Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6](C(=O)C)=[C:7]([CH3:9])[N:8]=1.[C:13](=O)([O:21]C1C=CC=CC=1)[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC.CN(C=O)C.C(Cl)(Cl)Cl>[CH3:9][C:7]1[N:8]=[C:4]([NH:3][C:13](=[O:21])[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:5][CH:6]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: CC(=O)c1sc(N)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1csc(NC(=O)Oc2ccccc2)n1
Yield: 100 %

Procedure:
In a round-bottom flask, NaH 60% dispersion in mineral oil (3.07 g, 77 mmol) was washed 2× with hexane and suspended in DMF. Then 2-amino-5-acetyl-4-methyl-thiazole (10.0 g, 64 mmol) was added and stirred while cooling in an ice bath. Stirring continued until the NaH was consumed. Diphenyl carbonate (34 g, 160 mmol) was added while cooling and after the addition was complete the reaction mixture was stirred for an additional 30 minutes at room temperature. The DMF was removed on a rotary evaporator (high vacuum, 40° C.) to yield a brown residue. This residue was dissolved in 1 L of CHCl3 and washed successively with 2 L of 0.5N HCl, 2×1 L of water, and finally by 1 L of brine. The aqueous portions were back extracted twice with 300 ml of CHCl3. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give a white solid. This was chromatographed on silica (15%-70% EtOAc/hexane) to give 15 g of the desired carbamate as a white solid. Mp 180-182° C. 1H NMR (300 MHz, CDCl3) δ 11.42 (bs, 1H), 7.47-7.40 (m, 2H), 7.33-7.27 (m, 1H), 7.22-7.18 (m, 2H), 2.72 (s, 3H), 2.50 (s, 3H). ESI MS: (M+H)+=277.1. Anal. Calcd for C13H12N2O3S: C, 56.51; H 4.39; N, 10.14; S, 11.60. Found: C, 56.42; H, 4.31; N, 10.11; S, 11.74. A similar procedure as described above for Example 1 was used to synthesize all the other examples listed in Table 1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]1[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:15])[CH3:5].[Cl:16][CH2:17][C:18](Cl)=[O:19]>>[Cl:16][CH2:17][C:18]([N:6]([C:7]1[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:15])[C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])=[O:19]
Reactant: O=C(Cl)CCl
Reactant: CCc1cccc(C)c1N[C@@H](C)COC
Product: CCc1cccc(C)c1N(C(=O)CCl)[C@@H](C)COC

Procedure:
(S)-N-(1-Methoxyprop-2-yl)-2-methyl-6-ethylphenylamine is acylated with chloroacetyl chloride in a manner known per se to yield the known (S)-N-chloroacetyl-N-(1-methoxyprop-2-yl)-2-methyl-6-ethylphenylamine (also known as S-metolachor).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1.Br[CH2:22][C:23]([OH:25])=[O:24]>CN(C)C=O>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][C:4]([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)([O:3][CH2:22][C:23]([OH:25])=[O:24])[CH2:5]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2nccs2)C1
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OCC(=O)O)(c2nccs2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ambient suspension of NaH (5.40 g, 135 mmol) in N,N-dimethylformamide (50 mL) was added dropwise a solution of tert-butyl 3-hydroxy-3-(thiazol-2-yl)pyrrolidine-1-carboxylate (7.30 g, 27 mmol) in N,N-dimethylformamide (20 mL). After 30 minutes, bromoacetic acid (7.50 g, 54.0 mmol) in N,N-dimethylformamide (20 mL) was added dropwise. The solution was stirred at room temperature for 16 hours and then heated to 50° C. for 3 hours. The reaction was cooled to room temperature and was quenched by the addition of water. The solution was basicified to pH 10 by the addition of 2.5 M NaOH solution. The aqueous layer was extracted with ether, and the organics discarded. The aqueous layer was acidified to pH 1 with 6 M HCl solution, and then extracted with ethyl acetate (2×). The combined organics were washed with water, brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the product. MS ESI(+) m/z 329.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.Cl[S:32]([N:35]1[CH2:39][CH2:38][CH2:37][C@H:36]1[C:40]([O:42][CH3:43])=[O:41])(=[O:34])=[O:33].C(N(CC)CC)C>C(#N)C>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:32]([N:35]3[CH2:39][CH2:38][CH2:37][C@H:36]3[C:40]([O:42][CH3:43])=[O:41])(=[O:33])=[O:34])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: COC(=O)[C@@H]1CCCN1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Temperature: 60 °C
Reaction time: 20 h
Yield: 16.1 %

