Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([O:7][CH2:8][CH2:9][OH:10])[C:3]=1[C:11]#[N:12].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>C(#N)C>[C:11]([C:3]1[C:4]([O:7][CH2:8][CH2:9][OH:10])=[N:5][NH:6][C:2]=1[N:1]=[CH:15][N:16]([CH3:18])[CH3:17])#[N:12]
Reactant: COC(OC)N(C)C
Reactant: N#Cc1c(OCCO)n[nH]c1N
Solvent: CC#N
Product: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
5-amino-3-(2-hydroxyethoxy)-1H-pyrazole-4-carbonitrile (prepared as described in Middleton, W. J., J. Am. Chem. Soc., 1958, 80, 2829/3.5 g, 20.8 mmol) and dimethylformamide dimethylacetal (4.15 ml, 31.3 mmol) were dissolved in acetonitrile (30 ml) and the mixture was stirred at 60° C. for 1 hour. The solvent was then removed under vacuum and the residue triturated in diethyl ether to provide a white solid, which was filtered and dried under vacuum to give N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (4.45 g, 96%); NMR Spectrum: 2.95 (s, 3H), 3.06 (s, 3H), 3.67 (t, 2H), 4.12 (t, 2H) 8.09 (s, 1H); Mass Spectrum: 238 (MH+).
Reaction SMILES: C(O)CCO.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24](I)=[CH:25][N:26]=2)[CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)C.CN(C)C=O>[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([C:11]3[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=3)=[CH:25][N:26]=2)[CH:23]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1ccc2ncc(I)n2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCCO
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(-c2cnc3ccc(Br)cn23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
0.81 mL 1,3-propane diol was added to a suspension of 1.69 g 4-methoxyphenylboronic acid in 15 mL diethyl ether, and the mixture was stirred a room temperature for 1 hour. Formed water was removed, and the organic solvent was evaporated, whereby an oil was obtained. 2.7 g 6-bromo-3-iodoimidazo[1,2-a]pyridine (compound in Production Example 49), 3.5 g potassium phosphate, 483 mg tetrakistriphenyl phosphine palladium and 40 mL N,N-dimethylformamide were added thereto and heated at 90° C. for 3 hours under nitrogen atmosphere. Insolubles were filtered off, the solvent was removed, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) to give 2 g of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:27])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Cl>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:27])[CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:20][CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(OC(F)(F)F)cc1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(OC(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
While stirring zinc chloride (3.98 g, 29.2 mmol) in diethyl ether (50 ml), sodium borohydride (2.21 g, 58.4 mmol) was added at room temperature and the mixture was stirred as it was for 2 hrs. The insoluble material of the mixture was removed by filtration and washed with diethyl ether to give a solution of zinc borohydride in diethyl ether. To the obtained solution was added a solution of ethyl 3-(4-fluorophenyl)-3-oxo-2-[4-(trifluoromethoxy)benzyl]propionate (5.610 g, 14.60 mmol) in diethyl ether (30 ml) at room temperature and the mixture was stirred as it was for 2 hrs. Dilute hydrochloric acid was added to the reaction solution by small portions to decompose excess zinc borohydride. The mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to give the objective substance.
Reaction SMILES: CC(C)=O.Br[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[CH3:15].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[N+:12]([C:10]1[CH:9]=[CH:8][C:7]([CH3:15])=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=1)([O-:14])=[O:13]
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc([N+](=O)[O-])cc1-c1ccccc1
Yield: 88.2 %

Procedure:
To a mixture of 70 mL of acetone and 85 mL of water was added 2-bromo-4-nitrotoluene 6.84 g (30 mmol), phenylboronic acid 3.84 g (31.5 mmol), potassium carbonate 10.35 g (75 mmol) and palladium acetate 336 mg (1.5 mmol). The mixture was refluxed for 10 hr and then extracted with ether and dilute hydrochloric acid. After evaporating solvents, the solid residue was recrystallized from methanol to give 5.64 g of 4-nitro-2-phenyltoluene (88% yield). 1H NMR (CDCl3) δ 8.09-8.11 (m, 2H), 7.40-7.49 (m, 4H), 7.30-7.33 (m, 2H), 2.37 (s, 3H).
Reaction SMILES: [CH2:1]([CH:3]1[NH:7][C:6](=O)[CH2:5][CH:4]1[CH3:9])C.F[B-](F)(F)F.[CH3:15][O+:16]([CH3:18])C>C(Cl)Cl>[NH:7]([CH:3]1[CH:1]=[C:15]([O:16][CH3:18])[CH2:5][CH:4]1[CH3:9])[CH3:6]
Reactant: CCC1NC(=O)CC1C
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CNC1C=C(OC)CC1C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a solution of 0.254 g (2 mmol) of 5-ethyl-4-methyl-2-pyrrolidone (from step B) in 3 mL of CH2Cl2 was added 0.355 g (2.4 mmol) of trimethyloxonium tetrafluoroborate under a N2 atmosphere. After stirring overnight the reaction mixture was quenched with saturated K2CO3 solution and diluted with Et2O. The solution was filtered and the filtrate was concentrated. The residue was purified by flash chromatography using Et2O-hexane to isolate 0.224 g (79%) of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([NH:18][C@:19]([CH3:26])([C:22]([O:24][CH3:25])=[O:23])[CH2:20][OH:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].CCN(CC)CC>C(Cl)Cl>[C:11]([O:15][C:16]([NH:18][C:19]([CH3:26])([CH:20]=[O:21])[C:22]([O:24][CH3:25])=[O:23])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)[C@](C)(CO)NC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)C(C)(C=O)NC(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
To a stirred solution of oxalyl chloride (2.93 g, 0.0231 mol) in CH2Cl2 (30 mL) at −60° C. was added DMSO (3.6 g, 0.0462 mol) during which the reaction temperature rose up to −55° C. The reaction mixture was stirred at this temperature for 10 min. before the addition of a solution of the methyl N-(tert-butoxycarbonyl)-2-methylserinate product of Example 1b (2.7 g, 0.01157 mol) in CH2Cl2 (20 mL) at −60° C. The reaction mixture was stirred for additional 20 min., quenched with Et3N (5.85 g, 0.0578 mol) between −60° C. to −30° C. and filtered. DI water (50 mL) and EtOAc (100 mL) were added to the filtrate and the layers were separated. The organic layer was dried over anhydrous MgSO4, filtered through Celite and concentrated on a rotovap to give the crude product as an yellow oil. This material was purified by column chromatography using 30% EtOAc in hexane as eluent to give the title product (yield 1.39 g, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:5]2.[NH4+:27].[Cl-]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([C:18]([NH2:27])=[O:20])[CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH:5]2
Reactant: O=C(O)C1CCC(Nc2cc(Cl)cc3cc(-c4ccccc4)[nH]c23)CC1
Reactant: [NH4+]
Agent: [Cl-]
Product: NC(=O)C1CCC(Nc2cc(Cl)cc3cc(-c4ccccc4)[nH]c23)CC1

Procedure:
4-(5-Chloro-2-phenyl-1H-indol-7-yl)amino-cyclohexane-1-carboxylic acid prepared in Example 102 and NH4Cl were reacted according to the same procedure as Example 92 to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:5].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCCC.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:5]
Reactant: CCOC(=O)C(=O)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)c1ccccc1CBr
Temperature: 0 °C
Yield: 43.2 %

Procedure:
To a solution of ethyl 2-methylbenzoylformate (10 g) in carbon tetrachloride (200 ml) were added N-bromosuccinimide (10 g) and 25%-hydrous benzoyl peroxide (1 g) and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled with ice-water and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give a yellow oil. The oil was subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to give the desired ethyl 2-(bromomethyl)benzoylformate (6.1 g, yield: 43%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:20]([O:22][C:23](=[O:30])[CH2:24][CH:25](Br)[CH2:26][CH2:27][CH3:28])[CH3:21].O>CN(C=O)C>[CH2:20]([O:22][C:23](=[O:30])[CH2:24][CH:25]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13]1)[CH2:26][CH2:27][CH3:28])[CH3:21]
Reactant: CCCC(Br)CC(=O)OCC
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CC(=O)OCC)n1ccc2cc(OCc3ccccc3)ccc21
Reaction time: 0.33 h
Yield: 40 %

Procedure:
A solution of 5-benzyloxyindole (5.00 g, 22.4 mmol) in DMF (20 mL) was added dropwise to a stirred solution of sodium hydride (0.91 g, 38.1 mmol) in DMF (50 mL) at 0° C. and stirred for 20 minutes. Ethyl-β-bromocaproate (5.59 g, 26.9 mmol) in DMF (20 mL) was added and the reaction was stirred at room temperature overnight. The reaction was then poured into cold H2O (150 mL) and extracted with ethyl acetate (3×50 mL), dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (40% ethyl acetate in hexane) to give the title compound as oil (40% yield). 1H NMR (CDCl3) δ 7.47 (d, 2H, J=7.2 Hz), 7.38 (t, 2H, J=7.1 Hz), 7.32 (d, 2H, J=8.8 Hz), 7.12 (dd, 2H, J=2.4, 13.7 Hz), 6.94 (dd, 1H, J=2.4, 10.2 Hz), 6.44 (d, 1H, J=3.1 Hz), 5.09 (s, 2H), 4.79 (m, 1H), 3.98 (q, 2H, J=7.1 Hz), 2.80 (m, 2H), 1.90 (m, 2H), 1.25 (m, 2H), 1.07 (t, 3H, J=7.2 Hz), 0.86 (t, 3H, J=7.3 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:12]2[O:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:16](=[O:17])[C:11]=2[S:10][CH:9]=1)=[O:7].[F:24][C:25]([F:41])([F:40])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>>[O:17]=[C:16]1[CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C:12]2[C:8]([C:6]([NH:5][CH2:4][CH2:3][CH2:2][N:37]3[CH2:36][CH2:35][N:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH2:26][C:25]([F:40])([F:24])[F:41])[CH2:39][CH2:38]3)=[O:7])=[CH:9][S:10][C:11]1=2
Reactant: O=C(NCCCCl)c1csc2c(=O)cc(-c3ccccc3)oc12
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(NCCCN1CCN(c2ccccc2OCC(F)(F)F)CC1)c1csc2c(=O)cc(-c3ccccc3)oc12
Temperature: 200 °C
Yield: 69.1 %

Procedure:
A mixture of 0.17 g of Compound 5A, 0.13 g of 1-[2-(2,2,2-trifluoroethoxy)phenyl]-piperazine (prepared as described by EP 0748 800, G. Bantle et al.) and 0.07 g of potassium carbonate was heated at 200° C. for 20 minutes. After cooling to 20-25° C., the crude residue was purified by flash chromatography in ethyl acetate/methanol gradient (95:5 to 9:1) to yield 0.193 g (70%) of the title compound. M.p. 152-158° C.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:7]2[C:8]([NH:10][CH:11]=[N:12][C:6]=2[S:5][C:4]=1[CH3:13])=O.S(Cl)([Cl:16])=O>CN(C=O)C>[Cl:16][C:8]1[C:7]2[C:3]([CH2:2][CH3:1])=[C:4]([CH3:13])[S:5][C:6]=2[N:12]=[CH:11][N:10]=1
Reactant: O=S(Cl)Cl
Reactant: CCc1c(C)sc2nc[nH]c(=O)c12
Solvent: CN(C)C=O
Product: CCc1c(C)sc2ncnc(Cl)c12
Reaction time: 0.17 h
Yield: 73 %

