Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH:9][CH3:10])=[S:8])[N:5]=[C:4]([NH:11][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:13])[N:3]=1.[C:19](OC(OCC)OCC)(=O)C>>[C:12]([NH:11][C:4]1[N:3]=[C:2]2[N:1]=[CH:10][N:9]([CH3:19])[C:7](=[S:8])[N:6]2[N:5]=1)([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:13]
Reactant: CCOC(=O)C(=O)Nc1nc(N)n(C(=S)NC)n1
Reactant: CCOC(OCC)OC(C)=O
Product: CCOC(=O)C(=O)Nc1nc2ncn(C)c(=S)n2n1
Yield: 78 %

Procedure:
The synthesis method of Example 55 was applied. The compound (551 mg) obtained in Example 35 and diethoxymethyl acetate (8 ml) were used as reagents. The mixture was reacted at 90° C. for 2 hours to give 442 mg of white powdery crystals (yield 78%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.[CH3:15][S:16]([C:19]1[CH:34]=[CH:33][C:22]([CH2:23][CH:24]([C:29](=O)[CH2:30][CH3:31])[C:25](=O)[CH2:26][CH3:27])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:25]([CH2:26][CH3:27])=[C:24]([CH2:23][C:22]1[CH:21]=[CH:20][C:19]([S:16]([CH3:15])(=[O:18])=[O:17])=[CH:34][CH:33]=1)[C:29]([CH2:30][CH3:31])=[N:13]2
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Reactant: CCC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)CC
Solvent: O
Product: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(CC)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 100 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (0.35 g), 4-(4-methanesulfonylbenzyl)heptane-3,5-dione (0.49 g) and polyphosphoric acid (5.0 g) was heated at 100° C. for 2 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (99.5:0.5 by volume) to afford title compound, 0.20 g.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:3][CH2:2]1.Cl.[F:20][C:21]([F:34])([F:33])[C:22]1[S:26][C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:24][CH:23]=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([N:30]2[CH2:31][CH2:32][N:27]([C:25]3[S:26][C:22]([C:21]([F:34])([F:20])[F:33])=[CH:23][N:24]=3)[CH2:28][CH2:29]2)=[O:10])[CH2:2][CH2:3]1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)O)c1
Agent: Cl
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(C(=O)N2CCN(c3ncc(C(F)(F)F)s3)CC2)c1
Yield: 22 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopropylmethoxy-5-methanesulfonyl-benzoic acid (Example A5) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as a white crystalline solid (yield 22%). MS (m/e): 490.3 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C=O)C.CCOC(C)=O>[CH2:22]([O:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(OC)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1cc(OC)ccc1C(=O)OC
Reaction time: 2 h

Procedure:
To a solution of methyl 4-methoxysalicylate (2.0 g, 11 mmol) in DMF (20 mL) at room temperature was added Cs2CO3 (1.3 eq, 4.7 g) and allyl bromide (1.3 eq, 1.23 mL). After 2 hr, reaction mixture was diluted with EtOAc and washed with water (3×), brine (1×). The organic layer was dried over Na2SO4 and concentrated to provide the product as a pale yellow oil. Product was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:20]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH:6]=1.[OH-].[Li+].Cl>C1COCC1>[CH2:25]([N:20]([CH2:19][C:13]1[CH:14]=[C:15]([Br:18])[CH:16]=[CH:17][C:12]=1[O:11][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[CH:10]=[CH:9][CH:8]=1)[C:21]([O:23][CH3:24])=[O:22])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN(Cc2ccccc2)C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)N(Cc1ccccc1)Cc1cc(Br)ccc1Oc1cccc(CC(=O)O)c1
Temperature: 25 °C

Procedure:
To (3-{2-[(benzyl-methoxycarbonyl-amino)-methyl]-4-bromo-phenoxy}-phenyl)-acetic acid methyl ester (0.07 g) in THF (2 mL) was added 1N aqueous lithium hydroxide (2 mL), and the reaction was stirred at room temperature until no starting material was seen by analytical LCMS. The mixture was acidified with 1N aqueous HCl to pH 3-4, and extracted three times with EtOAc. The combined organic layers were washed with H2O, dried, and concentrated to give the title compound. M+H=485.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]([OH:14])=O)[CH:10]=1)=[O:5])[CH3:2].Cl.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([NH:23][NH2:24])=O.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[F:16][C:17]([F:28])([F:29])[C:18]1[CH:19]=[C:20]([C:21]2[O:14][C:12]([CH2:11][N:9]3[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]3)=[N:24][N:23]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1cnn(CC(=O)O)c1
Reactant: NNC(=O)c1cccc(C(F)(F)F)c1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cnn(Cc2nnc(-c3cccc(C(F)(F)F)c3)o2)c1
Reaction time: 0.5 h
Yield: 35 %