Procedure:
The product of Example 205 (0.030 g, 0.0703 mmol) in acetonitrile (2 ml) was treated with the product of Example 461A (0.018 g, 0.077 mmol) and triethylamine (0.011 ml, 0.077 mmol), stirred at 60° C. for 20 hours and cooled to about 25° C. The solvent was evaporated under reduced pressure, and the residue was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile/10 mM ammonium acetate in water over 8 minutes (10 minutes run time) at a flow rate of 40 mL/min give the title compound (7 mg, 16%). 1H NMR (300 MHz, DMSO-d6) δ 0.99 (d, J=6.25 Hz, 6 H) 1.59 (m, 2 H) 1.67 (m, 2 H) 1.87 (m, 4 H) 2.09 (d, J=8.46 Hz, 1 H) 3.60 (s, 3 H) 4.26 (dd, J=8.64, 3.86 Hz, 1 H) 4.50 (m, 2 H) 7.55 (m, 4 H) 7.73 (d, J=8.82 Hz, 1 H) 8.57 (dd, J=8.09, 1.84 Hz, 1 H) 8.90 (dd, J=4.78, 1.84 Hz, 1 H) 10.53 (s, 1 H) 14.07 (s, 1 H). MS (ESI−) m/z 617 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]#N)=[CH:7][CH:6]=[CH:5][N:4]=1.[OH-:12].[Na+].Cl.C[OH:16]>>[CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]([OH:16])=[O:12])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CO
Reactant: COc1ncccc1CC#N
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COc1ncccc1CC(=O)O
Temperature: 100 °C

Procedure:
2.2 g of (2-methoxy-3-pyridyl)methyl cyanide, 35 ml of a 1N aqueous sodium hydroxide and 35 ml of methanol were stirred under heating at 100° C. for 1.5 hours. The mixture was cooled to room temperature, and then, 35 ml of a 5N aqueous hydrochloric acid was added thereto, and the solvent was evaporated. Ethanol was added to the residue and a solid was filtered off. Ethanol was evaporated, and ethanol was added again to the residue and a solid was filtered off. Ethanol was evaporated, to give 2.4 g of white crystals.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][CH:13]([F:16])[CH2:14][OH:15]>>[Br:1][C:2]1[C:3]([O:15][CH2:14][CH:13]([F:16])[F:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: OCC(F)F
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Product: O=C(O)c1cnc(OCC(F)F)c(Br)c1
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (4.7 g, a pale orange solid) from 5-bromo-6-chloronicotinic acid (3.0 g, 12.7 mmol) and 2,2-difluoroethanol (2.1 g, 25.4 mmol) instead of 2,2,2-trifluoroethanol by the similar manner in Step-1 of Amine-1.
Reaction SMILES: COB(OC)OC.B.CSC.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[CH:13]=1.Cl>C1COCC1>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C@H:18]([OH:22])[CH2:19][CH2:20][CH3:21])[CH:13]=1
Reactant: CCCC(=O)c1cccnc1
Agent: B
Agent: COB(OC)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: CCC[C@@H](O)c1cccnc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of S(−)-α,α-diphenyl-2-pyrrolidinemethanol (500 mg, 2 mmol) and trimethylborate (0.27 ml, 2.4 mmol) in THF (20 mL) was added borane-dimethylsulfide complex (20 mL, 2M in THF, 40 mmol). The mixture was cooled to 0° C. and 1-pyridin-3-ylbutan-1-one was added dropwise over 4 h. The solution was stirred at RT overnight and then treated with 2M HCl (175 mL) and stirring continued for 4 h. The-volatiles were removed under reduced pressure and the resulting cloudy solution basified to pH 11 with aqueous ammonia. The product was extracted into ethyl acetate (3×100 mL) and the combined organic layers washed with brine (100 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure afforded ˜3 g of product.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S(Cl)([Cl:23])=O.C1CCC(CN)(CC(O)=O)CC1.Cl>C(OCC)C>[ClH:23].[NH2:12][CH2:11][C:4]1([CH2:7][C:8]([O:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1
Reactant: OCc1ccccc1
Reactant: NCC1(CC(=O)O)CCCCC1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CCOCC
Product: NCC1(CC(=O)OCc2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 84 h
Yield: 90.7 %

Procedure:
A dry 500 mL, three-necked, round-bottomed flask was fitted with a magnetic stirring bar and a 60 mL pressure-equalizing addition funnel and flushed with nitrogen gas. The flask was charged with gabapentin (17.1 g, 0.1 mol) and benzyl alcohol (128 mL, 1.18 mol) and the mixture was cooled to 0° C. with an ice-water bath. Thionyl chloride (51.8 mL, 77.25 g, 0.65 mol) was added dropwise to the stirred solution over a period of 1 h. The reaction was monitored by LC/MS, with product and unreacted gabapentin hydrochloride being observed. After stirring at room temperature for 3.5 days the reaction mixture contained residual gabapentin hydrochloride (by LC/MS). Additional thionyl chloride (20 mL, 30 g, 0.25 mol) was added at 0° C., and the reaction mixture allowed to stir at room temperature for another 12 h (LC/MS shows traces of residual gabapentin hydrochloride). A final portion of thionyl chloride (10 mL, 15 g, 0.12 mol) was added at 0° C. and the reaction mixture allowed to stir at room temperature for 4 h (LC/MS showed no remaining gabapentin hydrochloride). The reaction mixture was then diluted with ethyl ether (200 mL) and cooled to 0° C. while stirring. White crystalline solid formed, which was collected by filtration. The crude compound was recrystallized from a mixture of ethanol and ethyl ether (50 mL: 150 mL). Finally the white crystals were washed with 250 mL of ethyl acetate to give product (6) as a white solid (27 g, 91% yield). 1H NMR (CDCl3, 400 MHz.): δ 1.43–1.52 (m, 10H), 2.64 (s, 2H), 3.08 (d, 2H), 6.04 (br. s, 11H), 7.25–7.33 (m, 5H), 8.44 (br. s, 3H). MS (ESI) m/z 262.26 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=[CH:3]1.S(=O)(=O)(O)O.O>C(OC(C)=O)CCC.C(O)CCC>[O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]([O:10][CH2:2][CH2:3][CH2:4][CH3:5])=[O:9])[CH:4]=[CH:3]1
Reactant: O=C(O)c1ccc(=O)[nH]n1
Agent: O=S(=O)(O)O
Solvent: CCCCO
Solvent: CCCCOC(C)=O
Solvent: O
Product: CCCCOC(=O)c1ccc(=O)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 170.5 %

Procedure:
A solution of 6-oxo-1,6-dihydropyridazine-3-carboxylic acid (British patent no. 856409) (52 g, 0.33 mol) in nBuOAc (80 ml) and butanol (80 ml) was treated with concentrated sulphuric acid (5 ml). The mixture was heated at reflux under a Dean-Stark trap. After 5 hours water production had ceased. The reaction was allowed to cool to ambient temperature and after standing overnight, the precipitate was filtered, washed with diethyl ether and dried to give butyl 6-oxo-1,6-dihydropyridazine-3-carboxylate as a white solid (55.2 g, 85%) m.p. 81-83° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[N:50]1([CH2:56][CH2:57][O:58][C:59]2[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[C:62]([NH2:69])=[CH:61][CH:60]=2)[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>CN(C=O)C.O>[N:50]1([CH2:56][CH2:57][O:58][C:59]2[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[C:62]([NH:69][C:8]([C:6]3[CH:5]=[C:4]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[N:3]=[C:2]([Cl:1])[N:7]=3)=[O:10])=[CH:61][CH:60]=2)[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1
Reactant: O=C(O)c1cc(N2CCOCC2)nc(Cl)n1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cc(N2CCOCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 83.8 %

Procedure:
2-Chloro-6-morpholin-4-ylpyrimidine-4-carboxylic acid (0.280 g, 1.15 mmol) in DMF (5 ml) is treated with HBTU (0.466 g, 1.5 eq) and diisopropylethylamine (0.367 ml). The mixture is stirred at room temperature for 5-10 min. 4-(2-Morpholin-4-yl-ethoxy)-naphthalen-1-ylamine (0.224 g, 0.82 mmol) is then added. The mixture is stirred at room temperature for an additional 15 h, diluted with water and extracted with ethyl acetate. The organic layer is dried over Na2SO4 and evaporated to dryness. The residue is purified by column chromatography on silica gel eluted with 2% MeOH in ethyl acetate to provide 2-chloro-6-morpholin-4-yl-pyrimidine-4-carboxylic acid [4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-amide as a solid (0.342 g). Mp: 95-93° C., 1H NMR (300 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.20 (m, 1H), 7.79 (s, 1H), 7.56 (m, 3H), 7.39 (s, 1H), 7.03 (d, J=8.1Hz, 1H), 4.31 (t, J=6.3 Hz, 2H), 3.60 (brt, 8H) 2.88 (t, 2H), 2.56 (brt, 8H). MS: 498 (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:35])([F:34])[CH:31]1[O:33][CH2:32]1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.O.C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:27])([F:28])[CH:24]([F:25])[F:26])[CH:17]=2)[CH2:32][CH:31]([OH:33])[C:30]([F:35])([F:34])[F:29])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)C1CO1
Reactant: FC(F)C(F)(F)Oc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Temperature: 50 °C
Yield: 62.9 %

Procedure:
To a mixture of the amine product (15.0 g, 0.038 mol) from EX-1B and 1,1,1-tri-fluoro-2,3-epoxypropane (8.58 g, 0.077 mol, TCI) was added a suspension of ytterbium (III) trifluoromethanesulfonate (2.37 g, 0.0031 mol) in 15 mL of acetonitrile. The resulting mixture was heated at 50° C. in a sealed glass vial for 1.5 h. The reaction mixture was cooled to room temperature then diluted with water and ethyl acetate and extracted. The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to afford 12.03 g (62%) of the desired (2RS)-3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy) phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil. Anal. calcd. for C24H20F7NO3: C, 57.26; H, 4.00; N, 2.78. Found: C, 56.96; H, 4.35; N, 2.69. HRMS calcd. 504.1410 [M+H]+. found: 504.1431. 1H NMR (CDCl3) δ 7.28 (m, 4H), 7.14 (t, 1H), 7.07, (m, 3H), 7.00 (s, 1H), 6.94 (d, 2H), 6.46 (dd, 1H), 6.38 (dd, 1H), 6.35 (t, 1H), 5.84 (t, 1H), 4.60 (t, 2H), 4.36 (m, 1H), 3.82 (d, 1H), 3.48 (m, 1H), 2.51 (s, 1H). 19F NMR (CDCl3) δ −79.0 (s, 3F), −88.21 (d, 2F), −137.05 (dd, 2F).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Cl)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:15]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH2:8])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCC=Cc1ccccc1
Reactant: Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1ccccc1NCC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
3.24 g of ortho-phenylenediamine was dissolved in 30 ml of dimithylformaide, to the solution were added 2.07 g of potassium carbonate and 1.52 g of cinnamyl chloride, and the mixture was stirred overnight at a room temperature. After adding 100 ml of water, the reaction mixture was extracted twice with 100 ml and 50 ml of chloroform, and the extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated to remove the solvent under a reduced pressure The resulting residue was applied to a silica gel column and eluted with chloroform, to obtain 2.0 g of the title compound as light brown crystals.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[CH:5]1([CH2:8][O:9][C:10]2[CH:11]=C([CH:15]=[CH:16][C:17]=2[O:18][CH:19]([F:21])[F:20])C=O)[CH2:7][CH2:6]1.S(=O)(=O)(O)N.Cl([O-])=O.[Na+]>O>[CH:5]1([CH2:8][O:9][C:10]2[CH:11]=[C:2]([CH:15]=[CH:16][C:17]=2[O:18][CH:19]([F:20])[F:21])[C:1]([OH:4])=[O:3])[CH2:6][CH2:7]1
Reactant: CC(=O)O
Reactant: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Product: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 7.5 °C

Procedure:
Glacial acetic acid (5 vol. with respect to 3-cyclopropylmethoxy 4-Difluoromethoxy benzaldehyde) was taken in a vessel and to this mixture of 3-cyclopropylmethoxy 4-Difluoromethoxy benzaldehyde and sulfamic acid (1.35 eq with respect to 3-cyclopropylmethoxy 4-Difluoromethoxy benzaldehyde) was added. The reaction mass was cooled to 5-10° C. under stirring. In another clean reaction vessel sodium chlorite (1.63 eq) was taken in water (1.5 vol. with respect to 3-cyclopropylmethoxy 4-Difluoromethoxy benzaldehyde) and added dropwise to the above prepared reaction solution at temperature below 10° C. The reaction mixture was stirred for 1 hr at 5-10° C. After completion of the reaction, water was added to get a white slurry. The solid was filtered and washed with water and dried under vacuum at 45-50° C. to get 3-cyclopropylmethoxy 4-Difluoromethoxy benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([C:9]#[N:10])=[C:6]([NH2:8])[N:7]=1.[OH-:13].[Na+].N.[OH2:16]>>[NH2:1][C:2]1[C:3]([C:11](=[O:16])[NH2:12])=[N:4][C:5]([C:9](=[O:13])[NH2:10])=[C:6]([NH2:8])[N:7]=1
Reactant: [OH-]
Reactant: O
Reactant: N#Cc1nc(C#N)c(N)nc1N
Agent: N
Agent: [Na+]
Product: NC(=O)c1nc(C(N)=O)c(N)nc1N
Reaction time: 0.05 h