Procedure:
A mixture of 5-ethyl-6-methyl-3-hydrothiopheno[2,3-d]pyrimidin-4-one (0.5 g), thionyl chloride (5 mL) and catalytic amount of DMF (0.2 mL) was refluxed for 1 h. Solvents were removed under vacuum and the mixture was diluted with ice cold water and stirred for 10 min. The solution was extracted with chloroform (3×100 mL) and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was triturated with hexane to give the product as a dark brown color solid (400 mg, 73%), mp 52-56° C. 1H NMR (400 MHz, CDCl3): δ 8.73 (1H, s), 3.05 (2H, q, J=7.5 Hz), 2.55 (3H, s), 1.24 (3H, t, J=7.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]3[N:11]([C:16]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][C:23]=4[F:28])=[O:20])=[CH:17][N:18]=3)[N:12]=[C:13](Cl)[CH:14]=2)[CH:5]=[C:4]([Cl:29])[CH:3]=1.[C@H:30]1([NH2:37])[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32][CH2:31]1>CN1C(=O)CCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]3[N:11]([C:16]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][C:23]=4[F:28])=[O:20])=[CH:17][N:18]=3)[N:12]=[C:13]([NH:36][C@H:33]3[CH2:34][CH2:35][C@H:30]([NH2:37])[CH2:31][CH2:32]3)[CH:14]=2)[CH:5]=[C:4]([Cl:29])[CH:3]=1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Nc1cc(Cl)cc(Nc2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Solvent: CN1CCCC1=O
Product: Nc1cc(Cl)cc(Nc2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Temperature: 110 °C

Procedure:
A mixture of 8-(6-amino-4-chloropyridin-2-ylamino)-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (42 mg, 0.073 mmol) and trans-cyclohexane-1,4-diamine (74.2 mg, 0.650 mmol) in NMP (0.4 mL) was heated at 110° C. overnight. The reaction mixture was then cooled to room temperature and purified by reversed-phase HPLC. The fractions containing the title compounds were lyophilized to dryness to afford 8-((6-amino-4-chloro-2-pyridinyl)amino)-6-((trans-4-aminocyclohexyl)amino)-N-(3-fluoro-4-pyridinyl)imidazo[1,2-b]pyridazine-3-carboxamide (16.5 mg, 25%). HPLC Rt=2.813 minutes (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+H]=511.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16]C(=O)C)[CH2:13][CH:12]1[CH2:20][C:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[N:23]([C:30](=[O:32])[CH3:31])[CH:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[CH2:13][CH:12]1[CH2:20][C:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[N:23]([C:30](=[O:32])[CH3:31])[CH:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC1CC(Cc2cn(C(C)=O)c3ncccc23)N(C(=O)OCc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)n1cc(CC2CC(O)CN2C(=O)OCc2ccccc2)c2cccnc21
Reaction time: 1.5 h

Procedure:
To a solution containing 70 (2.99 g, 5.88 mmol) in THF (20 ml) at 0° C. was added a solution of TBAF (1M in THF, 11.8 mL, 11.8 mmol) in a dropwise fashion. After 1.5 h, TLC analysis revealed complete consumption of 70 [1:1 hexanes EtOAc, Rf(70)=0.64; Rf(71)=0.3]. The solvent was removed in vacuo and the residue was dissolved in EtOAc and washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 2.11 g of crude 71 which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]1[CH2:12][S:11][C:10]([NH2:21])=[N:9]2.FC(F)(F)C(O)=O.S(=O)(=O)(O)O.[N+:34]([O-])([OH:36])=[O:35].[OH-].[Na+].[ClH:40]>O>[ClH:40].[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:34]([O-:36])=[O:35])=[CH:4][C:3]=1[C@:8]12[CH2:16][O:15][C@H:14]([C:17]([F:18])([F:19])[F:20])[C@H:13]1[CH2:12][S:11][C:10]([NH2:21])=[N:9]2
Reactant: O=[N+]([O-])O
Reactant: NC1=N[C@@]2(c3ccccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc([N+](=O)[O-])ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Temperature: 3.5 °C
Reaction time: 1.5 h
Yield: 80.1 %

