Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[CH2:3]([O:10][C:11]1[CH:28]=[CH:27][C:14]([CH:15]=[C:16]([C:22]([O:24]CC)=[O:23])C(OCC)=O)=[C:13]([O:29][CH3:30])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C-:31]#[N:32].[K+]>O>[CH2:3]([O:10][C:11]1[CH:28]=[CH:27][C:14]([CH:15]([C:31]#[N:32])[CH2:16][C:22]([OH:24])=[O:23])=[C:13]([O:29][CH3:30])[CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [C-]#N
Reactant: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1OC)C(=O)OCC
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc(OCc2ccccc2)ccc1C(C#N)CC(=O)O
Temperature: 70 °C
Yield: 100 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged with methanol (20 mL) and water (5 mL). To the stirred solvent was added diethyl [4-(benzyloxy)-2-methoxybenzylidene]propanedioate (0.775 g, 2.02 mmol), followed by potassium cyanide (0.262 g, 4.04 mmol). The RM was heated at 70° C. for 2 h. The RM was concentrated, diluted with saturated NaHCO3 solution (50 mL) and washed with ethyl acetate (50 mL×2). The aqueous layer was acidified to pH 3 with 1N hydrochloric acid and extracted with ethyl acetate (50 mL×2). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as brown liquid. (0.62 g, yield: 100.0%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17](F)[CH:16]=1.O>CN(C=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:16]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: Sc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)cc1Sc1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Mercaptopyridine (1.1 1 g, 10 mmol) and K2CO3 (1.38 g, 10 mmol) were suspended in DMF (10 mL) and stirred at room temperature for 15 min. The mixture was treated with 4-chloro-2-fluoro-1-nitro-benzene (1.75 g, 10 mmol) and heated at 50° C. for 16 h. After cooling to room temperature, water (50 mL) was added and the mixture extracted 3 times with ethyl acetate. The organic layer was combined the ethyl acetate and then reduced in vacuo. The residue was dissolved in DMF (30 mL) and treated with SnCl2.2H2O. The mixture was heated at 50° C. for 16 hr. The DMF was distilled off under vacuum and the reduction product was purified by flash chromatography on silica gel column (50-100% EtOAc/hexane) to afford 4-chloro-2-(pyridin-4-ylsulfanyl)-phenylamine as light yellow solid. The title sulfonamide compound was prepared according to the general procedure using 118 mg of 4-chloro-2-(pyridin-4-ylsulfanyl)-phenylamine prepared above and 116 mg of 4-tert-Butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.33 (s, 9H), 7.06 (d, 2H, J=6.8 Hz), 7.45 (d, 2H, J=8.4 Hz), 7.51 (m, 2H), 7.66 (d, 2H, 8.4 Hz), 7.71 (d, 1H, J=9.2 Hz), 8.43 (d, 2H, J=6.4 Hz). MS: m/z 433.9 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]([OH:28])[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21](OC(C)(C)C)=O)[CH2:17][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O1CCOCC1.O.C(O)(=O)C>[OH:28][C@H:13]([CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CNC(=O)OCc2ccccc2)CC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CN1CCN(C[C@@H](O)CNC(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
