH:11]=1
Reactant: NO
Reactant: N#Cc1ccc(Cl)nc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(=NO)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a solution of sodium methoxide (15.6 g of 25-30% in methanol, 72 mmol) in methanol (70 mL) at 0° C. was added hydoxylamine hydrochloride (5.02 g, 72 mmol) and the mixture was then stirred at room temperature for 30 minutes. 5-cyano-2-chloropyridine (10 g, 72 mmol) was added and the reaction was heated to reflux for 3 hours. The reaction was cooled to room temperature, filtered to remove precipitated sodium chloride and the filtrate was evaporated to dryness. The residue was dissolved in ethanol in order to crystallise the product but this was unsuccessful, so the solvent was removed in vacuo to give the title compound as a white solid (12 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]([CH3:17])([CH2:11][CH2:12][C:13](Cl)([CH3:15])[CH3:14])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[C:13]([CH3:15])([CH3:14])[CH2:12][CH2:11][C:9]2([CH3:17])[CH3:10]
Reactant: Brc1ccccc1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A 200 ml round-bottomed flask equipped with a stir bar and a reflux condenser was charged with a solution of bromobenzene (109 mmol, 17 ml) and 2,5-dichloro-2,5-dimethyl hexane (10 grams, 54.6 mmol) in dichloromethane (30 ml). Aluminum chloride (1.45 grams, 10.9 mmol) was added to the solution slowly, until spontaneous reflux subsides. After stirring for 10-15 minutes at room temperature, the reaction was poured into ice water (30 ml) and the layers were separated. The aqueous layer was extracted with EtOAc (5×20 ml). The combined organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated, to yield a 6-bromo-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:9]([CH2:17][OH:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)N([O])C(C)(C)CCC1.[Br-].[Na+].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@H:9]([CH:17]=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H](CO)Cc1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H](C=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100.3 %

Procedure:
To a solution of 0.32 g(0.94 mmoles) of N-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninol in 2.8 mL of toluene was added 2.4 mg (0.015 mmoles) of 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO), 0.1 g (0.97 mmoles) of sodium bromide, 2.8 mL of ethyl acetate and 0.34 mL of water. The mixture was cooled to 0° C. and an aqueous solution of 4.2 mL of 5% household bleach containing 0.23 g (3.0 mL, 2.738 mmoles) of sodium bicarbonate was added slowly over 30 minutes. The mixture was stirred at 0° C. for 10 minutes. Three more additions (0.4 mL each) of bleach was added followed by stirring for 10 minutes after each addition to consume all the stating material. The two phase mixture was allowed to separate. The aqueous layer was extracted twice with 8 mL of toluene. The combined organic layer was washed with 1.25 mL of a solution containing 0.075 g of potassium iodide, sodium bisulfate(0.125 g) and water(1.1 mL), 1.25 mL of 10% aqueous sodium thiosulfate solution, 1.25 mL of pH 7 phosphate buffer and 1.5 mL of brine solution. The organic solution was dried over magnesium sulfate, filtered and concentrated under reduced pressure co give 0.32 g (100% yield) of N-(t-Butoxycarbonyl)-N-benzyl-L-phenylalaninal.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([OH:43])(=[O:42])/[CH:31]=[CH:32]/[C:33]1[CH:41]=[CH:40][C:38]([OH:39])=[C:35]([O:36][CH3:37])[CH:34]=1>CO>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([O-:43])(=[O:42])/[CH:31]=[CH:32]/[C:33]1[CH:41]=[CH:40][C:38]([OH:39])=[C:35]([O:36][CH3:37])[CH:34]=1
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CO
Product: COc1cc(/C=C/C(=O)[O-])ccc1O
Temperature: 30 °C