Procedure:
To a cooled vessel containing (4aS,5S,7aS)-7a-(2-fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (184.1 g, 574.8 mmol) was added trifluoroacetic acid (0.954 kg) in portions while the temperature was maintained below 20° C. The mixture was cooled to 3.5° C. and sulfuric acid (146 mL, 2.73 mol) was added over 20 min while the temperature was maintained below 5° C. Fuming nitric acid (39.8 mL, 0.948 mol) was added over 30 min, while the temperature was maintained below 10° C. After 1.5 h at 0-10° C., the reaction mixture was slowly quenched by transferring into an aq. solution of NaOH (575 g, 14.4 mol) in water (4.6 L) cooled to 5° C. The resulting suspension was stirred for 1 h at 21° C. The suspension was then filtered and the solid rinsed with cold water (920 mL). The solid was dried under vacuum until constant weight, and then dissolved into ethanol (1.05 L). The solution was heated to 35° C., and conc. HCl (55.6 mL, 0.690 mol) was added while maintaining temperature below 40° C. The suspension was then cooled to −5° C., held for 1 hr and filtered. The solid was rinsed with cold ethanol (420 mL) and dried until constant weight to obtain the title compound (185.0 g, 87.3%). 1H NMR (500 MHz, DMSO) δ ppm 11.80 (s, 2H), 8.45-8.36 (m, 1H), 8.31 (dd, J=6.6, 2.5 Hz, 1H), 7.66 (dd, J=11.1, 9.3Hz, 1H), 4.96-4.72 (m, 1H), 4.58 (d, J=10.0 Hz, 1H), 4.27 (d, J=9.9 Hz, 1H), 3.76-3.66 (m, 1H), 3.39 (dd, J=14.9, 3.6 Hz, 1H), 3.24 (dd, J=14.3, 4.6 Hz, 1H); 13C NMR (125 MHz, DMSO) δ ppm 168.34, 163.33 (d, JCF=257.8 Hz), 144.58, 127.61 (d, JCF=11.6 Hz), 125.84, 124.10, 119.28 (d, JCF=26.5 Hz), 77.38 (q, JCF=31.5 Hz), 75.99, 65.88 (d, JCF=4.8 Hz), 40.36, 23.98.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[S:30][C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][C:27]=4[N+:36]([O-])=O)=[CH:21][CH:20]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+]>C(O)C.O1CCCC1.O.C(OCC)(=O)C.[Fe]>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[S:30][C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][C:27]=4[NH2:36])=[CH:21][CH:20]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(N)c(Sc2ccc(NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)s1
Yield: 80.5 %

Procedure:
A solution of the product of Example 430C (0.918 g, 1.679 mmol) in ethanol (14 mL) and tetrahydrofuran (14 mL) was treated with iron powder (0.577 g, 10.33 mmol) and a solution of ammonium chloride (0.588 g, 10.99 mmol) in water (7 mL), then refluxed for one hour. The reaction was cooled, diluted with ethyl acetate (100 mL), and washed with water (3×25 mL) and brine (25 mL). The organic extract was dried over sodium sulfate, filtered, and concentrated by rotary evaporation to afford the title compound as a yellow solid (0.698 g, 1.351 mmol, 80%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.27 (t, J=6.99 Hz, 3 H) 4.19-4.36 (m, 3 H) 4.48 (d, J=6.62 Hz, 2 H) 5.56 (s, 2 H) 7.10 (d, J=8.09 Hz, 2 H) 7.28-7.55 (m, 7 H) 7.74 (d, J=7.35 Hz, 2 H) 7.90 (d, J=7.35 Hz, 2 H) 9.73 (s, 1 H); MS (ESI+) m/z 517 (M+H)+, 539 (M+Na)+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([NH:23][C:24](=[O:34])[CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:20][C@H:19]1[CH2:35][OH:36])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([NH:23][C:24](=[O:34])[CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:20][C@H:19]1[CH:35]=[O:36])=[O:17])([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C=O)N(C(=O)OC(C)(C)C)C1
Reaction time: 0.25 h
Yield: 97.9 %

