Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:34]=[C:33]3[C:28]([C:29]([NH2:35])=[N:30][CH:31]=[N:32]3)=[CH:27][CH:26]=2)[C:20](=[O:36])[CH2:19]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:35][C:29]1[C:28]2[C:33](=[CH:34][C:25]([CH2:24][N:21]3[CH2:22][CH2:23][N:18]([CH2:17][C:9]4[NH:8][C:16]5[CH:15]=[CH:14][N:13]=[CH:12][C:11]=5[CH:10]=4)[CH2:19][C:20]3=[O:36])=[CH:26][CH:27]=2)[N:32]=[CH:31][N:30]=1
Reactant: CC(C)(C)OC(=O)n1c(CN2CCN(Cc3ccc4c(N)ncnc4c3)C(=O)C2)cc2cnccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2cc(CN3CCN(Cc4cc5cnccc5[nH]4)CC3=O)ccc12
Reaction time: 16 h

Procedure:
To a solution containing 2-[4-(4-amino-quinazolin-7-ylmethyl)-3-oxo-piperazin-1-ylmethyl]-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (50 mg, 0.12 mmol) in CH2Cl2 (5 mL is added TFA (1 mL) at ambient temperature. After 16 h, the reaction mixture is concentrated to dryness, diluted with water and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 45% B over 30 min] to provide 34 mg (73%, two steps) of the title compound as a white, lyophilized solid. 1H NMR (300 MHz, CDCl3) δ2.77 (s, 3H), 3.23 (s, 2H), 3.31 (m, 2H), 3.89 (s, 2H), 4.00 (br s, 3H), 4.71 (s, 2H), 6.94 (s, 1H), 7.60 (m, 2H), 7.84 (d, J=6.5 Hz, 1H), 8.36 (m, 2H), 8.81 (s, 1H), 9.18 (s, 1H), 9.73 (br s, 2H), 12.87 (s, 1H) ppm; MS (ion spray): m/z 388 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.N1CC[CH2:16][CH2:15][CH2:14]1.C(O)(=[O:21])C>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:14][C:15](=[O:21])[CH3:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC(=O)O
Reactant: C1CCNCC1
Solvent: CC(C)=O
Product: COc1ccc(C=CC(C)=O)cc1OC
Yield: 56.4 %