Procedure:
A solution of the compound (1.0 g) obtained in Example 115b in dichloromethane (15 ml) was cooled in an ice bath, N,N′-carbonyldiimidazole (0.81 g) was added and the mixture was stirred for 30 min. 3-(Trifluoromethyl)benzohydrazide hydrochloride (1.2 g) was added, and the mixture was stirred at the same temperature for 45 min. Then, carbon tetrabromide (3.32 g) and triphenylphosphine (2.6 g) were added, and the mixture was further stirred at the same temperature for 2 hr. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (carrier: silica gel, eluent: petroleum ether-ethyl acetate) to give the title compound (0.64 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[CH2:23][OH:24])=[CH:17][CH:16]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]=[CH:22][CH:23]=[O:24])=[CH:19][CH:20]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(/C=C/CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(C=CC=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
Activated manganese dioxide (MnO2) (9.0 g) was added to a solution of (E)-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-propen-1-ol (3.7 g) in dichloromethane (80 ml), which was stirred for one hour at room temperature. The reaction mixture was subjected to filtration through celite layer. The filtrate was concentrated under reduced pressure to give 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamoaldehyde (2.6 g, 70%), which was recrystallized from ethyl acetate--hexane to yield colorless prisms, m.p.114°-115° C.
Reaction SMILES: [Cl:1][CH:2]([CH2:7][C:8]1[CH:9]=[N:10][C:11]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)[C:3]([O:5][CH3:6])=[O:4].ClC1C=CC=C(C(OO)=[O:29])C=1>ClCCl>[Cl:1][CH:2]([CH2:7][C:8]1[CH:9]=[N:10][C:11]([S:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:29])=[CH:12][CH:13]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C(Cl)Cc1ccc(Sc2ccccc2)nc1
Solvent: ClCCl
Product: COC(=O)C(Cl)Cc1ccc(S(=O)c2ccccc2)nc1

Procedure:
Methyl 2-chloro-3-(6-phenylthio-3-pyridyl)propionate (10.5 g), prepared in substantially the same manner as in Reference Example 5 using the corresponding starting materials, is dissolved in 100 ml of dichloromethane. To the solution, 7.1 g of m-chloroperbenzoic acid is added slowly with stirring under cooling in an ice-water bath. The mixture is stirred at room temperature for 1 hour, washed with saturated sodium carbonate solution, dried over magnesium sulfate, and concentrated to give crude methyl 2-chloro-3-(6-phenylsulfinyl-3-pyridyl)propionate. To the sulfinyl compound is added 170 ml of 4N sodium hydroxide solution, and the mixture is refluxed with stirring for 4 hours. After cooling, the resulting precipitate is collected to give 4.1 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:45])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:35](=[O:44])[NH:36][C:37]2[CH:42]=[CH:41][C:40]([Br:43])=[CH:39][CH:38]=2)[CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C)C)=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.F.F.[F-]>C1COCC1>[C:1]([O:5][C:6](=[O:46])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:45])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:35](=[O:44])[NH:36][C:37]2[CH:38]=[CH:39][C:40]([Br:43])=[CH:41][CH:42]=2)[CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccc(C(CCO[Si](C)(C)C(C)(C)C)C(=O)Nc2ccc(Br)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccc(C(CCO)C(=O)Nc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-[2-(3-{4-[1-(4-bromo-phenylcarbamoyl)-3-(tert-butyl-dimethyl-silanyloxy)-propyl]-phenyl}-acryloylamino)-phenyl]-carbamic acid tert-butyl ester (1.6 g, 2.26 mmol) in THF (40 mL) was added tetrabutylammonium dihydrogen trifluoride (1.36 g, 4.52 mmol). This mixture was stirred at room temperature overnight and then evaporated to remove THF. The mixture was dissolved in water and extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine, dried with Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography (CH2Cl2:EtOAc=10:1) to get yellow solid product. MS: calc'd 594 (MH+), exp 594 (MH+).
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, enzyme reaction product was measured as follows: 10 mg of scyllo-inosose, 40 mg of NADPH, and IOU 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 Φ4.6×250 mm: Shodex) using an RI detector under conditions of a column temperature of 40° C. and a mobile phase flow rate of 1.5 ml (80% acetonitrile). As a result, the Atu4375 gene product and the Atu3234 gene product of Agrobacterium tumefacience C58, the BG14057 gene product of Bacillus subtilis 168, the Xcc3438 gene product of Xanthomonas campestris pv. campestris, and the Atu4375 gene product, and the Atu3234 gene product of AB10121 strain were found to have a high enzyme activity, and 100% of the product was scyllo-inositol obtained by the reduction, while myo-inositol that is an isomer thereof was not detected. As a result, recombinant enzymes derived from the above-mentioned genes were found to have a high scyllo-inositol dehydrogenase activity, and the gene products were scyllo-inositol dehydrogenase. Meanwhile, in the products obtained by the reduction reaction of scyllo-inosose, only scyllo-inositol was detected, and the enzymes were found to stereospecifically reduce scyllo-inosose into scyllo-inositol.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][C:8]2[C:9]([O:25][CH2:26][CH3:27])=[C:10]([CH:14]([C:16]3[C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[OH:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][C:8]2[C:9]([O:25][CH2:26][CH3:27])=[C:10]([C:14]([C:16]3[C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)=[O:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOc1c(OCc2ccc(Cl)cc2)cccc1C(O)c1c[nH]c2ncccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: CCOc1c(OCc2ccc(Cl)cc2)cccc1C(=O)c1c[nH]c2ncccc12
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 73.7 %