Tert-butyl 4-[(2S)-3-benzyloxycarbonylamino-2-hydroxy-propyl]piperazine-1-carboxylate 21a (1.45 g, 3.70 mmol) was dissolved in 30 mL of dichloromethane followed by the addition of 20 mL of a 4 M solution of hydrogen chloride in dioxane. The reaction solution was stirred for 0.5 hours and concentrated under reduced pressure. The residue was added with 40 mL of dichloromethane, formaldehyde (222 mg, 7.40 mmol) and 0.1 mL of acetic acid successively. The resulting solution was stirred for 0.5 hours followed by the addition of sodium triacetoxyborohydride (2.35 g, 11.10 mmol), stirred for another 12 hours. The resulting solution was added with 50 mL of water and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound benzyl N-[(2S)-2-hydroxy-3-(4-methylpiperazin-1-yl)propyl]carbamate 21b (840 mg, yield: 74.0%) as a yellow oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[CH:23]=2)[N:18]=[CH:17]1.[CH:34]1([NH2:38])[CH2:37][CH2:36][CH2:35]1>N1C=CC=CC=1>[CH:34]1([NH:38][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][C:7]([CH3:6])=[C:8]([N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)[CH:23]=4)[N:18]=[CH:17]3)[CH:9]=2)[CH2:37][CH2:36][CH2:35]1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Reactant: NC1CCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)NC2CCC2)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Temperature: 120 °C

Procedure:
Phosphorus oxychloride (0.08 ml) was added to a mixture of 4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoic acid (0.30 g), cyclobutylamine (0.09 ml) and pyridine (5 ml) and the resultant was heated to 120° C. for 5 minutes in a microwave (Personal Chemistry Emrys Optimizer with 300 W magnetron). The mixture was evaporated. The residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was dried (magnesium sulphate) and evaporated and the residue purified by column chromatography on a silica column using initially methylene chloride and then a 9:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.16 g); NMR Spectrum: (DMSOd6) 1.68 (m, 2H), 2.05 (m, 2H), 2.14 (s, 3H), 2.20 (m, 2H), 2.24 (s, 3H), 2.48 (m, 4H), 3.29 (m, 4H), 4.42 (m, 1H), 7.49 (d, 1H), 7.53 (d, 1H), 7.65 (m, 2H), 7.87 (d, 1H), 7.92 (m, 1H), 8.10 (s, 1H), 8.60 (d, 1H); Mass Spectrum: M+H+ 432.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[NH2:34][C@H:35]([CH3:42])[CH2:36][CH2:37][NH:38][CH:39]([CH3:41])[CH3:40].C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:5]3[C:3](=[O:2])[N:34]4[C@H:35]([CH3:42])[CH2:36][CH2:37][N:38]([CH:39]([CH3:41])[CH3:40])[C@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Reactant: CC(C)NCC[C@@H](C)N
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N1CC[C@@H](C)N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@H]12
Yield: 55.5 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (40 mg, 0.088 mmol) and [(3R)-3-aminobutyl](1-methylethyl)amine (78 mg, 0.60 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4R,12aR)—N-[(4-fluorophenyl)methyl]-4-methyl-1-(1-methylethyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (26 mg, 56%). This material was hydrogenated in a second step as described in example Z-2 to give (4R,12aR)—N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (21 mg, 90%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 1.01 (d, J=5.6 Hz, 3H), 1.06 (d, J=6.0 Hz, 3H), 1.31 (d, J=6.8 Hz, 3H), 1.57 (m, 1H), 1.98 (m, 1H), 2.70-2.82 (m, 2H), 3.15 (m, 1H), 4.15-4.19 (m, 1H), 430 (m, 1H), 4.48 (s, 1H), 4.54-4.59 (m, 2H), 4.97 (m, 1H), 6.98 (m, 2H), 7.29-7.32 (m, 2H), 8.27 (s, 1H), 10.49 (s, 1H), 12.52 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:26](=[CH:27][CH:28]=1)[C:12]1[NH:13][C:14]([C:16]3[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])=[N:15][C:11]=1[C:10]1[CH:9]=[CH:8][C:7]([Cl:29])=[CH:6][C:5]2=1.[H-].[Na+].[CH3:32][Si:33]([CH3:40])([CH3:39])[CH2:34][CH2:35][O:36][CH2:37]Cl>C1COCC1>[Br:1][C:2]1[CH:28]=[CH:27][C:26]2[C:12]3[N:13]=[C:14]([C:16]4[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][C:17]=4[C:18]#[N:19])[N:15]([CH2:37][O:36][CH2:35][CH2:34][Si:33]([CH3:40])([CH3:39])[CH3:32])[C:11]=3[C:10]3[C:5](=[CH:6][C:7]([Cl:29])=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1