Procedure:
3,4-Dimethoxybenzaldehyde (30.1 g) was dissolved in acetone (900 ml), and then piperidine (23.2 ml) and acetic acid (13.4 ml) were added prior to reflux for 4 hours. After distilling off the reaction solvent under reduced pressure, it was dissolved in 600 ml of ethyl acetate and washed with saturated sodium bicarbonate water and saturated saline. After drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure producing yellow crystals which were then washed in isopropyl ether to give 21.0 g of 4-(3,4-dimethoxyphenyl)-3-buten-2-one (56.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([O:9][CH3:10])[CH:3]=1.C([Li])(CC)C.[CH3:16][S:17]SC>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([S:17][CH3:16])[C:5]([F:8])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Cl)ccc1F
Reactant: CSSC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1cc(Cl)cc(SC)c1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-chloro-1-fluoro-2-methoxybenzene (2.0 g) and THF (dry) (100 mL) was added sec-butyllithium (1.04 mol/L cyclohexane solution, 23.95 mL) dropwise over a period of 45 min at −78° C. After stirring at −78° C. for 30 min, to the mixture was added dimethyl disulfide (2.468 mL) at the same temperature. The mixture was stirred at −78° C. for 1.5 h under argon atmosphere. The mixture was quenched with saturated aqueous NH4Cl at −78° C. and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give a solid. The solid was washed with hexane to give the title compound (1.77 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](C(=O)C(Cl)(Cl)Cl)[NH:5][CH:6]=1.[CH3:13][O-:14].[Na+].[CH3:16][OH:17]>O>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([O:17][CH3:16])=[O:14])[NH:5][CH:6]=1
Reactant: CO
Reactant: C[O-]
Reactant: O=C(c1cc(Br)c[nH]1)C(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(Br)c[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of Example 1B (20 g, 68 mmol) in methanol (100 mL), a solution of NaOMe (1M in MeOH, 34 mL, 34 mmol) was added slowly. This mixture was then stirred at ambient temperature for 1 h after which it was diluted with water (300 mL) and the organic layer was separated. The aqueous phase was extracted with CH2Cl2 and the combined organic layer and extracts were washed with water (2×50 mL), dried (MgSO4) and evaporated under reduced pressure. Recrystallization of the residue from hexane gave 4-Bromo-2-methoxycarbonylpyrrole (Example 1C, 12 g, 85%) as a white solid. LC-MS, [M−H]+=203. 1H NMR (DMSO-d6, 400 MHz): δ 12.31 (brs, 1H), 7.16 (s, 1H), 6.81 (s, 1H), 3.75 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:26]=1[N:34]=[C:35]=[O:36])([CH3:24])[CH3:23]>>[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:32])[CH3:33])[C:26]=1[NH:34][C:35](=[O:36])[N:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=1)([CH3:23])[CH3:24]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CC(C)c1ccc(NCc2ccc(C(F)(F)F)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(C(F)(F)F)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 34.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (4-isopropylphenyl)[(4-trifluoromethylphenyl)methyl]amine (2.4 g) and 2,6-diisopropylphenyl isocyanate (2.1 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)-N-[(4-trifluoromethylphenyl)methyl]urea (1.4 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][N:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[N:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([NH:25]C(=O)OC(C)(C)C)[CH2:20]2)=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[NH2:25][C@H:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:12]2[C:11]3[C:16](=[CH:17][N:18]=[C:9]([C:3]4[C:2]([NH2:1])=[CH:7][CH:6]=[C:5]([C:37]5[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=5)[N:4]=4)[CH:10]=3)[N:15]=[CH:14][CH:13]=2)[CH2:20]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3cnc(-c4nc(Cl)ccc4N)cc23)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: Nc1ccc(-c2ccc(F)cc2)nc1-c1cc2c(N3CCC[C@H](N)C3)ccnc2cn1
Yield: 61 %

Procedure:
A solution of (S)-tert-butyl 1-(6-(3-amino-6-chloropyridin-2-yl)-1,7-naphthyridin-4-yl)piperidin-3-ylcarbamate (1.0 equiv.), 4-fluorophenylboronic acid (3.0 equiv.) and Pd(dppf)Cl2—CH2Cl2 (0.15 equiv.) in 3:1 DME/2M Na2CO3 was heated in a microwave at 120° C. for 20 minutes. Upon cooling, the solution was partitioned between EtOAc and Na2CO3(sat.) washed further with NaCl(sat.), dried over MgSO4, concentrated and purified by RP HPLC. Upon lyophilization, the Boc group was deprotected by treatment with 25% TFA/CH2Cl2, concentrated, purified by RP-HPLC and lyophilized to yield (S)-2-(4-(3-aminopiperidin-1-yl)-1,7-naphthyridin-6-yl)-6-(4-fluorophenyl)pyridin-3-amine (61%). LC/MS=415.2 (M+H), LC=2.32 min.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:14]=1)[O:11][C:10]([C:22](O)=[O:23])=[CH:9][C:8]2=[O:25])[CH3:3].C(Cl)(=O)C([Cl:29])=O>CN(C=O)C.C(Cl)Cl>[CH2:2]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:14]=1)[O:11][C:10]([C:22]([Cl:29])=[O:23])=[CH:9][C:8]2=[O:25])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOc1cc(N2CCN(C)CC2)c2oc(C(=O)O)cc(=O)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1cc(N2CCN(C)CC2)c2oc(C(=O)Cl)cc(=O)c2c1
Reaction time: 2 h

Procedure:
Into a 100 mL round bottom flask equipped with a reflux condenser, nitrogen inlet and magnetic stirrer is placed 250 mg (0.68 mmol, 1.0 equiv.) of 6-Ethoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride salt (Reference Example 23d) and 20 mL of methylene chloride. To the stirring suspension is then added 129.5 mg, 164 L (1.02 mmol, 1.5 equiv.) of oxalyl chloride followed by addition of one drop of DMF from a 50 microliter syringe to act as catalyst. The mixture is stirred for 2 hours, then concentrated to dryness on a rotary evaporator under a nitrogen atmosphere, followed by drying under high vacuum. The completeness of the reaction was ascertained by analysis of an aliquot, which was quenched with a THF solution of methylamine, by LC/MS. The crude material was used as obtained in the subsequent amidation reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:13][C:8]3([NH:12][CH2:11][CH2:10][NH:9]3)[C:6]=2[CH:7]=1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CO>[ClH:1].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][S:13][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=2[C:8]2[NH:12][CH2:11][CH2:10][N:9]=2)=[CH:17][CH:16]=1
Reactant: Clc1ccc2c(c1)C1(NCCN1)S2
Reactant: ClCc1ccc(Cl)cc1
Solvent: CO
Product: Cl
Product: Clc1ccc(CSc2ccc(Cl)cc2C2=NCCN2)cc1

Procedure:
53 Parts of 4-chlorobenzothietane-2-spiro-2'-imidazolidine is reacted with 40 parts of p-chlorobenzyl chloride in 500 parts of methanol as described in Example 11. The yield is 84 parts (91% of theory) and the melting point is 248° to 250° C.).
Reaction SMILES: C(O[C:9]([N:11]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH:23](C)[CH3:24])[CH:15]=1)C)=O)C1C=CC=CC=1.C(OC(N(CC1C2C(=CC=CC=2)N(CC2C=CC=CC=2)C=1)C)=O)C1C=CC=CC=1>>[CH2:23]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([CH2:13][NH:11][CH3:9])=[CH:15]1)[CH3:24]
Reactant: CC(C)n1cc(CN(C)C(=O)OCc2ccccc2)c2ccccc21
Agent: CN(Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)OCc1ccccc1
Product: CCn1cc(CNC)c2ccccc21
Yield: 87.3 %

Procedure:
According to the procedure of Preparation 17 (c), except substituting 3-[N-(Benzyloxycarbonyl)-N-methylaminomethyl]-1-isopropyl-1H-indole (0.99 g, 2.98 mmole) for the 3-[N-(Benzyloxycarbonyl)-N-methylaminomethyl]-1-benzyl-1H-indole, the title compound (0.49 g, 82%) was prepared as a white solid: MS (ES) m/e 405 (2M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]1[C:9]2[C:10]([CH3:15])=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[N:7]([CH2:16][C:17]([OH:19])=O)[C:6]1=[O:20].[NH2:22][C:23]1[CH:24]=[C:25]2[CH2:40][C:30]3([C:38]4[C:33](=[N:34][CH:35]=[CH:36][CH:37]=4)[NH:32][C:31]3=[O:39])[CH2:29][C:26]2=[N:27][CH:28]=1.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:14][C:12]1[CH:11]=[C:10]([CH3:15])[C:9]2[N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:21])[C:6](=[O:20])[N:7]([CH2:16][C:17](=[O:19])[NH:22][C:23]3[CH:24]=[C:25]4[CH2:40][C:30]5([C:38]6[C:33](=[N:34][CH:35]=[CH:36][CH:37]=6)[NH:32][C:31]5=[O:39])[CH2:29][C:26]4=[N:27][CH:28]=3)[C:8]=2[CH:13]=1
Reactant: COC(=O)Cn1c(=O)n(CC(=O)O)c2cc(C)cc(C)c21
Reactant: Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cn1c(=O)n(CC(=O)Nc2cnc3c(c2)CC2(C3)C(=O)Nc3ncccc32)c2cc(C)cc(C)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [3-(2-methoxy-2-oxoethyl)-4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetic acid (67 mg, 0.23 mmol, described in Intermediate 9), (±)-3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in Intermediate 4), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:16][C:17]([F:27])([F:26])C1C=C(C=CC=1)CBr.[Mg].C(OCC)(=O)C(OCC)=O>>[F:16][C:17]([F:27])([F:26])[C:7]1[CH:2]=[C:3]([CH2:8][C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(=O)Cc1ccccc1F
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: [Mg]
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)Cc1cccc(C(F)(F)F)c1
Yield: 78 %

