Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]1[CH:21]=[CH:20][N:19]2[N:22]=[CH:23][C:24]([C:25]([O:27]CC)=[O:26])=[C:18]2[CH:17]=1.Cl>CO.C1COCC1.O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]1[CH:21]=[CH:20][N:19]2[N:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[C:18]2[CH:17]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCCC3c3cc(F)ccc3F)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnn2ccc(N3CCCC3c3cc(F)ccc3F)cc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 39.1 %

Procedure:
5N aqueous solution of NaOH (2 mL) was added to stirred solution of ethyl 5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (50 mg, 0.134 mmol) in a mixture of MeOH (4 mL) and THF (4 mL) and continued stirring at 80° C. for 4 h. The reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product thus obtained was diluted with cold water, acidified with concentrated HCl solution to obtain a solid precipitate. This solid precipitate was filtered and dried well to afford 18 mg of 5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid as off white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CS(O[CH2:11][CH:12]([CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])(=O)=O>CN(C)C=O>[CH:21]1([CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH2:11][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CS(=O)(=O)OCC(c1ccc(Cl)cc1Cl)C1CCCC1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Clc1ccc(C(Cn2ccnc2)C2CCCC2)c(Cl)c1

Procedure:
A mixture of 18 parts of 1H-imidazole, 18 parts of 2,4-dichloro-β-cyclopentylbenzeneethanol methanesulfonate and 225 parts of N,N-dimethylformamide is stirred and refluxed overnight. The reaction mixture is cooled and poured onto water. The product is extracted three times with trichloromethane. The combined extracts are washed three times with water and stirred with silicagel. The latter is filtered off and the filtrate is evaporated. The residue is crystallized from petroleumether. The product is filtered off and recrystallized from a mixture of 2,2'-oxybispropane and petroleum-ether, yielding 6.8 parts of 1-[2-cyclopentyl-2-(2,4-dichlorophenyl)-ethyl]-1H-imidazole; mp. 97.6° C.
Reaction SMILES: C(OC(=O)COC1C=CC(SCC2C=C(C3C=CC(C(F)(F)F)=CC=3)OC=2)=CC=1C)C.[CH2:32]([O:34][C:35](=[O:46])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][C:39]=1[CH3:45])[CH3:33].[F:47][C:48]1[CH:53]=[C:52]([C:54]([F:57])([F:56])[F:55])[CH:51]=[CH:50][C:49]=1[C:58]1[S:62][C:61]([CH2:63]O)=[C:60]([CH3:65])[CH:59]=1>>[CH2:32]([O:34][C:35](=[O:46])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:63][C:61]2[S:62][C:58]([C:49]3[CH:50]=[CH:51][C:52]([C:54]([F:56])([F:55])[F:57])=[CH:53][C:48]=3[F:47])=[CH:59][C:60]=2[CH3:65])=[CH:40][C:39]=1[CH3:45])[CH3:33]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2F)sc1CO
Reactant: CCOC(=O)COc1ccc(O)cc1C
Agent: CCOC(=O)COc1ccc(SCc2coc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3F)cc2C)cc1C

Procedure:
The title compound was prepared by a method analogous to that used for the preparation of ethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate (example 1) using ethyl(4-hydroxy-2-methylphenoxy)acetate (intermediate 7) and {5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methanol (intermediate 124).
Reaction SMILES: [C:1]1([C:7]2O[N:10]=[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:18]1[NH:22]C(=O)[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:30]>Cl[Ti](Cl)(Cl)Cl.O1CCOCC1>[C:1]1([C:7]2[C:8]3[C:9](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:18]([C:19]([NH:20][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:30])[N:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC1NC(=O)N(c2ccccc2)C1=O
Reactant: c1ccc(-c2onc3ccccc23)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)c1nc(-c2ccccc2)c2ccccc2n1
Yield: 82 %

Procedure:
The reaction between 3-phenylbenzo[c]isoxazole and 5-methoxy-3-phenyl-2,4-imidazolidinedione in refluxing dioxane containing TiCl4 as catalyst to give 82% of 4,N-diphenyl-2-quinazolinecarboxamide [39];
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:11]=[C:12]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[S:13][C:14]=2[C:15]2[N:19]=[CH:18][N:17](COCC[Si](C)(C)C)[N:16]=2)[OH:9])=[CH:4][CH:3]=1.C(Cl)Cl.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[N:11]=[C:12]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[S:13][C:14]=2[C:15]2[N:19]=[CH:18][NH:17][N:16]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2sc(-c3ccncc3)nc2C(O)c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC(c1ccc(Cl)cc1)c1nc(-c2ccncc2)sc1-c1nc[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102 %