Reactant: N#Cc1cccc(C#N)c1-c1nc2c3ccc(Cl)cc3c3cc(Br)ccc3c2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(-c2c(C#N)cccc2C#N)nc2c3ccc(Br)cc3c3cc(Cl)ccc3c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.6 %

Procedure:
To a solution of 2-(6-bromo-9-chloro-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile (5 g, 10.9 mmol) from Example 36 in THF (30 mL) was added NaH (60% dispersion in oil, 1.31 g, 32.7 mmol). The mixture was stirred at room temperature for 10 minutes, after which 2-(trimethylsilyl)ethoxymethylchloride (5.8 mL, 32.7 mmol) was added. After 1 hour, the reaction was quenched by slow addition of water. The aqueous layer was extracted with ethyl acetate, the organic layer washed once with water, once with brine, dried over anhydrous MgSO4 and concentrated to afford crude 2-(6-bromo-9-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile (6.06 g).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[C:3]=1[Cl:12].C([O-])([O-])=O.[Na+].[Na+]>CCO.O>[Br:1][C:2]1[C:3]([Cl:12])=[C:4]([NH2:9])[C:5]([NH2:6])=[CH:7][CH:8]=1
Reactant: Nc1ccc(Br)c(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Br)c(Cl)c1N
Yield: 96.3 %

Procedure:
To a stirred solution of 4-bromo-3-chloro-2-nitroaniline (0.200 g, 0.797 mmol) in EtOH (100 mL), was added SnCl2-2H2O (0.9 g, 3.985 mmol). The reaction mixture was heated to reflux for 3.5 h. The cooled solution (to rt) was diluted with H2O and the pH was adjusted to ca. 10 with Na2CO3. Extraction with CHCl3 (×3), was followed by washing with brine, drying over Na2SO4, and filtration. Concentration afforded an orange solid that was dried under vacuum to obtain 0.17 g product: 1H NMR (400 MHz, CDCl3) δ 6.92 (d, J=8.4 Hz, 1H), 6.51 (d, J=8.4 Hz, 1H), 3.90 (s, 2H), 3.40 (s, 2H); MS (ESI) m/z 223 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:22])=[CH:7][N:8]3[C:15](=[O:16])[C:14]([C:17]([O:19]CC)=[O:18])=[CH:13][N:12]=[C:9]32)=[CH:4][CH:3]=1>C(O)(=O)C.Cl.O>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:22])=[CH:7][N:8]3[C:15](=[O:16])[C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=[C:9]32)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2c3cc(N)ccc3c(C)cn2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1cn2c(=O)c(C(=O)O)cnc2c2cc(N)ccc12
Yield: 74.5 %

Procedure:
A suspension of ethyl 10-amino-7-methyl-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (400 mg) in a mixture of acetic acid (6 ml) and 36% hydrochloric acid (3 ml) was refluxed for 55 minutes. The mixture was cooled and diluted with water. The precipitated solid obtained was collected and dissolved into 6 ml of 1N aqueous sodium hydroxide. The resulting solution was filtered for removal of insoluble materials. The filtrate obtained was cooled and adjusted to pH 6 with 1N hydrochloric acid and neutralized with acetic acid to give 10-amino-7-methyl-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylic acid (270 mg).