Procedure:
Sunitinib (1.0 g) was suspended in methanol (152 mL), followed by addition of ferulic acid (0.48 g) at 25-35° C. over a period of 15 minutes. After the stipulated time period, methanol was completely distilled off under vacuum below 45° C. The residue was treated with acetonitrile (38 mL) and refluxed. The reaction mass was maintained at reflux temperature for 60 minutes. The reaction mass was cooled to 25-35° C. for crystallization. The solid obtained was filtered, washed with acetonitrile, suck dried and dried under vacuum at 60° C. over 4-5 hr period to obtain sunitinib ferulate. (1.2 g; yield:81%)
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[C:3]([NH2:5])=[O:4].[O:10]1[C:14]2=[N:15][C:16]3[C:22](=[O:23])[O:21][C:19](=[O:20])[C:17]=3[CH:18]=[C:13]2[CH:12]=[CH:11]1>O1CCCC1>[C:3]([C:2]([NH:1][C:22]([C:16]1[N:15]=[C:14]2[O:10][CH:11]=[CH:12][C:13]2=[CH:18][C:17]=1[C:19]([OH:21])=[O:20])=[O:23])([CH3:9])[CH:6]([CH3:8])[CH3:7])(=[O:4])[NH2:5]
Reactant: O=C1OC(=O)c2nc3occc3cc21
Reactant: CC(C)C(C)(N)C(N)=O
Solvent: C1CCOC1
Product: CC(C)C(C)(NC(=O)c1nc2occc2cc1C(=O)O)C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
2-Amino-2,3-dimethylbutyramide (2.1 g, 0.016 mol) is added to a stirred suspension of furo[2,3-b]pyridine-5,6-dicarboxylic acid anhydride (3.0 g, 0.016 mol) in tetrahydrofuran (7.5 mL) and the mixture allowed to stir at room temperature for 16 hours. The reaction mixture is then stirred at 60° C. for one hour, cooled to room temperature, either added, and the solid filtered off and dried to give 5 g of 6-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]furo[2,3-b]pyridine-5-carboxylic acid mp 192°-196° C. (dec).
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:50]1[CH:55]=[C:54]([O:56][C@@H:57]([C@@H:59]2[CH2:63][O:62][C:61]([CH3:65])([CH3:64])[O:60]2)[CH3:58])[N:53]=[C:52]([S:66][CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[C:70]([F:74])[C:69]=2[F:75])[N:51]=1.[Cl-].[NH4+]>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:75][C:69]1[C:70]([F:74])=[CH:71][CH:72]=[CH:73][C:68]=1[CH2:67][S:66][C:52]1[N:51]=[C:50]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:55]=[C:54]([O:56][C@@H:57]([C@@H:59]2[CH2:63][O:62][C:61]([CH3:64])([CH3:65])[O:60]2)[CH3:58])[N:53]=1
Reactant: NS(=O)(=O)N1CCC1
Reactant: C[C@@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1
Temperature: 100 °C

Procedure:
A mixture of azetidine-1-sulphonamide (prepared according to patent WO 2004/011443, 0.16 g), tris(dibenzylideneacetone)-dipalladium (0) (33 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (17 mg), cesium carbonate (0.28 g) and 4 chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy]-pyrimidine (the product of step i) (0.25 g) in dioxane (10 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 20 min. Saturated ammonium chloride was added and the resulting mixture extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using EtOAc/isohexane (3:7) as eluent to give the subtitle compound as a yellow oil. Yield: 0.13 g.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:59]C(C)=O)[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].NN.O.CCOCC>C(O)C>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:59])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6]
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: NN
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Yield: 86.2 %

Procedure:
A solution of taxol (0.026 g, 0.030 mmol) and 98% hydrazine (0.035 g, 1.1 mmol) in 95% ethanol (1.0 mL) is stirred at room temperature for 2 hr. The solution is poured into water and ether, the mixture is shaken well, and the layers separated. The aqueous layer is extracted with additional ether. The combined ether extracts are dried over Na2SO4, filtered and concentrated, giving 0.021 g of the title compound: 1H NMR spectrum in CDCl3 is identical to the spectrum reported for 10-deacetyltaxol (Ringel, I.; Horwitz, S. B. J. Pharmacol. Exp. Ther. 1987, 242, 692) and is identical to the spectrum of an authentic sample.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([NH:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N[C@H](CO)C(=O)O
Reactant: O=Cc1ccccc1
Product: O=C(O)[C@@H](CO)NCc1ccccc1

Procedure:
The title compound was prepared from D-serine and benzaldehyde according to Method W and was obtained as a white solid (88%) that was used crude. δH (DMSO-d6) 7.45-7.30 (5H, m), 4.04-3.91 (2H, m), 3.70-3.61 (3H, m), 3.17 (1H, t, J 5.8 Hz). Not all exchangeable protons were observed.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C([BH3-])#N.[Na+].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([NH:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@H](CO)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(O)[C@@H](CO)NCc1ccccc1
Temperature: 0 °C
Reaction time: 60 h
Yield: 7.3 %

Procedure:
To a mixture of D-serine (25.0 g, 0.237 mol) and 200 mL anhydrous methanol was added sodium cyanoborohydride (11.95 g, 0.190 mol), while maintaining the temperature at 0° C. with an ice bath. Then, benzaldehyde (26.5 mL, 0.261 mol) was added to the reaction flask, dropwise, at 30° C. The mixture was stirred for 60 hr at room temperature. Then, the mixture was filtered and rinsed with methanol (50 mL). The white solid was dried in a vacuum oven at 40° C. and 10 mmHg over 2 nights: 24.5 g. The filtrate was retained and the solvent was evaporated. This oil was passed through a silica gel column (10% MeOH/CH2Cl2) and 3.4 g of the desired compound was isolated. The total amount of the product was 27.9 g (60.0% yield). 1H NMR (DMSO-d6) δ 3.25 (m, 1H, CH), 3.85 (m, 2H, CH2), 4.11 (d, 2H, benzylic CH2), 7.45-7.53 (m, 5H, ArH).
Reaction SMILES: P([O-])([O-])([O-])=O.[C:6]([OH:13])(=[O:12])/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10].[NH3:14]>>[NH2:14][C@H:7]([C:6]([OH:13])=[O:12])[CH2:8][C:9]([OH:11])=[O:10]
Reactant: N
Reactant: O=C(O)/C=C/C(=O)O
Agent: O=P([O-])([O-])[O-]
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
The culture of H-9183 strain as obtained in the controlled aeration condition in Example 1 was centrifuged to isolate the cells. The cells were suspended in a phosphate buffer (0.01 M potassium phosphate; pH 7.4), and homogenized along with glass beads to disrupt them into an extract. The extract was passed through a column filled with a resin, Duolite A-7 to thereby make the protein existing in the extract adsorbed by the resin. Then, an aqueous solution of fumaric acid (150 g/liter; adjusted the pH at 8.5 with aqueous ammonia) was passed through the column at 37° C. to thereby obtain a solution of L-aspartic acid (171 g/liter). The pH of the solution(1 liter) was adjusted to 2.7 with sulfuric acid, and 161 g of L-aspartic acid crystals was obtained.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:9]1)=[O:7])(C)(C)C>OS(O)(=O)=O>[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:10]([CH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 107.7 %