Procedure:
The title compound was prepared as described for B4 using 3-trifluoromethylbenzyl bromide (2.5 g, 10.46 mmol), magnesium (0.280 g, 11.50 mmol) and diethyl oxalate (3.06 g, 20.92 mmol). The product was isolated in the form of colorless oil in 78% yield and use instantly in next step.
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:20])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:40][C:41]([O:43][CH3:44])=[O:42]>CN(C)C=O.C(#N)C>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([CH:10]2[C:9]3[C:8](=[O:20])[CH2:7][CH2:6][CH2:5][C:4]=3[N:3]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)[C:2](=[O:1])[N:11]2[CH2:40][C:41]([O:43][CH3:44])=[O:42])=[CH:19][CH:18]=1)#[N:17]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Reactant: COC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 0 °C

Procedure:
A solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 1, 3.56 g, 6.12 mmol) in a mixture of N,N-dimethyl-formamide (10 mL) and acetonitrile (30 mL) is cooled at 0° C. in an ice bath. Lithium diisopropylamide (2.0 M in tetrahydrofuran, 6.7 mL, 13.4 mmol) is added while the temperature is kept below 5° C. Methyl bromoacetate is added dropwise while the temperature is kept below 10° C. After 1.5 h the ice bath is removed and stiffing is continued over night. The mixture is concentrated under reduced pressure and the residue is purified by preparative HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 1.87 g; ESI mass spectrum [M+H]+=484; Retention time HPLC: 0.95 min (Z018_S04).
Reaction SMILES: [C@H:1]1([OH:12])[CH:7]([OH:8])[C@@H:6]([OH:9])[C@H:5]([OH:10])[C:3](=[O:4])[C@@H:2]1[OH:11].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1.C(#N)C.[C@@H]1(O)[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)[C@H]1O>C(O)C(N)(CO)CO>[CH:3]1([OH:4])[CH:2]([OH:11])[CH:1]([OH:12])[CH:7]([OH:8])[CH:6]([OH:9])[CH:5]1[OH:10]
Reactant: O=C1[C@@H](O)[C@H](O)C(O)[C@H](O)[C@H]1O
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: NC(CO)(CO)CO
Agent: O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CC#N
Product: OC1C(O)C(O)C(O)C(O)C1O
Reaction time: 0.17 h

Procedure:
Meanwhile, the enzyme reaction product was measured as follows: 10 mg of scyllo-inosose, 40 mg of NADPH, and 10 U of the enzyme were allowed to react in 1.0 ml of 100 mM Tris buffer (pH 8.0) at 36° C. for 4 hours, and a heat treatment was performed at 80° C. for 10 min, followed by cooling. Then, 100 μl of a strong base cation exchange resin, 100 μl of a strong acid anion exchange resin, and 10 mg of activated carbon were added, and the mixture was stirred and centrifuged. Then, the supernatant was diluted 2-fold, and measurement was performed by HPLC (Shodex Asahipak NH2P-50 4E Φ 4.6×250 mm: Shodex) using an RI detector under the condition of a column temperature of 40° C. and a mobile phase flow rate of 1.5 ml (80% acetonitrile). As a result, the ydgJ gene product was found to have a high scyllo-inositol dehydrogenase activity, and 100% of the product was scyllo-inositol obtained by reduction, while myo-inositol that is an isomer thereof was not detected. As a result, the solution of a recombinant enzyme derived from the ydgJ gene was found to have a high scyllo-inositol dehydrogenase activity, and the gene product was scyllo-inositol dehydrogenase. Meanwhile, in the product obtained by the reduction reaction of scyllo-inosose, only scyllo-inositol was detected, and the enzyme was found to stereospecifically reduce scyllo-inosose into scyllo-inositol. Meanwhile, the sequence of the ydgJ gene is shown in SEQ ID NO: 1, and the amino acid sequence corresponding thereto is shown in SEQ ID NO: 2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:39]([O:43][C:44]([N:46]1[CH2:50][CH:49]([C:51]#[N:52])[CH2:48][CH:47]1[C:53]1[NH:54][C:55]([C:58]2[CH:67]=[CH:66][C:65]3[C:60](=[CH:61][CH:62]=[C:63](Br)[CH:64]=3)[CH:59]=2)=[CH:56][N:57]=1)=[O:45])([CH3:42])([CH3:41])[CH3:40].C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:39]([O:43][C:44]([N:46]1[CH2:50][CH:49]([C:51]#[N:52])[CH2:48][CH:47]1[C:53]1[NH:54][C:55]([C:58]2[CH:67]=[CH:66][C:65]3[C:60](=[CH:61][CH:62]=[C:63]([C:26]4[CH:25]=[CH:24][C:23]([C:20]5[NH:19][C:18]([CH:17]6[CH2:16][C:13]7([CH2:14][CH2:15]7)[CH2:12][N:11]6[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:38])[CH:6]([CH3:8])[CH3:7])=[N:22][CH:21]=5)=[CH:28][CH:27]=4)[CH:64]=3)[CH:59]=2)=[CH:56][N:57]=1)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)CC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CC(C#N)CN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Temperature: 25 °C
Yield: 51 %

Procedure:
[2-Methyl-1-(6-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-propyl]-carbamic acid methyl ester (997 mg, 1.91 mmol), 2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester, Pd(PPh3)4 (184 mg, 0.159 mmol), and K2CO3 (2 M in H2O, 1.9 mL, 3.8 mmol) were combined in 1,2-dimethoxyethane (16 mL) The reaction mixture was degassed with bubbling N2 for 10 minutes then heated to reflux for 3.5 h. After heating, the reaction mixture was cooled to RT, diluted with EtOAc and washed with H2O and brine. The organic phase was dried over MgSO4, then filtered and concentrated. The resulting residue was purified with silica column chromatography 0% to 100% (10% MeOH/DCM)/EtOAc to afford the title compound (641 mg, 51%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH:3]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[C:4]([OH:6])=O.[CH2:13](Cl)CCl.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O-:24])=[O:23])=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:12][N:2]([CH3:1])[CH:3]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[C:4]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O:24][CH3:13])=[O:23])=[CH:20][CH:19]=1)=[O:6]
Reactant: Nc1ccc(C(=O)[O-])cc1
Reactant: CN(C)C(C(=O)O)c1ccsc1
Reactant: ClCCCl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)C(c2ccsc2)N(C)C)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To 2-(dimethylamino)-2-(thiophen-3-yl)acetic acid in pyridine was added EDC, DMAP and 4-aminobenzoate and the solution was stirred for 10 hours at room temperature. The mixture was poured into NaHCO3 (sat) and extracted with EtOAc. The extracts were dried (MgSO4), filtered and evaporated. Column chromatography (SiO2, 0-100% EtOAc/Hex) gave pure methyl 4-(2-(dimethylamino)-2-(thiophen-3-yl)acetamido)benzoate (E114).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[F:14])C=C.C(N(CC)[C:18]1[CH:23]=CC=C[CH:19]=1)C>>[CH2:23]([C:10]1[CH:9]=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[C:6]([F:14])[C:5]=1[OH:4])[CH:18]=[CH2:19]
Reactant: C=CCOc1ccc([N+](=O)[O-])cc1F
Reactant: CCN(CC)c1ccccc1
Product: C=CCc1cc([N+](=O)[O-])cc(F)c1O
Yield: 60 %

Procedure:
Compound 2 (25 g, 126.8 mmol) was solved in diethyl aniline (150 mL, 937.7 mmol) and the resulting solution was refluxed for 48 h. The crude was evaporated in vacuo and the residue was purified by column chromatography, eluted at 10% ethyl acetate/hexane. Fractions were collected to obtain the desired compound 3 (15 g, yield 60%).
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]([C:11]([O:13]C)=O)=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:7]=1.O.[NH2:16][NH2:17]>CO>[NH2:2][C:3]1[S:4][C:5]([C:11]([NH:16][NH2:17])=[O:13])=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:7]=1
Reactant: NN
Reactant: COC(=O)c1sc(N)nc1C1CC1
Agent: Br
Solvent: O
Solvent: CO
Product: NNC(=O)c1sc(N)nc1C1CC1
Temperature: 55 °C
Reaction time: 72 h

Procedure:
Methyl 2-amino-4-cyclopropyl-1,3-thiazole-5-carboxylate hydrobromide (1.78 g) was dissolved in methanol (4.0 ml), hydrazine monohydrate (2.0 ml) was added thereto, followed by stirring at 55° C. for 3 days. After cooling to room temperature, an insoluble substance was filtered, the mother solution was mixed with basic silica gel and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel chromatography (chloroform:methanol) to obtain, as a dark brown solid, 2-amino-4-cyclopropyl-1,3-thiazole-5-carbohydrazide (224 mg).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=[CH:13][C:12]=1[Cl:24])[C:6](=O)[CH2:7][CH3:8])C.[CH3:26][O:27][C:28](=[O:40])[C@@H:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([NH2:39])[CH:33]=1)[CH3:30]>>[CH3:26][O:27][C:28](=[O:40])[C@@H:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]2[C:33]=1[C:4](=[O:3])[C:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][C:12]=1[Cl:24])=[C:6]([CH2:7][CH3:8])[NH:39]2)[CH3:30]
Reactant: CCOC(=O)C(Cc1ccc(C(=O)N2CCCC2)cc1Cl)C(=O)CC
Reactant: COC(=O)[C@H](C)Oc1ccc(F)c(N)c1
Product: CCc1[nH]c2c(F)ccc(O[C@@H](C)C(=O)OC)c2c(=O)c1Cc1ccc(C(=O)N2CCCC2)cc1Cl

Procedure:
The title compound was prepared by the method of Preparation 65c using 2-[2-chloro-4-(pyrrolidine-1-carbonyl)benzyl]-3-oxopentanoic acid ethyl ester and (S)-2-(3-amino-4-fluorophenoxy)propionic acid methyl ester.
Reaction SMILES: [C:1]1([C@H:7]2[C@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH3:21]I>CO.O>[CH3:21][S:18][C:9]1[NH:8][C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: CI
Reactant: S=C1N[C@@H](c2ccccc2)[C@H](c2ccccc2)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSC1=N[C@@H](c2ccccc2)[C@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.8 g of trans-4,5-diphenyl-imidazolidine-2-thione are dissolved in 20 ml of methanol, a solution of 0.3 g of sodium hydroxide in 2 ml of water and also 1.2 g of methyl iodide are added and the mixture is stirred at room temperature for 4 hours and left to stand overnight at 0°. The reaction mixture is evaporated to dryness, the residue is shaken with a mixture of 40 ml of water and 40 ml of ethyl acetate, the organic phase is separated off and the aqueous phase is washed with ethyl acetate. The organic phases are dried over sodium sulfate and evaporated to dryness. The crystalline residue is recrystallised, first from methanol and then from a mixture of diethyl ether and petroleum ether. Trans-2-methylthio-4,5-diphenyl-imidazoline with a melting point of 135°-137° is obtained.