Procedure:
To a solution of [3-(4-chloro-benzyloxy)-2-ethoxy-phenyl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (65, 20 mg, 0.05 mmol) in tetrahydrofuran (8 mL) was added Dess-Martin periodinane (52 mg, 0.12 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 50 minutes. The reaction was quenched with a saturated solution of sodium thiosulfate, extracted with ethyl acetate, washed with sodium bicarbonate, brine, and dried over magnesium sulfate. After removal of solvent, the residue was washed with a mixture of ethyl ether and hexanes (1:1) to provide the compound as a yellow solid (P-1892, 15 mg, 75%). MS (ESI) [M+H+]+=407.38.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:16](=[O:28])[NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])[N:19]=1)[CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)(C)(C)C.[ClH:30]>CO>[ClH:30].[NH2:7][CH:8]([CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:16]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH2:23][C:24]([OH:27])([CH3:25])[CH3:26])[N:19]=1)=[O:28]
Reactant: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCOCC2)NC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: CO
Product: CC(C)(O)Cn1ccc(NC(=O)C(N)CC2CCOCC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of [1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-2-(tetrahydro-pyran-4-yl)-ethyl]-carbamic acid t-butyl ester (3.2 g, 7.8 mmol) in methanol (150 mL) was treated with hydrogen chloride gas for 2 min at 0° C. and then stirred at room temperature for 1 h. After this time the mixture was concentrated in vacuo and the residue treated with acetonitrile (50 mL). The mixture was concentrated in vacuo which afforded 2-amino-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide hydrochloride (3.0 g, 100%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=1.CN(C)C=O>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:40][C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([Cl:33])[CH:35]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Oc1cccc(Cl)c1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 3.0 g (8.2 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole, 1.59 g (11.5 mmol) of powdered potassium carbonate, 1.48 g (11.5 mmol) of 3-chlorophenol and 20 ml of dry dimethylformamide is stirred at room temperature for 5 days, then poured into 60 ml of water and extracted four times with methylene chloride. The organic extracts are washed once with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue obtained is chromatographed on silica gel while eluting with ethyl acetate and then crystallized from ethanol. There is obtained m-chlorophenyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 194°-195°.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[C:17]([O:28][CH3:29])[CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.C(OCC)(=O)C>[CH3:29][O:28][C:17]1[CH:16]=[C:15]([C:13]2[CH:12]=[N:11][C:6]3[NH:7][C:8]4[CH:9]=[N:10][C:2]([C:34]5[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=5)=[CH:3][C:4]=4[C:5]=3[CH:14]=2)[CH:20]=[CH:19][C:18]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1cc(-c2cnc3[nH]c4cnc(Br)cc4c3c2)ccc1CN1CCCCC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(-c2cnc3[nH]c4cnc(-c5cnn(C)c5)cc4c3c2)ccc1CN1CCCCC1
Temperature: 130 °C
Yield: 17.3 %