Procedure:
A solution of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester (3.78 g, 7.75 mmol) in conc. H2SO4 (20 mL) was stirred at rt for 2 hrs. The mixture was then poured into ice and extracted with EtOAc. The organic phase was separated, dried over Na2SO4, and concentrated. The residue was then triturated with EtOAc and nHexane and the precipitates were collected by filtration and washed with ether to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3.60 g, 100%) as a white solid which was used in the next step without further purification: HRMS (ES+) m/z Calcd for C23H24Cl2N2O2+H [(M+H)+]: 431.1288. found: 431.1287.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)cc4)CC3)nn2C(C)(C)C)cc1

Procedure:
82 mg (55%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 1-(4-chlorophenyl)piperazine (80 mg, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)s (189 mg, 0.891 mmol).
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].[C:4](=[O:7])([OH:6])[OH:5].[CH:8]([CH:10]=[CH2:11])=[CH2:9]>>[CH2:1]=[CH:2][CH3:3].[C:4]1(=[O:6])[O:5][CH2:11][CH:10]([CH:8]=[CH2:9])[O:7]1
Reactant: C=CC=C
Reactant: O=C(O)O
Solvent: C=CC
Product: C=CC1COC(=O)O1
Temperature: 23 °C
Reaction time: 20 h

Procedure:
A 200 mL flame dried pear-shaped Schlenk flask equipped with a magnetic stir bar and capped with a septum was charged with (2,6-di-isopropylphenylimino)-1,4-dithiane Pd(II) catalyst XII (100 mg) in an argon filled glove box. Upon removal from the glove box, the flask was evacuated and backfilled with propylene. The catalyst was dissolved in CH2Cl2 (20 mL) and immediately treated with vinyl ethylene carbonate (5 mL). The resulting orange solution was stirred at 23° C. under a propylene atmosphere (1 atm) for 20 hours. A small amount of polymer had precipitated out of solution. The polymerization was quenched with MeOH and acetone leaving oil adhering to the walls of the flask. The polymer was washed several times with acetone and MeOH to remove any remaining monomer. The polymer was dissolved in CH2Cl2 and transferred to a storage jar. The solvent was left to evaporate and the resulting oily polymer was dried in vacuo at ~80° C. for 2 days to afford a tacky solid (0.8 g, 284 TO). 1H NMR was consistent with a copolymer containing approximately 91.9 weight % propylene and 8.1 weight % vinyl ethylene carbonate monomer units.; Mn 4000 g /mol ; Mw 8110 g /mol.
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])=[CH:8][C:6]=2[N:7]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:5]2[S:10][C:9]([CH2:11][OH:12])=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 from Example 3 (500 mg) in methanol (20 mL) at 0° C. was added sodium borohydride (66 mg). The reaction was stirred for 2 h then quenched with 1:1 saturated aqueous sodium hydrogencarbonate solution:water (20 mL). The mixture was stirred for 10 min and then filtered, washed with water and air dried to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol as a white solid (489 mg).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:11])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:17]([O-])([O-])=O.[K+].[K+].CI.Cl>CC(C)=O.O>[CH3:1][C:2]1[C:6]2[C:7]([O:11][CH3:17])=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)c1oc2cccc(OC)c2c1C
Reaction time: 15 h

Procedure:
To a solution of ethyl 3-methyl-4-hydroxybenzofuran-2-carboxylate 20 (5.02 g, 22.8 mmol) in acetone (85 mL) was added sequentially K2CO3 (6.3 g, 45.6 mmol) and methyl iodide (6.47 g, 45.6 mmol). The resulting suspension was heated to reflux with stirring for 15 hours, allowed to cool, diluted with water (125 mL), and acidified with 2N HCl (50 mL). The resulting mixture was extracted with ethyl acetate (1×100 mL then 2×50 mL) and the combined extracts were dried and concentrated to a brown oil. Chromatographic purification (Preparative HPLC, 5% ethyl acetate in hexane as eluant) afforded pure ethyl 3-methyl-4-methoxybenzofuran-2-carboxylate as a colorless oil which crystallized on standing. mp 67°-69° C.; 1H NMR d 1.47 (3H, t, J=6 Hz), 2.78 (3H, s), 3.96 (3H, s), 4.48 (2H, q, J=6 Hz), 6.66 (1H, d, J=8 Hz), 7.16 (1H, d, J=8 Hz), 7.36 (1H, t, J=8 Hz).