Procedure:
(4-Chlorophenyl)[2-pyridin-4-yl-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-4-yl]methanol (266.0 mg, 0.530 mmol) was dissolved in methylene chloride (3.0 mL, 47 mmol). Trifluoroacetic acid (3.0 mL, 39 mmol) was added and the solution was stirred at rt overnight. After the reaction wars completed, saturated NaHCO3 was added and the reaction was stirred at it for 20 min, then EtOAc (5 mL) was added, the organic layer was separated, washed with brine, dried over MgSO4, filtered, concentrated and the obtained residue was purified by column chromatography (SiO2, elution with 2-20% MeOH in DCM) to give the title compound as a white solid (200 mg). The racemic isomers were separated by chiral prep HPLC to yield 17 (34 mg, 12.7%) (peak 1, ret. time 13.04 min). LCMS: (FA) ES+, 370. 1H NMR (400 MHz, d6-DMSO) δ: 8.76 (s, 1H), 8.69-8.71 (dd, J=1.5 Hz, 2H), 7.86-7.88 (dd, J=1.5, 2H), 7.55-7.58 (d, J=8.5 Hz, 2H), 7.34-7.38 (d, J=8.5 Hz, 2H), 6.84-6.86 (s, br, 1H) and 70 (34.8 mg, 13.0%) (peak 2, ret. time 13.2 min). LCMS: (FA) ES+, 370. 1H NMR (400 MHz, d6-DMSO) δ: 8.68-8.72 (m, 3H), 7.86-7.88 (dd, J=1.69 Hz, J=1.5 Hz, 2H), 7.54-7.58 (d, J=8.47 Hz, 2H), 7.34-7.38 (d, J=8.47 Hz, 2H), 6.81-6.82 (s, br, 1H).
Reaction SMILES: [C:1]([N:9]1[C:13]2([CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[S:12][CH2:11][C@H:10]1[C:29]([OH:31])=[O:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32](O)[CH3:33].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([N:9]1[C:13]2([CH2:18][CH2:17][CH:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:27])[CH3:28])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[S:12][CH2:11][C@H:10]1[C:29]([O:31][CH2:32][CH3:33])=[O:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(OC2CCC3(CC2)SC[C@@H](C(=O)O)N3C(=O)c2ccccc2)cc1
Reactant: CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CSC2(CCC(Oc3ccc(C(C)C)cc3)CC2)N1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 56 ml of methylene chloride was dissolved 2.80 g of (3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid, to which were successively added at 0-5° C. 0.56 ml of ethanol, 0.16 g of N,N-dimethylaminopyridine and 1.98 g of dicyclohexyl carbodiimide. After stirring the mixture at ambient temperature for 24 hours, the insoluble matter was filtered off. The filtrate was poured into ice water, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: toluene:ethyl acetate=50:1] gave 0.85 g of ethyl (3R)-4-benzoyl-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decane-3-carboxylate as a colorless oily product.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:26][CH:25]=3)=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH2:38](O)[CH:39]=[CH2:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.C(Cl)Cl>[CH2:40]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:26][CH:25]=3)=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=3)[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)[CH:39]=[CH2:38]
Reactant: O=c1oc2cc(O)ccc2c(Cc2ccc(OCCN3CCCC3)cc2)c1-c1ccc(C(F)(F)F)cc1
Reactant: C=CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCOc1ccc2c(Cc3ccc(OCCN4CCCC4)cc3)c(-c3ccc(C(F)(F)F)cc3)c(=O)oc2c1
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution containing 7-hydroxy-4-{(4-(2-pyrrolidinylethoxy)phenyl)methyl}-3-(4-(trifluoromethyl)phenyl)-2H-chromen-2-one (0.550 g.) in tetrahydrofuran (6 mL) and methylene chloride (6 mL) was added allyl alcohol (0.226 mL) and triphenylphosphine (0.641 g.). Diisopropylazodicarboxylate (0.437 mL) was then added dropwise to the solution. The resultant mixture was allowed to stir for about one hour (or until the starting material was consumed). The solution was concentrated under reduced pressure and extracted with methylene chloride (3×) and water. The organic layers were dried over magnesium sulfate, the magnesium sulfate was filtered and the solvent was concentrated under reduced pressure to provide an orange oil. The oil was purified via silica gel chromatography (6–10% methanol/methylene chloride) to afford 7-prop-2-enyloxy-4-{(4-(2-pyrrolidinylethoxy)phenyl)methyl}-3-(4-(trifluoromethyl) Phenyl)-2H-chromen-2-one (0.245 g., 40% yield). MS (m/z) 550 (M+1)+.
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.CCN(CC)CC.[CH:39]1([C:42](Cl)=[O:43])[CH2:41][CH2:40]1>CN(C=O)C>[CH:39]1([C:42]([N:22]2[CH2:23][C:18]3[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@H:25]4[CH3:30])=[N:16][C:15]([C:12]4[CH:13]=[CH:14][C:9]([NH:8][C:6]([NH:5][CH:2]5[CH2:3][CH2:4]5)=[O:7])=[CH:10][C:11]=4[F:31])=[N:20][C:19]=3[CH2:21]2)=[O:43])[CH2:41][CH2:40]1
Reactant: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CN(C(=O)C1CC1)C2
Temperature: 20 °C
Reaction time: 0.03 h