Procedure:
A slurry consisting of 7.00 g (43.8 mmol) of 3,5-diamino-2,6-dicyanopyrazine in 1.2l of water in which was dissolved 3.50 g (97.6 mol) of sodium hydroxide was heated rapidly to reflux. The reaction mixture became homogeneous within 3 min at reflux, followed in 1 min by the precipitation of 3,5-diamino-2,6-dicarbamoylpyrazine. After a total of 3 hr 10 min at reflux a homogeneous solution was again obtained. Reflux was continued for an additional 40 min as a stream of nitrogen was passed through the reaction medium to eliminate any residual ammonia. Cooling in an ice bath resulted in the precipitation of 3.30 g (16.9 mmol) of 3,5-diamino-2,6-dicarbamoylpyrazine which was collected by filtration and oven dried. Acidification of the filtrate to pH 3 with hydrochloric acid gave 5.00 g (24.4 mmol) of 3,5-diamino-6-carbamoylpyrazinoic acid after collection by filtration and oven drying. This represents a 61% conversion and 94% yield of the amide acid.
Reaction SMILES: C([O:8][C@@H:9]([C@@H:12]1[O:20][C@H:19]2[C@H:15]([N:16]=[C:17]([N:21]([CH3:23])[CH3:22])[S:18]2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@@H:13]1[O:32]CC1C=CC=CC=1)[CH:10]=[O:11])C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.[NH4+].[OH-]>ClCCl>[OH:8][C@@H:9]([C@H:12]1[O:20][C@H:19]2[C@H:15]([N:16]=[C:17]([N:21]([CH3:23])[CH3:22])[S:18]2)[C@@H:14]([OH:24])[C@@H:13]1[OH:32])[CH2:10][OH:11]
Reactant: CN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]([C@@H](C=O)OCc3ccccc3)O[C@@H]2S1
Agent: ClB(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H]([C@H](O)CO)O[C@@H]2S1
Reaction time: 0.13 h
Yield: 9.2 %

Procedure:
A solution of 102 (500 mg, 0.9 mmol) in dichloromethane (20 mL) was treated with BCl3 (9 ml, 9 mmol, 1 M in dichloromethane) at −60° C. under nitrogen for 30 min. The reaction was then quenched with methanol (20 mL). Volatiles were distilled out to give a residue, which was dissolved into methanol (5 mL) and neutralized with Con. NH4OH (2 ml, 26% aqueous solution). After concentration, the crude product was purified by a silica gel column, eluted with 10° A) methanol in dichloromethane to give a mixture of the two epimers; the two epimers were separated by Prep-HPLC with the following conditions: Agilent Prep 1200 Detecl): Column, SunFire Prep C18; mobile phase, Water with 0.05% ammonia and CH3CN; 5% CH3CN up to 60% in 8 min; Detector, 220 nm) to afford (3aR,5R,6S,7R,7aR)-5-((R)-1,2-dihydroxyethyl)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol as a white solid (23.1 mg, 9%), Faster eluting isomer; (ES, m/z): [M+H]+ 279.0; 1H NMR (300 MHz, D2O) δ 6.17 (d, J=6.3 Hz, 1H), 4.13 (t, J=6.0 Hz, 1H), 3.95 (t, J=4.5 Hz, 1H), 3.78-3.83 (m, 1H), 3.61-3.71 (m, 2H), 3.50-3.54 (m, 2H), 2.88 (s, 6H); and (3aR,5R,6S,7R,7aR)-5-((S)-1,2-dihydroxyethyl)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol as a white solid (37.5 mg, 13%), Slower eluting isomer; (ES, m/z): [M+H]+ 279.0; 1H NMR (300 MHz, D2O) δ 6.18 (d, J=6.3 Hz, 1H), 4.05 (t, J=6.0 Hz, 1H), 3.90 (t, J=5.1 Hz, 1H), 3.75-3.81 (m, 1H), 3.65-3.69 (m, 1H), 3.44-3.53 (m, 3H), 2.87 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH2:4][N:3]=1.[CH2:16]([Br:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[Br-:23].[CH2:16]([N+:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)[C:2]=1[CH3:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc2c(cc1OC)C(C)=NCC2
Solvent: CC(C)=O
Product: COc1cc2c(cc1OC)C(C)=[N+](Cc1ccccc1)CC2
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a stirred solution of 1-methyl-6,7-dimethoxy-3,4-dihydroisoquinoline in acetone was added benzyl bromide and the reaction mixture was stirred at room temperature for 16 hours. A yellow precipitate formed which was filtered, washed with ice cold acetone and dried in vacuo. The product was further purified by recrystallisation from a hexane/dichloromethane mix and pentane to afford the desired compound in 81% yield.