Reaction SMILES: [CH2:1]([N:9]1[CH2:15][CH2:14][CH2:13][C@@H:12]2[CH2:16][CH2:17][NH:18][C@@H:11]2[CH2:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)(=O)C.O>[CH2:25]([O:32][C:33]([N:18]1[C@@H:11]2[CH2:10][N:9]([CH2:1][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:15][CH2:14][CH2:13][C@@H:12]2[CH2:16][CH2:17]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(CCN2CCC[C@@H]3CCN[C@@H]3C2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CC[C@H]2CCCN(CCc3ccccc3)C[C@H]21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of (3aR,8aS)-7-Phenethyl-decahydro-pyrrolo[2,3-c]azepine (4.0 g, 16.37 mmol) (Reference: PCT Int. Appl., 2005097791, 20 Oct. 2005) in ethyl acetate (100 mL) was added a solution of potassium carbonate (6.79 g, 49.1 mmol, 3.0 eq) in water (100 mL). The biphasic solution was cooled to 0° C. then benzylchloroformate (2.80 mL, 19.64 mmol, 1.2 eq) added dropwise. The resulting mixture was stirred for 3 hr at 23° C. The mixture was partitioned and the aqueous layer extracted with Ethyl Acetate. The combined organic layers were washed with water followed by brine and the organic layer dried (Na2SO4), filtered, and the filtrate concentrated to yield an orange oil. The crude was purified using silica gel chromatography (1:2 Ethyl Acetate/Heptane to 100% Ethyl Acetate followed by 12:1 CH2Cl2/Methanol) giving (3aR,8aS)-7-Phenethyl-octahydro-pyrrolo[2,3-c]azepine-1-carboxylic acid benzyl ester.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14]O)=[C:12]([C:16]([CH3:18])=[CH2:17])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].CS([Cl:23])(=O)=O.C(N(CC)CC)C.O>ClCCl>[Cl:23][CH2:14][C:13]1[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)=[N:10][S:11][C:12]=1[C:16]([CH3:18])=[CH2:17]
Reactant: CS(=O)(=O)Cl
Reactant: C=C(C)c1snc(-c2ccc(CC)cc2)c1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=C(C)c1snc(-c2ccc(CC)cc2)c1CCl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of [3-(4-ethylphenyl)-5-(prop-1-en-2-yl)-1,2-thiazol-4-yl]methanol (305.3 mg, 1.18 mmol, 1.00 equiv) in dichloromethane (15 mL), MsCl (268.8 mg, 2.00 equiv), triethylamine (297.6 mg, 2.94 mmol, 2.50 equiv). The resulting solution was stirred for 40 min at 25° C. 10.0 mL water was added to the mixture. The organic phase was separated and washed by 10.0 mL brine, dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum and residue used in next step directly without further purification. Mass spectrum (ESI, m/z): Calcd. for C15H16ClNS, 278.8 (M+H). found 278.8.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:5][C:4]=2[CH:3]=1.[CH3:18][C:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][N:21](C(OC(C)(C)C)=O)[N:20]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:18][C:19]1[NH:20][N:21]=[CH:22][C:23]=1[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:5][C:4]=2[CH:3]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=c1[nH]c(CN2CCCC2)nc2cc(Br)sc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1[nH]ncc1-c1cc2nc(CN3CCCC3)[nH]c(=O)c2s1
Temperature: 100 °C
Reaction time: 3 h
Yield: 43.8 %

Procedure:
6-Bromo-2-(pyrrolidin-1-ylmethyl)thieno[3,2-d]pyrimidin-4(3H)-one (100 mg), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (294 mg), sodium carbonate (95 mg), 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (26 mg) was added, and the atmosphere in the flask was purged again with argon. The reaction system was stirred at 100° C. for 3 hr, 8M aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at 100° C. for 30 min. After stirring, the mixture was extracted with ethyl acetate/tetrahydrofuran mixture, and the extract was dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate), and the obtained pale-yellow solid was crystallized from methanol/ethyl acetate to give the title compound (44 mg) as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.II.CO[C:13](=[O:26])[CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C(OCC)C>[OH:26][C:13]([C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1)([C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1)[CH2:14][NH:15][C:16](=[O:17])[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cccc(Br)c1
