Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[CH:11]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=4[Cl:23])[O:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH2:24][OH:25])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[CH:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[O:12][CH2:13][CH2:14][CH2:15][N:7]21
Reactant: OCc1ccc(Cl)c2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Cl)c2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl
Reaction time: 5 h

Procedure:
To a stirred solution of [10-chloro-1-(2,4-dichlorophenyl)-4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-a]benzimidazol-7-yl]methanol (113 mg, 0.284 mmol) in acetonitrile (2.8 mL) was added Dess-Martin reagent (145 mg, 0.341 mmol) at room temperature. After 5 h, the reaction mixture was diluted with ethyl acetate, quenched with aqueous sodium hydrogen carbonate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous (88.1 mg, 0.223 mmol, 78%).
Reaction SMILES: CN(C)CCCOC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][C:38]=3[C:44]([F:47])([F:46])[F:45])=[N:33][CH:32]=2)=[CH:27]1.Cl.Cl[CH2:50][CH2:51][N:52]([CH:56]([CH3:58])[CH3:57])[CH:53]([CH3:55])[CH3:54]>C(Cl)Cl.CO>[CH:53]([N:52]([CH:56]([CH3:58])[CH3:57])[CH2:51][CH2:50][O:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]2[S:35][C:31]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)=[CH:32][N:33]=2)=[C:38]([C:44]([F:47])([F:46])[F:45])[CH:39]=1)([CH3:55])[CH3:54]
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1
Reactant: CC(C)N(CCCl)C(C)C
Agent: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)N(CCOc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1)C(C)C

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-ylamino)-3-trifluoromethyl-phenol (Example 28) and using (2-chloroethyl)-diisopropylamine hydrochloride. The title compound: ES-MS: 469.9 [M+H]+; single peak at tR=3.67 min (System 2); Rf=0.38 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[C:21][C:22]4[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=4)[CH:18]=3)[S:13][C:12]([CH3:34])([CH3:33])[CH:11]=2)=[CH:6][CH:5]=1)(C)[CH3:2].[OH-].[Na+].Cl>C1COCC1.CCO>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=4)[CH:18]=3)[S:13][C:12]([CH3:33])([CH3:34])[CH:11]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(C)C)cc2)=CC(C)(C)S3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1ccc(C2=CC(C)(C)Sc3ccc(CCc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of ethyl 4-[[4-(4-isopropylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoate (Compound 228, 89.0 mg, 0.19 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (80.0 mg, 2.0 mmol, 2.0 mL of a 1M aqueous solution). The resulting solution was heated to 45° C. and stirred overnight. Upon cooling to room temperature the reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 78.0 mg (93%) of the title compound as a pale-yellow solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.00 (2H, d, J=8.4 Hz), 7.58 (2H, d, J=8.4 Hz), 7.45-7.21 (7H, m), 5.93 (1H, s), 2.95 (1H, hept, J=7.0 Hz), 1.47 (6H, s), 1.25 (6H, d, J=7.0 Hz).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=S)[CH3:2].[C:11]([NH:19][NH2:20])(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)CCC>O>[CH3:2][C:1]1[N:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:19][N:20]=1
Reactant: CC(=S)Nc1ccccc1
Reactant: NNC(=O)c1ccccc1
Solvent: CCCCO
Solvent: O
Product: Cc1nnc(-c2ccccc2)n1-c1ccccc1
Yield: 18 %

Procedure:
First, 5.04 g of thioacetanilide, 5.44 g of benzoylhydrazine, and 50 mL of 1-butanol were put into a round-bottom flask provided with a reflux pipe, and the air in the flask was replaced with argon. This reaction container was irradiated with microwaves (2.45 GHz, 100W) for 2 hours and 45 minutes to be heated. Then, water was added to this solution and the organic layer was extracted with dichloromethane. The obtained organic layer was washed with water and dried over magnesium sulfate. The solution which had been dried was filtered. The solvent of this solution was distilled off, and the resulting residue was purified by silica gel column chromatography using ethyl acetate as a developing solvent, so that 3-methyl-4,5-diphenyl-4H-1,2,4-triazole (abbreviation: HMptz) was obtained (a pale yellow powder, 18% yield). A scheme of the synthesis of Step 1 is shown in the following (c-1).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=O)=[C:4]([OH:18])[CH:3]=1.C[O:20][C:21](=O)[CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:22][C:21](=[O:20])[O:18]2)=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C(=O)c2ccc(F)cc2)c(O)cc1Br
Solvent: Cc1ccccc1
Product: Cc1cc2c(-c3ccc(F)cc3)cc(=O)oc2cc1Br
Temperature: 25 °C

Procedure:
(4-Bromo-2-hydroxy-5-methylphenyl)(4-fluorophenyl)methanone (1.61 g, 5.21 mmol) and methyl(triphenylphosphoranylidene)acetate (2.26 g, 6.77 mmol) were heated in refluxing toluene (15 mL) for 24 h. The reaction mixture was allowed to cool to rt and concentrated. The yellow solid obtained was subjected to column chromatography on silica gel (EtOAc-toluene, 0% to 2%) to afford the title compound. 1H NMR (500 MHz, acetone-d6): δ 7.70 (s, 1H), 7.66 (m, 2H), 7.46 (s, 1H), 7.39 (m, 2H), 6.39 (s, 1H), 2.40 (s, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].[CH3:6][S:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11].[OH-].[Na+]>O.O1CCCC1>[CH3:6][S:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:5][CH2:4][C:3]#[N:2])=[O:11]
Reactant: N#CCN
Reactant: CSc1ncccc1C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1ncccc1C(=O)NCC#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a stirred solution of aminoacetonitrile hydrochloride (5.95 g) in a mixture of water (100 ml) and tetrahydrofuran (100 ml) was added slowly 2 -(methylthio)nicotinoyl chloride (10 g) at 0° C. while adjusting pH to 8-9 with 4N-aqueous sodium hydroxide. After stirring for 30 minutes at 0° C., the solvent was evaporated to give a residue, which was chromatographed on silica gel (350 ml) eluting with ethyl acetate to give [2-(methylthio)nicotinoyl]aminoacetonitrile (9.9 g).
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.O[CH2:17][C:18]1[S:19][C:20]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:21]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)[C:22]=1[CH2:23][C:24]([OH:26])=[O:25]>C(Cl)Cl>[CH3:34][S:33][C:30]1[CH:31]=[CH:32][C:27]([C:21]2[C:22]3[CH2:23][C:24](=[O:26])[O:25][CH2:17][C:18]=3[S:19][C:20]=2[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:28][CH:29]=1
Reactant: CSc1ccc(-c2c(-c3ccccc3)sc(CO)c2CC(=O)O)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: CSc1ccc(-c2c(-c3ccccc3)sc3c2CC(=O)OC3)cc1
Reaction time: 8 h

Procedure:
(±)-10-camphorsulfonic acid (5 mg) was added to a solution of [2-hydroxymethyl-4-(4-methylsulfanylphenyl)-5-phenylthiophen-3-yl]acetic acid (100 mg) (Step 3) in CH2Cl2 (5 mL) and the resulting solution was stirred overnight. The solution was diluted with CH2Cl and washed with a saturated solution of NaHCO3, dried over MgSO4, filtered and the solvent was evaporated under vacuum. Purification by silica gel chromatography using 20% of EtOAc in hexane gave the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[I:11]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:11][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[S:6][C:2]=1[CH3:1]
Reactant: II
Reactant: COC(=O)c1ccc(C)s1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)c1cc(I)c(C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-methylthiophene-2-carboxylate (287 mg, 1.837 mmol) in MeOH (7 mL), was added silver sulfate (687 mg, 2.205 mmol) and I2 (513 mg, 2.021 mmol). The mixture was stirred at room temperature under N2 overnight. The reaction was quenched with sat. Na2SO3. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine (1×), dried (Na2SO4) and concentrated in vacuo. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 10% EtOAc in hexanes over 1140 mL) to afford in order of elution methyl 4-iodo-5-methylthiophene-2-carboxylate. LCMS calc.=207.1. found=206.9 (M+Na)+. 1H NMR (500 MHz, CDCl3): δ 767 (s, 1H); 3.87 (s, 3H); 2.46 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)=O.Cl.[CH3:21][NH:22][C:23](=[S:26])[NH:24][NH2:25]>C(O)C>[ClH:1].[C:16]([C:7]1[CH:6]=[C:5]([C:3]2[CH2:2][S:26][C:23]([NH:22][CH3:21])=[N:24][N:25]=2)[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]=1[OH:15])([CH3:19])([CH3:18])[CH3:17]
Reactant: CNC(=S)NN
Reactant: CC(C)(C)c1cc(C(=O)CCl)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCO
Product: CNC1=NN=C(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CS1
Reaction time: 0.5 h

Procedure:
10.7 g (0.038 mol) of 2-chloro-1-(3,5-di-tert.butyl-4-hydroxyphenyl)-ethanone from step (a) and 4.8 g (0.034 mol) of 4-methylthiosemicarbazide hydrochloride were dissolved in 120 ml of ethanol, and the mixture was heated to boiling for 30 minutes. After cooling, the solvent was removed by distillation under reduced pressure, and the resinous residue was dissolved in 60 ml of warm ethyl acetate. On standing, the product immediately precipitated in crystalline form, and was filtered off and recrystallized again from 150 ml of a mixture of ethyl acetate and methylene chloride (10 : 1).
Reaction SMILES: [C:1]1([CH:7]2[O:24][C:11]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].FC(F)(F)S(O[CH2:36][C:37]([F:40])([F:39])[F:38])(=O)=O>C(O)C>[C:1]1([CH:7]2[O:24][C:11]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][CH2:12]3)[CH2:10][N:9]([CH2:36][C:37]([F:40])([F:39])[F:38])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(c1ccccc1)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)(F)F)CC(c1ccccc1)O2
Temperature: 80 °C
Yield: 94.7 %

Procedure:
To tert-butyl 10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (0.98 g, 2.93 mmol) and NaHCO3 (0.99 g, 11.73 mmol) in ethanol at room temperature was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.82 g, 545 μL, 3.52 mmol) and the reaction mixture was heated at 80° C. for 6 hours. The reaction mixture was cooled, the solid precipitate was removed by filtration and the solvent was removed in vacuo. The residue was taken up in DCM and washed sequentially with 1:1 NaOH(1N):NaHCO3 and then brine. The organics were separated, dried over sodium sulfate and concentrated in vacuo to give tert-butyl 10-phenyl-8-(2,2,2-trifluoroethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (1.15 g, 95%). ESI-MS m/z calc. 414.2. found 415.3 (M+1)+; Retention time: 2.46 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.44-7.26 (m, 5H), 4.81 (dd, J=10.5, 2.6 Hz, 1H), 3.73 (s, 2H), 3.31 (s, 1H), 3.09 (s, 1H), 2.98 (m, 3H), 2.74 (dd, J=11.0, 1.5 Hz, 1H), 2.51 (d, J=14.1 Hz, 1H), 2.40-2.29 (m, 2H), 1.58 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[C@@H:14]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:15][O:16][CH2:17][C:12]3=[N:11][C:4]=1[CH:5]=[N:6]2.C1C=C(Cl)C=C(C(OO)=[O:30])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[O-:30][N+:6]1[C:7]2[C:2](=[CH:1][CH:10]=[CH:9][CH:8]=2)[C:3]2[N:13]3[C@@H:14]([C:18]([OH:21])([CH3:19])[CH3:20])[CH2:15][O:16][CH2:17][C:12]3=[N:11][C:4]=2[CH:5]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(O)[C@H]1COCc2nc3cnc4ccccc4c3n21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(O)[C@H]1COCc2nc3c[n+]([O-])c4ccccc4c3n21
Reaction time: 1.25 h
Yield: 99.9 %

Procedure:
2-[(11R)-10,11-Dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propan-2-ol (755 mg, 2.67 mmol) was dissolved in 30 mL of CH2Cl2 and treated with MCPBA (57-86%, 806 mg). After stirring for 75 minutes, the reaction was treated with 50 mL of 2% Na2CO3 solution and the layers were separated. The aqueous layer was then extracted with 10% methanol/CHCl3 (10×10 mL). The combined organic layers were washed with 10 mL of brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced to give 2-[(11R)-5-oxido-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propan-2-ol (798 mg) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[N:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.O1CCOCC1.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>O>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][CH:10]=[N:11]2)=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(-n2ncnc2-c2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(-n2ncnc2-c2ccc(F)cc2)cc1
Temperature: 90 °C

Procedure:
A 5.0 g. portion of 5-(p-fluorophenyl)-1-(p-nitrophenyl)-1H-1,2,4-triazole in 42 ml. of dioxane is added to 9.9 g. of sodium sulfide nonahydrate in 42 ml. of water and the mixture is stirred and heated at reflux (90° C.) for 1.5 hours. The solution is cooled and poured into 300 ml. of ice and water with stirring. The solid is collected by filtration, dried, recrystallized from 30 ml. of acetonitrile, washed with ether and dried giving 2.6 g. of the desired product as tan crystals, mp. 147°-150° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:18]1CCOCC1.ClC(OCC(C)C)=O>O1CCCC1>[C:14]([C@@H:9]1[CH2:10][C:11](=[CH2:13])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:16])[NH2:18]
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: C=C1C[C@@H](C(N)=O)N(C(=O)OC(C)(C)C)C1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
(S)-1-(tert-Butoxycarbonyl)-4-methylenepyrrolidine-2-carboxylic acid (1.05 g, 4.48 mmol) and N-methylmorpholine (0.64 mL, 5.83 mmol) were dissolved in tetrahydrofuran (25 mL) and cooled to −15° C. in a dry ice/acetone bath. Isobutyl chloroformate (0.65 mL, 4.93 mmol) was added dropwise and the solution was stirred for 15 minutes. The internal temperature was lowered to −25° C. and ammonia (g) was bubbled through the solution for 2 minutes, then the flask was transferred to an ice bath and stirred for another 20 minutes. The solution was poured into brine and extracted into ethyl acetate, dried over magnesium sulfate, filtered and concentrated. This residue was triturated with ether/hexanes, filtered, and dried to give 0.97 g (81%) of (S)-tert-butyl 2-carbamoyl-4-methylenepyrrolidine-1-carboxylate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](O)=O)=[N:4][C:5]([Cl:11])=[C:6]([Cl:10])[C:7]=1[NH:8][NH2:9].ClC1[N:21]=C(C#N)C(Cl)=C(Cl)C=1Cl.NN.Cl>>[Cl:1][C:2]1[C:3]([C:12]#[N:21])=[N:4][C:5]([Cl:11])=[C:6]([Cl:10])[C:7]=1[NH:8][NH2:9]
Reactant: NNc1c(Cl)c(Cl)nc(C(=O)O)c1Cl
Reactant: N#Cc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: Cl
Agent: NN
Product: N#Cc1nc(Cl)c(Cl)c(NN)c1Cl

Procedure:
The 3,5,6-trichloro-4-hydrazinopicolinic acid can be prepared in a variety of ways. In one such method, tetrachloropicolinonitrile is reacted with hydrazine in the presence of a reaction medium and hydrogen chloride acceptor. The 3,5,6-trichloro-4-hydrazinopicolinonitrile product thus formed is reacted with an acid hydrolysis agent to prepare 3,5,6-trichloro-4-hydrazinopicolinic acid.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[NH2:24])(=[O:3])[CH3:2].[CH3:25][C:26]([CH:28]1[C:34](=[O:35])[CH2:33][C:32]([CH3:37])([CH3:36])[CH2:31][C:29]1=[O:30])=O>CO>[C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[NH:24][C:26](=[C:28]1[C:34](=[O:35])[CH2:33][C:32]([CH3:37])([CH3:36])[CH2:31][C:29]1=[O:30])[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)C1C(=O)CC(C)(C)CC1=O
Reactant: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1N
Solvent: CO
Product: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1NC(C)=C1C(=O)CC(C)(C)CC1=O
Yield: 59.6 %

Procedure:
A mixture of 2-Acetamido-2-deoxy-3,4,6-tri-O-acetyl-β-D-glucopyranosyl amine (80 mg, 0.23 mmol) and 2-acetyldimedone (55 mg, 0.30 mmol) in MeOH (5 ml) was refluxed for 5 h. The reaction mixture was evaporated, the residue was purified by chromatography using CHCl3/MeOH 10:0.5 as the mobile phase, to give 2-Acetamido-3,4,6-tri-O-acetyl-1,2-dideoxy-1-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-β-D-glucopyranose (19) (70 mg, 60%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:38]=[CH:39][CH:40]=1)[CH2:8][NH:9][C@@H:10]1[C@@H:15]([OH:16])[C@H:14]([CH2:17][C:18]2[CH:23]=[C:22]([O:24][C@H:25]([CH2:30][O:31][CH3:32])[C:26]([F:29])([F:28])[F:27])[C:21]([N+:33]([O-])=O)=[C:20]([F:36])[CH:19]=2)[CH2:13][S@@:12](=[O:37])[CH2:11]1)([CH3:4])([CH3:3])[CH3:2]>CCO.[Ni]>[NH2:33][C:21]1[C:22]([O:24][C@H:25]([CH2:30][O:31][CH3:32])[C:26]([F:29])([F:27])[F:28])=[CH:23][C:18]([CH2:17][C@H:14]2[C@H:15]([OH:16])[C@@H:10]([NH:9][CH2:8][C:7]3[CH:38]=[CH:39][CH:40]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=3)[CH2:11][S@:12](=[O:37])[CH2:13]2)=[CH:19][C:20]=1[F:36]
Reactant: COC[C@@H](Oc1cc(C[C@@H]2C[S@@](=O)C[C@H](NCc3cccc(C(C)(C)C)c3)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F
Agent: [Ni]
Solvent: CCO
Product: COC[C@@H](Oc1cc(C[C@@H]2C[S@@](=O)C[C@H](NCc3cccc(C(C)(C)C)c3)[C@H]2O)cc(F)c1N)C(F)(F)F

Procedure:
A solution of (1R,3R,4S,5S)-3-(3-tert-butyl-benzylamino)-5-[3-fluoro-4-nitro-5-((R)-2,2,2-tri-fluoro-1-methoxymethyl-ethoxy)-benzyl]-1-oxo-tetrahydro-thiopyran-4-ol (1.34 g, 2.27 mmol) in EtOH (27 mL) was hydrogenated at 1 bar over Ra—Ni at 40° C. for 7 h. Filtration over Celite and charcoal afforded the title compound after evaporation as an amorphous solid: TLC (toluene-ETA 95:5) Rf=0.28; HPLC RtH1=0.86 min; ESIMS [M+H]+=561; 1H NMR (600 MHz, CDCl3): δ 7.34 (s, 1H), 7.24 (m, 2H), 7.12 (m, 1H), 6.72 (s, 1H), 6.63 (d, 1H), 5.08 (s, 1H), 5.00 (s, 1H), 4.57 (s, 2H), 3.80-3.67 (m, 3H), 3.57 (m, 1H), 3.30 (s, 3H), 3.18-3.05 (m, 3H), 2.98 (m, 1H), 2.70 (m, 1H), 2.49-2.23 (m, 5H), 1.25 (s, 9H).
Reaction SMILES: C([O:3][C:4](=[O:51])[CH:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:29][S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:32])=[O:31])[C:16](=[O:28])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:10][C:9]=1[N:39]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[CH3:40])[F:6])C.[OH-].[K+]>CCO>[C:33]1([S:30]([NH:29][C@H:15]([C:16](=[O:28])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:14][C:11]2[CH:12]=[CH:13][C:8]([O:7][CH:5]([F:6])[C:4]([OH:51])=[O:3])=[C:9]([N:39]([C:41]([O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[O:42])[CH3:40])[CH:10]=2)(=[O:32])=[O:31])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCOC(=O)C(F)Oc1ccc(C[C@H](NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)cc1N(C)C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN(C(=O)OCc1ccccc1)c1cc(C[C@H](NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)ccc1OC(F)C(=O)O
Reaction time: 8 h

Procedure:
[4-[(2S)-2-Benzenesulfonylamino-2-(4-phenyl-butylcarbamoyl)-ethyl]-2-(benzyloxycarbonyl-methyl-amino)-phenoxy]-fluoro-acetic acid ethyl ester of Step C is dissolved in EtOH (2 mL) and 1N KOH (0.32 mL) is added. The mixture is stirred overnight. The solution is concentrated, and suspended in ETOAC and loaded on silica gel plug. The plug is washed with ETOAC (100 mL) to remove the impurities. The product is eluted from the plug by using 2% HOAC in ETOAC. The filtrate is concentrated to provide [4-[(2S)-2-benzenesulfonylamino-2-(4-phenyl-butylcarbamoyl)-ethyl]-2-(benzyloxycarbonyl-methyl-amino)-phenoxy]-fluoro-acetic acid.
Reaction SMILES: [I-:1].[CH3:2][N:3]([CH3:29])[C:4]1[CH:13]=[CH:12][C:11]2[N+:10]3[CH:14]=[C:15]4[CH:24]=[CH:23][C:22]5[CH:21]=[C:20]([C:25](C)(C)[CH3:26])[CH:19]=[CH:18][C:17]=5[N:16]4[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:5]=1>CO.CCOCC>[I-:1].[CH3:2][N:3]([CH3:29])[C:4]1[CH:13]=[CH:12][C:11]2[N+:10]3[CH:14]=[C:15]4[CH:24]=[CH:23][C:22]5[CH:21]=[C:20]([CH2:25][CH3:26])[CH:19]=[CH:18][C:17]=5[N:16]4[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:5]=1
Reactant: CN(C)c1ccc2c(ccc3n4c(ccc5cc(C(C)(C)C)ccc54)c[n+]23)c1
Agent: [I-]
Solvent: CO
Solvent: CCOCC
Product: CCc1ccc2c(ccc3c[n+]4c5ccc(N(C)C)cc5ccc4n32)c1

Procedure:
3-Dimethylamino-10-(1,1-dimethylethyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium Iodide; m.p. 360° C., from methanol/ether.