Procedure:
The following reaction was carried under argon. Dimethyl sulfoxide (288 μL) was added to a stirred solution of oxalyl chloride (177 mL) in dichloromethane (3 mL) at −78° C. After stirring at the same temperature for 15 min, a solution of (2S,4R)-N-tert-butoxycarbonyl-4-(N-tert-butoxycarbonylglycylamino)-2-hydroxymethylpyrrolidine (151 mg) in dichloromethane (3 mL) was added. The mixture was stirred at −78° C. for 2 hr, and triethylamine (848 μL) was added to the reaction mixture. The mixture was stirred at 0° C. for 1 hr, quenched with saturated ammonium chloride, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform then chloroform:methanol=99:1 to 97:3, v/v) to give the titled compound (147 mg) as a colorless foam.
Reaction SMILES: C(O[CH2:9][CH2:10][C:11]1([CH2:16][CH:17]2[CH:26]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:25]3[C:20](=[C:21]([F:38])[CH:22]=[CH:23][C:24]=3[F:37])[O:19][CH2:18]2)[O:15][CH2:14][CH2:13][O:12]1)C1C=CC=CC=1.[H][H].CCN(CC)CC.O>C(OCC)(=O)C.[OH-].[OH-].[Pd+2].C(Cl)Cl>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([S:27]([C@@:26]23[CH2:9][CH2:10][C:11]4([O:15][CH2:14][CH2:13][O:12]4)[CH2:16][C@H:17]2[CH2:18][O:19][C:20]2[C:21]([F:38])=[CH:22][CH:23]=[C:24]([F:37])[C:25]3=2)(=[O:29])=[O:28])=[CH:31][CH:32]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1c2c(F)ccc(F)c2OCC1CC1(CCOCc2ccccc2)OCCO1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Cl)cc1)[C@@]12CCC3(C[C@H]1COc1c(F)ccc(F)c12)OCCO3
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3-[2-(2-Benzyloxy-ethyl)-[1,3]dioxolan-2-ylmethyl]-4-(4-chloro-benzenesulfonyl)-5,8-difluoro-chroman (6.3 g, 11.2 mmole) was dissolved in 200 ml EtOAc and Pd(OH)2 (0.5 g) was added. Hydrogen was introduced via a balloon. The reaction was stirred at room temperature for 45 minutes. The catalyst was filtered and the filtrate was concentrated. The residue was dissolved in 200 ml DCM and MSCl (1.4 g, 12 mmole) and NEt3 (1.7 g, 17 mmole) were added. The mixture was stirred at room temperature for ten minutes. 200 ml water and 100 ml DCM were added. The organic layer was washed with 1N HCl (100 ml), water (100 ml), brine (100 ml), dried over Na2SO4 and concentrated. The residue was dissolved in 200 ml THF and KOt-Bu (1 M in THF, 14 ml) was added. The mixture was stirred at room temperature for twenty minutes. 200 ml water and 200 ml EtOAc were added. The organic layer was washed with brine (200 ml), dried over Na2SO4 and concentrated. The product was purified by column (EtOAc/hexane from 0/100 to 25/75 in 45 minutes). Yield: 3.1 g, 61%. 1H NMR (CDCl3 400 MHz δ 7.61 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.07 (m, 1H), 6.42 (m, 1H), 5.23 (dd, J=11.7 and 2.9 Hz, 1H), 4.12 (d, J=11.0 Hz, 1H), 3.88-4.01 (m, 4H), 2.97 (dt, J=13.2 and 2.9 Hz, 1H), 2.53 (dt, J=13.1 and 2.9 Hz, 1H), 2.33 (tt, J=13.2 and 2.9 Hz, 1H), 1.62-1.81 (m, 3H), 1.23-1.35 (m, 1H).