Reactant: COC(=O)CNC(=O)OCc1ccccc1
Agent: II
Solvent: CCOCC
Product: Cc1cccc(C(O)(CNC(=O)OCc2ccccc2)c2cccc(C)c2)c1
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
3-Bromotoluene (0.8 mL, 6.6 mmol) was added to Mg turnings (0.312 g, 13 mmol) in diethyl ether (5 mL) and an iodine crystal was also added. The reaction was stirred for 30 minutes. The solution was then transferred to another flask (via a pipet) to separate from the excess Mg. A solution of carbobenzyloxyglycine methyl ester (0.294 g, 1.32 mmol) in diethyl ether (3 mL) was then added to the solution of the Grignard reagent and the reaction was stirred for 1 hour. The reaction was then quenched with sat. aq ammonium chloride and the aqueous phase was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified on Biotage chromatography (10% to 10% ethyl acetate/hexane) to give the title material (0.309 g, 62%) as an oil. 1H NMR (400 MHz, DMSO-d6) δ: 2.26 (6H, s), 3.82 (2H, d, J=5.81 Hz), 4.99 (2H, s), 5.76 (1H, s), 6.79 (1H, t, J=5.56 Hz), 7.01 (2H, d, J=7.07 Hz), 7.09-7.40 (11H, m). LC/MS (M−H)−: 374. HPLC ret. time (Condition B): 2.133 min.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[O:11][CH:10]([CH3:13])[CH2:9][CH2:8][C:7]=2[C:6]([CH3:14])=[CH:5][CH:4]=1)[NH2:2].C(N(C(C)C)CC)(C)C.Cl[C:25]([O:27]C)=[O:26]>C1COCC1>[CH3:13][CH:10]1[CH2:9][CH2:8][C:7]2[C:6]([CH3:14])=[CH:5][CH:4]=[C:3]([NH:1][NH:2][C:25]([OH:27])=[O:26])[C:12]=2[O:11]1
Reactant: COC(=O)Cl
Reactant: Cc1ccc(NN)c2c1CCC(C)O2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(NNC(=O)O)c2c1CCC(C)O2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A stirred mixture of the 1F, 200 ml of THF and 12.4 g of N,N-diisopropyl-N-ethylamine was chilled to 0° C. and 9.1 g of methyl chloroformate was added, drop-by-drop, over five minutes. The mixture was poured over ice water and extracted with ether. The extract was dried (MgSO4) and concentrated to dryness, to give the methyl ester of 2-(3,4-dihydro-2,5-dimethyl-2H-1-benzopyran-8-yl)hydrazinecarboxylic acid (1G), as an amber syrup.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[O:11][CH2:12][CH3:13])[CH3:2].[Br:14]N1C(=O)CCC1=O.CCCCCC>C(#N)C>[Br:14][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([O:11][CH2:12][CH3:13])[C:6]=1[F:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1cccc(F)c1OCC
Solvent: CCCCCC
Solvent: CC#N
Product: CCOc1ccc(Br)c(F)c1OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 1,2-diethoxy-3-fluorobenzene (150.00 g, 814 mmoL) in acetonitrile (900 mL), a solution of N-bromosuccinimide (NBS) (153.72 g, 864 mmoL) in acetonitrile (1.5 L) was added dropwise under ice cooling and stirred overnight at room temperature. After evaporation of the solvent, ethyl acetate was added to the residue, followed by washing with water. The resultant aqueous layer was re-extracted with ethyl acetate, and the extract was mixed with the previously obtained organic layer. The organic layer was washed with water, saturated saline and water in this order and then dried over anhydrous magnesium sulfate. The resultant solution was concentrated to obtain an oily material. Hexane was added to the oily material, and the crystals deposited were removed by filtration. The solution was re-concentrated to obtain an oily material, which was distilled under reduced pressure to give 205.65 g of the captioned compound (yield: 96%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:18]C(OCC2C=CC=CC=2)=O)([CH:14]([CH3:17])[CH2:15][OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH2:18])([CH:14]([CH3:17])[CH2:15][OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(CO)C1(NC(=O)OCc2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CC(CO)C1(N)CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 14 h
Yield: 109.3 %

Procedure:
To a solution of an optically-active compound of 3-benzyloxycarbonylamino-3-(2-hydroxy-1-methylethyl)piperidine-1-carboxylic acid tert-butyl ester (374 mg) in methanol (6 ml) was added 10% palladium carbon (38 mg), and the mixture was hydrogenated at room temperature under ordinary pressure for 14 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the titled compound (269 mg).