Procedure:
A degassed mixture of 6-bromo-3-(3-methoxy-4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (350 mg, 0.78 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (242 mg, 1.16 mmol), 1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (64 mg, 0.08 mmol) in 2N aqueous sodium carbonate solution (8 mL) and acetonitrile (8 mL) was heated under microwave irradiation at 130° C. for 20 minutes. The cooled reaction mixture was diluted with ethyl acetate (75 mL) and washed with water (50 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 50 g column, Biotage, 0-25% methanol in DCM) to afford the title compound as an off-white solid (61 mg, 17%). 1H NMR (DMSO-D6, 300 MHz): 8.95-8.92 (m, 2H), 8.85 (d, J=1.0 Hz, 1H), 8.49 (d, J=1.1 Hz, 1H), 8.22 (s, 1H), 8.00 (s, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.38-7.33 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.48 (s, 2H), 2.44-2.34 (m, 4H), 1.55-1.48 (m, 4H), 1.45-1.37 (m, 2H).
Reaction SMILES: C1(C([O:14][C:15](=[O:41])[C@@H:16]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:19]=2)C2C=CC=CC=2)C=CC=CC=1.[H][H]>C(O)(C)(C)C.C(O)C.[Pd]>[CH3:39][C:37]([CH3:40])([O:36][C:34]([NH:33][C@@H:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:19]=1)[C:15]([OH:41])=[O:14])=[O:35])[CH3:38]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Solvent: CC(C)(C)O
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Yield: 92.9 %

Procedure:
(S)-2-[[(1,1-Dimethylethoxy)carbonyl]amino]-3-[4-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]phenyl]propanoic acid diphenylmethyl ester (1.6 g, 2.8 mmol) and 10% Pd/C (300 mg) in t-butanol (20 mL) was blanketed with hydrogen (1 atm). To prevent the solvent from freezing, a warm water bath (40° C.) was used to heat the reaction mixture. Upon the consumption of 2 equivalents of hydrogen, the mixture was filtered through celite. The celite pad was washed with ethanol (50 mL) and the filtrates combined and concentrated. The residue was purified by recrystallization from hexanes to give (S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-3-[4-[3-(1,1-dimethylethoxy)3-oxopropyl]phenyl]propanoic acid (1.0 g, 2.6 mmol) in 94% yield, mp. 88.5°-90° C., [α]D -21.2° (0.90% in ethanol).
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:42](=[NH:44])[NH2:43])[CH:38]=2)[CH:33]=1)(=O)=O>N1C=CC=CC=1>[CH3:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([O:5][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:42](=[NH:43])[NH2:44])[CH:38]=2)[CH:33]=1)=[O:4]
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: CC(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CC(C(=O)Oc1ccc2cc(C(=N)N)ccc2c1)c1ccccc1
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
To 50 ml of dried pyridine, were added 3.0 g of α-methylphenylacetic acid and 4.9 g of DCC. The mixture was stirred for 30 minutes under cooling in ice. After adding 5.6 g of 6-amidino-2-naphthol methanesulfonate, while being cooled in ice, the mixture was stirred for one hour, then overnight. The reaction mixture was filtered to collect the precipitate. The precipitate was washed with pyridine and ethyl ether, added to DMF and heated. The insolubles were filtered off and ethyl ether was added to the filtrate to collect the precipitate by filtration. The precipitate was recrystallized from a mixed solvent comprising ethanol and ethyl ether to obtain 1.8 g of a white powder of 6-amidino-2-naphthyl α-methylphenylacetate methanesulfonate.
Reaction SMILES: N1C2OCC(N)C=2C=CN=1.CO[N:13]=[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][C:21]=2[O:23][CH3:24])[O:16][CH2:15]1>>[CH3:24][O:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]2[O:16][CH2:15][CH:14]([NH2:13])[C:22]=12
Reactant: CON=C1COc2nccc(OC)c21
Agent: NC1COc2nnccc21
Product: COc1ccnc2c1C(N)CO2

Procedure:
This compound was prepared using a method analogous to that of 5,6-dihydrofuro[2,3-c]pyridazin-5-amine (A.2.3.4), 4-methoxyfuro[2,3-b]pyridin-3(2H)-one O-methyl oxime replacing furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime;