Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([OH:14])[C:10]([CH3:23])([CH3:22])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][C:10]2([CH3:22])[CH3:23])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(C)(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCCC1(O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a cooled (0° C.) solution of 4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidine-1-carboxylic acid tert-butyl ester (10.42 g, 30.7 mmol) in methylene chloride (300 mL) was slowly added trifluoroacetic acid (60 mL) over 1.25 hours. The resulting yellow solution was stirred at 0° C. for an additional 1.5 hours. The mixture was concentrated under reduced pressure and the residue dissolved in ethyl acetate (1.2 L), and washed with aqueous sodium hydroxide (1 N, 150 mL). The aqueous layer was extracted with additional ethyl acetate (200 mL) and the combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting solid residue was triturated with ether to afford 4-(4-Chloro-phenyl)-3,3-dimethyl-piperidin-4-ol as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:26](=[O:27])[CH2:25][C:24](=[O:28])[NH:23][C:22]3[C:29]4[C:34]([CH:35]=[CH:36][C:21]2=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:16][CH:15]=1.ClC1C=C(Cl)C=CC=1CC(Cl)=O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:26](=[O:27])[CH2:25][C:24](=[O:28])[NH:23][C:22]3[C:29]4[C:34]([CH:35]=[CH:36][C:21]2=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:16][CH:15]=1)=[O:12]
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C(Cl)Cc1ccc(Cl)cc1Cl
Product: O=C(Cc1ccc(Cl)cc1Cl)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 33.9 %

Procedure:
2,4-Dichlorophenylacetic acid (65 mg, 0.317 mmol) was made into acid chloride in a conventional manner. By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50 mg, 0.158 mmol) obtained in Example 1, (3), and 2,4-dichlorophenylacetic acid chloride mentioned above, the title compound (27 mg, yield 34%) was obtained in the same manner as that of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=3)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]([NH:25][C:26](=NC(=O)OC)SC)=[O:24].C(O)(=O)C>ClC(Cl)Cl>[CH3:21][O:22][C:23](=[O:24])[NH:25][C:26]1[NH:19][C:16]2[CH:17]=[CH:18][C:13]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[O:9][CH2:10][CH2:11][O:12]3)=[CH:14][C:15]=2[N:20]=1
Reactant: Nc1ccc(C2(c3ccc(F)cc3)OCCO2)cc1N
Reactant: COC(=O)N=C(NC(=O)OC)SC
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cc(C3(c4ccc(F)cc4)OCCO3)ccc2[nH]1
Yield: 42 %

Procedure:
A mixture of 5.5 parts of 4-[2-(4-fluorophenyl)-1,3-dioxolan2-yl]-1,2-benzenediamine, 6.2 parts of methyl [(methoxycarbonylamino)(methylthio)methylene]carbamate, 4.8 parts of acetic acid and 225 parts of trichloromethane is stirred and refluxed for 17 hours. The reaction mixture is evaporated in vacuo. The residue is triturated in methanol. The product is filtered off, washed with 2,2' -oxybispropane and dried, yielding 3 parts (42%) of methyl{ 5-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-1H-benzimidazol-2-yl}carbamate; mp. 227.7° C.
Reaction SMILES: [C:1]([C:3](=[N:9]O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]>C(O)C.O=[Pt]=O>[NH2:9][CH:3]([C:1]#[N:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C#N)=NO
Agent: O=[Pt]=O
Solvent: CCO
Product: CCOC(=O)C(N)C#N
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of ethyl 2-cyano-2-(hydroxyimino)acetate (1 eq) in ethanol (1.4 M) was added PtO2 (0.05 eq) and the solution was put under an H2 atmosphere (4 bar) in a steel bomb and was stirred overnight. The reaction was filtered through a pad of celite, rinsing with CH2Cl2 and upon removal of volatiles in vacuo ethyl 2-amino-2-cyanoacetate was obtained in 89% yield. LC/MS (m/z): 129.0 (MH+), Rt: 0.25 min.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[CH:11][N:12]2[C:17]=1[C:16](=[O:18])[N:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([CH:26]=[O:27])=[N:13]2)=[O:8]>C(Cl)Cl>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[CH:11][N:12]2[C:17]=1[C:16](=[O:18])[N:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([CH:26]([OH:27])[CH2:1][CH3:2])=[N:13]2)=[O:8]
Reactant: COC(=O)c1ccn2nc(C=O)n(Cc3ccccc3)c(=O)c12
Reactant: CC[Mg]Br
Solvent: ClCCl
Product: CCC(O)c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
Ethyl magnesium bromide (1 M, 0.77 ml, 0.77 mmol) was added dropwise to a −78° C. solution of 3-benzyl-2-formyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid methyl ester (0.12 g, 0.39 mmol) in CH2Cl2 (6.0 mL) over 45 min. The reaction mixture was stirred at −78° for 30 min, quenched with saturated NH4Cl (10 mL) and warmed to room temperature. The reaction mixture was extracted with CHCl3 (3×25 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 1/1 hexane/EtOAc to afford the title compound (0.070 g, 50%) as a solid: MS (ESI+) 342 (M++H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([F:16])[C:7]=1[CH:8]=[O:9]>S(=O)(=O)(O)O>[F:5][C:6]1[C:13]([N+:1]([O-:4])=[O:2])=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([F:16])[C:7]=1[CH:8]=[O:9]
Reactant: COc1cc(F)c(C=O)c(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1cc(F)c(C=O)c(F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of cold (−5° C.) nitric acid (2.7 mL) was added concentrated sulfuric acid (1.75 mL, 32 mmoL) dropwise keeping the temperature below 5° C. The solution was added to a cooled solution of 2,6-difluoro-4-methoxy benzaldehyde (5.0 g, 29 mmoL) in sulfuric acid (20 mL) over 15 minutes keeping the temperature below 5° C. After stirring at 0° C. for 2 hours the orange solution was poured on to ice, the white precipitate which formed was collected by filtration to give the title compound as a white solid (6.33 g, 100%). 1H NMR (CDCl3) 10.20 (1 H, t, J=1.17 Hz), 6.69 (1 H, dd, J=11.68, 1.93 Hz), 4.03 (3 H, s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14](O)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:45][C:44]3[CH:46]=[CH:47][C:41]([Cl:40])=[CH:42][CH:43]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4ccc(Cl)cc4)C3)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (150 mg, 0.439 mmol), EDC (118 mg, 0.615 mmol), and HOBT (83 mg, 0.615 mmol) in DMF (3 mL) was added 4-chloroaniline (56 mg, 0.44 mmol), and the reaction mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound as a yellow solid. LC-MS (ES) m/z=451 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][CH2:30][CH2:31][NH2:32].C(N(CC)CC)C.CC(O)=O>CS(C)=O>[NH2:1][C:2]1[C:11]([Cl:12])=[C:10]([NH:32][CH2:31][CH2:30][NH:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: NCCNc1ccccn1
Reactant: COc1c(F)c(Cl)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1c(NCCNc2ccccn2)c(Cl)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 0 °C
Yield: 73.2 %

Procedure:
A solution of 5-amino-6-chloro-1-cyclopropyl-7-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (180 mg, 0.551 mmol), N-2-pyridyl-1,2-ethanediamine (113 mg, 0.827 mmol) and triethylamine (0.115 mL, 0.827 mmol) in DMSO (5 mL) was stirred at 100° C. for 8 h. After the reaction mixture was poured into ice-water, AcOH was added to pH<3 and the resulting precipitate was collected by filtration in vacuo, washed successibly with water and hot EtOH, dried to yield 5-amino-6-chloro-1-cyclopropyl-1,4-dihydro-8-methoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (179 mg, 73%) as a pale yellow solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:10]([OH:14])[CH2:11][CH2:12][CH3:13]>F[B-](F)(F)F.C[N+](C)(C)C>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[O:14][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCCC1
Reactant: CCCCO
Agent: C[N+](C)(C)C
Agent: F[B-](F)(F)F
Product: CCCCOC1CCCCN1C(C)=O
Yield: 57.1 %

Procedure:
In the same manner as indicated in Example 6 there are electrolyzed 8.5 g of N-acetylpiperidine and 49.7 g of n-butanol in the presence of 0.3 g of tetramethylammonium tetrafluoroborate as conducting salt. After throughput of 2.5 Faraday per mol of N-acetylpiperidine the current is switched off. The calculated mean cell voltage is 91 volts. Work-up of the electrolysis solution gives 7.6 g of 1-acetyl-2-n-butoxypiperidine (boiling point 70° C./0.1 mbar; nD25 =1.4656), which corresponds to a product yield of 56.8% and a current efficiency of 45.5%.
Reaction SMILES: [Li].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1.CC(C1C=CC(OC)=CC=1)=O.C(OC(=O)C(OCC)=O)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Cl.[CH3:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([NH:60][NH2:61])=[CH:56][CH:55]=1>C(O)C>[CH3:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([N:60]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:61]2)=[CH:56][CH:55]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(OC)cc1
Reactant: COc1ccc(NN)cc1
Agent: COc1ccc(C(C)=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)n(-c2ccc(OC)cc2)n1
Reaction time: 24 h
Yield: 91 %

Procedure:
Ethyl 4-(4-methoxyphenyl)-2,4-dioxobutanoate lithium salt (60.0 g, 0.23 M) synthesized from 4-methoxyacetophenone and diethyloxalate employing lithium hexamethyldisilazide as base, and 4-methoxyphenylhydrazine hydrochloride (44 g, 0.25 M) were combined in ethanol (2 1) and stirred atRT for 24 hr, concentrated in vacuo and crystallized to afford ethyl 1,5-bis (4-methoxyphenyl)pyrazole-3-carboxylate as a white solid, 75 g, 91% yield; mp=97°-98° C.; MS, (m/e) 352 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].I[CH:15]([CH3:17])[CH3:16].C(OCC)C>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:15]([CH3:17])[CH3:16])=[C:4]([Cl:11])[N:3]=1
Reactant: CC(C)I
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reaction time: 1 h

Procedure:
The 2,6-dichloropurine (5.00 g, 26.46 mmol) was suspended in 55 ml of dry DMF at room temperature and treated with sodium hydride, 60% dispersion (1.27 g, 31.75 mmol) added in portions. After stirring for 1 hr, 2-iodopropane (4.5 ml, 44.98 mmol) was added and the reaction stirred for 2 days. The reaction was poured into diethyl ether and washed once with saturated sodium bicarbonate solution and once with water. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The concentrate was chromatographed over silica gel eluting with 10% acetone in dichloromethane solution to give the desired N-9 alkylation product as a white solid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:25]=[CH:24][C:18]2[NH:19][C:20]([CH2:22]Cl)=[N:21][C:17]=2[CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]([F:36])([F:35])[C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:25]=[CH:24][C:18]2[NH:19][C:20]([CH2:22][O:34][C:31]3[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:35])[F:36])=[CH:33][CH:32]=3)=[N:21][C:17]=2[CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc2[nH]c(CCl)nc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Yield: 30.6 %

Procedure:
A mixture of N-tert-butyl-2-(2-chloromethyl-1H-benzoimidazol-5-yl)benzenesulfonamide (100 mg, 0.26 mmol), α,α,α-trifluoro-p-cresol (43.0 mg, 0.26 mmol), Na2CO3 (28.1 mg, 0.26 mmol), Cs2CO3 (86.5 mg, 0.26 mmol), and catalytic KI (1.5 mg, 0.009 mmol) in acetone (2 mL) was refluxed for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography (silica, EtOAc: hexanes, 1:1) to afford the title compound as an off-white solid (40.1 mg, 30% yield). Calcd. For C25H24F3N3O3S: 504.54 (M+H), Found 504.2.
Reaction SMILES: C[C:2]1[CH:10]=[C:9]([NH:11][C:12](=[O:36])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[N:23]=[C:22]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:21]=3)=[CH:16][CH:15]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[CH:27]([O:26][C:24]1[N:23]=[C:22]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[N:21]=[C:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:12]([NH:11][C:9]3[CH:8]=[CH:7][C:3]([C:4]([N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)=[O:6])=[CH:2][CH:10]=3)=[O:36])=[CH:19][CH:18]=2)[N:25]=1)([CH3:28])[CH3:29]
Reactant: CN1CCNCC1
Reactant: Cc1cc(NC(=O)Nc2ccc(-c3nc(OC(C)C)nc(N4CCOCC4)n3)cc2)ccc1C(=O)O
Product: CC(C)Oc1nc(-c2ccc(NC(=O)Nc3ccc(C(=O)N4CCN(C)CC4)cc3)cc2)nc(N2CCOCC2)n1
Yield: 44 %

Procedure:
Starting from methyl 4-({[4-(4-isopropoxy-6-morpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoic acid (160 mg, 0.33 mmol) and 4-methylpiperazine following the procedure as outlined in Experimental 71, 80 mg (44% Yield) of the titled compound was isolated as white solid. MS (ESI) m/z 281.2.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[N:13]=[C:12]([O:14][CH2:15][CH3:16])[S:11][N:10]=1.[CH2:17]([O:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24])[CH3:18]>O1CCCC1>[CH3:18][CH2:17][O:19][CH2:20][CH2:21][NH:22][C:23]([N:10]1[C:9](=[O:8])[N:13]=[C:12]([O:14][CH2:15][CH3:16])[S:11]1)=[O:24]
Reactant: CCOCCN=C=O
Reactant: CCOc1nc(O)ns1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOCCNC(=O)n1sc(OCC)nc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
1 ml of triethylamine was added to a solution of 14.6 g of 3-hydroxy-5-ethoxy-1,2,4-thiadiazole in 140 ml of tetrahydrofuran and then 23 g of ethoxyethyl isocyanate were added dropwise. The mixture was stirred for 2 hours at 25° C and was concentrated to dryness. The residue was chromatographed over silica gel and elution with a 4-6 benzene-ethyl acetate mixture yielded 14 g of 2-(N-β-ethoxyethylcarbamoyl)-5-ethoxy-1,2,4-thiadiazole-3-one melting at <50° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.C(N(CC)CC)C.Br[CH2:37][C:38]([NH2:40])=[O:39]>C(#N)C>[CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][N:19]1[CH2:37][C:38](=[O:39])[NH2:40])=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: CCCCCC1CNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)C1
Reactant: NC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCC1CC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)N(CC(N)=O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide (200 mg, 0.48 mmol, 1 equiv), in anhydrous acetonitrile (3 mL), at room temperature, under nitrogen atmosphere, was added triethylamine (0.2 mL, 1.44 mmol, 3 equiv) followed by bromoacetamide (80 mg, 0.58 mmol, 1.2 equiv). The resulting mixture was stirred at room temperature for 18 h, and evaporated to dryness. The residue obtained was first purified over silica gel, with an eluant of 7% methanolic-ammonia/dichloromethane. The desired fractions were collected, evaporated to dryness, and repurified by HPLC (to remove, the side-product from the reaction of the base with bromoacetamide). After lyophilization the desired title compound for example 40 was obtained (2.0 mg) as a white fluffy powder: HPLC: Rt=4.11 min (220.0 nm); 1H NMR (300 MHz, CD3OD) δ (rotamers) 5.46 (d, J=5.5, 1), 4.47 (dd, J=3.02, 2.7, 1.1), 4.31-4.25 (m, 3.3), 4.11 (d, J=3.02, 1.6), 2.31 (s, 3), 1.65-1.52 (m, 9.5), 1.12-1.09 (m, 10.3). MS (ESPOS): 476.5 [M+H]+, (ESNEG): 474.5[M−H]−.
Reaction SMILES: [OH-].[Na+:2].[O:3]=[C:4]([OH:16])[C@@H:5]([C@H:7]([C@@H:9]([C@@H:11]([C:13]([O-:15])=[O:14])[OH:12])[OH:10])[OH:8])[OH:6].[K+:17]>O>[O:3]=[C:4]([O-:16])[C@@H:5]([C@H:7]([C@@H:9]([C@@H:11]([C:13]([O-:15])=[O:14])[OH:12])[OH:10])[OH:8])[OH:6].[K+:17].[Na+:2]
Reactant: O=C([O-])[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)[O-]
Reaction time: 48 h

Procedure:
Aqueous sodium hydroxide solution (21 mL, 2 M) was added to a slurry of monopotassium D-glucarate (10.0 g, 40.3 mmol) in water (50 mL) until all of the solid dissolved and a constant pH of 10 was reached. The volume of the solution was reduced to 20 mL by rotary evaporator. Methanol (15 mL) was added, producing a cloudy solution which cleared upon heating. The solution was allowed to sit undisturbed at 5° C. Crystals grew from the solution over a 48 h period. The crystals were isolated by filtration, washed with cold 1:1 methanol/water (3×5 mL), and dried under reduced pressure to give sodium potassium D-glucarate as colorless crystals (10.2 g, 33.2 mmol as the dihydrate, 82.4%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][OH:44])=[CH:38][C:37]=1[F:45].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:27]=[CH:28][C:29]([O:44][CH2:43][CH2:42][C:39]3[CH:40]=[CH:41][C:36]([Cl:35])=[C:37]([F:45])[CH:38]=3)=[CH:30][CH:31]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCc1ccc(Cl)c(F)c1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C)CC2)c1-c1ccc(OCCc2ccc(Cl)c(F)c2)cc1
Reaction time: 18 h
Yield: 25.6 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (20 mg, 0.043 mmol), 2-(4-chloro-3-fluorophenyl)ethanol (37.3 mg, 0.213 mmol) and Ph3P-resin (55.8 mg, 0.213 mmol) in THF (2 mL) was added DEAD (0.014 mL, 0.085 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (0.854 mL, 0.854 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(5-(4-(4-chloro-3-fluorophenethoxy)phenyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid (6.6 mg, 0.011 mmol, 25.9% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.53 (t, J=8.1 Hz, 1H), 7.42 (d, J=10.6 Hz, 1H), 7.22 (t, J=7.9 Hz, 2H), 7.07-6.95 (m, 3H), 5.83 (s, 1H), 4.34-4.19 (m, 2H), 3.28 (d, J=11.7 Hz, 2H), 3.09 (t, J=6.6 Hz, 2H), 2.79 (t, J=12.3 Hz, 1H), 2.43 (s, 3H), 2.18 (d, J=11.0 Hz, 1H), 2.05 (s, 3H), 1.97-1.91 (m, 1H), 1.49 (br. s., 1H), 1.35-1.22 (m, 1H), 1.17 (d, J=11.0 Hz, 1H), 1.12 (s, 9H), 1.06-0.95 (m, 1H), 0.85 (s, 3H), 0.59 (s, 3H). LCMS (M+H)=597.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10]C)=[O:8])=[CH:5][C:4]=1[NH:14][S:15]([CH3:18])(=[O:17])=[O:16].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N:14]([CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CCOC(=O)c1ccc(OC)c(NS(C)(=O)=O)c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC)c(N(CCN2CCOCC2)S(C)(=O)=O)c1
Temperature: 25 °C
Yield: 104.7 %

Procedure:
To a solution of ethyl 4-methoxy-3-(methylsulfonamido)benzoate (0.600 g, 2.314 mmol) in dry DMF (23 ml), 4-(2-chloroethyl)morpholine hydrochloride (0.517 g, 2.78 mmol) and K2CO3 (0.704 g, 5.09 mmol) were sequentially added stirring at RT under nitrogen, and the reaction was heated at 70° C. overnight. Water (40 ml) was added, and the mixture was extracted Et2O (3×) and then with EtOAc (3×). The combined organic layers were dried over Na2SO4, and the solvent was removed. The crude was purified by flash chromatography on silica gel column (EtOAc:MeOH=97:3) affording methyl 4-methoxy-3-(N-(2-morpholinoethyl)methylsulfonamido)-benzoate (0.902 g, yield supposed to be quantitative, MS/ESI+ 373.0 [MH]+). This crude was used as such, without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=O)[S:5][C:6]=1[N+:7]([O-:9])=[O:8].C(O)C.N1C=CC=CC=1.Cl.[NH2:22][OH:23]>CCCCCCC.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[N:22][OH:23])[S:5][C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: O=Cc1cc(Br)c([N+](=O)[O-])s1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=[N+]([O-])c1sc(C=NO)cc1Br
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A 12-L three neck, round bottom flask equipped with mechanical stirring, a temperature probe and a reflux condenser was charged with 4-Bromo-5-nitro-thiophene-2-carbaldehyde (Example 25: step b, 426.0 g, 1.805 mol), absolute ethanol (4 L) and pyridine (189.9 mL, 2.35 mol). Hydroxylamine hydrochloride (163.3 g, 2.35 mol) was added in one portion and the mixture was heated. The mixture became a slurry at 27° C., turned clear at 50° C. and was refluxed at 80° C. for 1.5 hour. TLC analysis showed reaction completion (2:1 heptane/EtOAc). The cooled reaction mixture was concentrated in vaccuo then dried azeotrophically using toluene (1 L). The resulting moist solids were transferred to a 10-L glass carboy and stirred with H2O (3 L). After 1 hour, the solids were isolated by filtration, rinsed with H2O (3 L) and heptane (3 L), then dried in vacuum oven to give the desired title compound as a brown powder (441.65 g, 97%). 1H-NMR (DMSO): δ 13.0 (1H, br s), 8.1 (1H, s), 7.8 (1H, s).