Reaction SMILES: C([C:3]1[C:4]([OH:10])=[N:5][S:6][C:7]=1[S:8][CH3:9])#N.[H-].[Na+].S(C1C=CC(C)=CC=1)([O-])(=O)=[O:14].O.[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]\[C:28]([OH:30])=[O:29].[C:33]([C:35]1[C:36]([O:42][CH2:43][CH:44]([OH:51])[CH2:45][NH:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[N:37][S:38][C:39]=1[S:40][CH3:41])#[N:34].[C:52]([C:54]1[C:55]([O:61][CH2:62][CH:63]([OH:70])[CH2:64][NH:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[N:56][S:57][C:58]=1[S:59][CH3:60])#[N:53].[C:71]([OH:78])(=[O:77])/[CH:72]=[CH:73]\[C:74]([OH:76])=[O:75]>CN(C=O)C.O>[OH2:10].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]\[C:28]([OH:30])=[O:29].[C:33]([C:35]1[C:36]([O:42][CH2:43][CH:44]([OH:51])[CH2:45][NH:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[N:37][S:38][C:39]=1[S:40][CH3:41])#[N:34].[C:52]([C:54]1[C:55]([O:61][CH2:62][CH:63]([OH:70])[CH2:64][NH:65][C:66]([CH3:68])([CH3:67])[CH3:69])=[N:56][S:57][C:58]=1[S:59][CH3:60])#[N:53].[C:71]([OH:78])(=[O:77])/[CH:72]=[CH:73]\[C:74]([OH:76])=[O:75].[CH3:9][S:8][C:7]1[S:6][N:5]=[CH:4][CH:3]=1.[OH2:14].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]\[C:28]([OH:30])=[O:29].[CH3:9][S:8][C:7]1[S:6][N:5]=[CH:4][CH:3]=1.[CH3:9][S:8][C:7]1[S:6][N:5]=[CH:4][CH:3]=1.[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]\[C:28]([OH:30])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CSc1snc(O)c1C#N
Agent: CSc1snc(OCC(O)CNC(C)(C)C)c1C#N
Agent: O=C(O)/C=C\C(=O)O
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccns1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into a dry flask under N2 is added 4-cyano-3-hydroxy-5-methylthioisothiazole (8.6 g., 0.05 m.), DMF (120 ml.) and NaH (50% mineral oil, 2.5 g., 0.052 m.). After stirring at room temperature for 15 minutes, the tosylate of (S) 2-phenyl-3-tert. butylamino-5-hydroxymethyloxazolidine (0.05 m.) in DMF (80 ml.) is added and the solution heated at 80° C. with stirring. After 15 hours, the solution is cooled to 0°-10°, poured into H2O (600 ml.) and extracted with ether (4 × 100 ml.). The organic layer is washed with H2O (2 × 100 ml.) and 1N HCl (3 × 100 ml.). The acid layer is poured into NaOAc.3H2O (41 g., 0.3 m.) and the solution stirred at room temperature. After 5 hours, the solution is extracted with ether (2 × 100 ml.). The aqueous layer is neutralized with saturated Na2CO3 and extracted with CHCl3 (4 × 150 ml.). The organic layer is dried over Na2SO4, filtered and concentrated to dryness. The residue is chromatographed on silica gel 60 and the product eluted with CHCl3 saturated with ammonia. There is obtained 6.3 g. (42%) of (S) 4-cyano-3-tert. butylamino-2-hydroxypropoxy)-5-methylthioisothiazole, which on treatment with maleic yields the (S) 4-cyano-3-(3-tert. butylamino-2-hydroxypropoxy(-5-methylthioisothiazole hydrogen maleate salt hemihydrate, m.p. 199°-200° C.