Procedure:
To a stirring solution of (R)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (intermediate 33) (112 mg, 0.25 mmol) in DMF (2 ml), was added Et3N (70 μL, 0.5 mmol). Reaction mixture was stirred at room temperature (20° C.) for 2 minutes followed by the addition of cyclopropanecarbonyl chloride (23 μL, 0.25 mmol) followed by stirring at room temperature for two hours. The reaction mixture was concentrated in vacuo before partitioning between water (10 ml) and DCM (10 ml). The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo. Residue was then purified by prep. HPLC at high pH to afford the title compound as an off white solid (25 mg, 0.052 mmol, 21%).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)#[N:4].[Cl:15][C:16]1[CH:30]=[CH:29][C:19]([C:20]([N:22]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH3:23])=[O:21])=[CH:18][N:17]=1>CN(C)C=O>[ClH:15].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([OH:14])=[C:8]2[C:16]1[CH:30]=[CH:29][C:19]([C:20]([N:22]([CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])[CH3:23])=[O:21])=[CH:18][N:17]=1)#[N:4]
Reactant: CN(C)CCN(C)C(=O)c1ccc(Cl)nc1
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCN(C)C(=O)c1ccc(-c2c(O)[nH]c3ccc(C#N)cc23)nc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 4.2 %

Procedure:
A mixture of sodium hydride (330 mg, 8.2 mmol, 60% dispersion in oil, pre-washed with hexane) in N,N-dimethylformamide (2 mL) was added to 5-cyanooxindole (980 mg, 6.2 mmol) in N,N-dimethylformamide (4 mL). The formed brown mixture was stirred at room temperature for 20 min and 6-chloro-N-[2-(dimethylamino)ethyl]-N-methylnicotinamide (500 mg, 2.1 mmol) in N,N-dimethylformamide (3 mL) was added. The obtained red solution was heated at 150° C. for 30 min and was then allowed to reach room temperature overnight. The solvent was removed in vacuo and the residue was partitioned between a 2 M aqueous HCl solution and ethyl acetate. The mixture was alkalized to pH 8 by adding NaHCO3 (s) and extracted with ethyl acetate. The combined extracts were dried (Na2SO4) and the solvent was removed in vacuo to afford 450 mg of a crude product. The residue was purified on a silica gel column using chloroform/methanol/conc. NH3(aq), (80:19:1), as the eluent. Fractions containing product were collected, evaporated in vacuo and dried at 25° C. in vacuo to afford 70 mg. The residue was purified by preparative HPLC (column: Xterra, 19×300 mm, eluent: 0.05 M NH4OAc buffert/acetonitrile, 9:1-3:7). Fractions containing product were collected, evaporated in vacuo and dried at 25° C. in vacuo to afford 35 mg (4.6% yield) of the title compound as the base: 1H NMR (D2O, 400 MHz) δ 7.89 (s, 1 H), 7.59 (d, J=9 Hz, 1 H), 6.96 (s, 1 H), 6.92 (d, J=8 Hz, 1 H), 6.84 (d, J=9 Hz, 1 H), 6.65 (d, J=8 Hz, 1 H), 3.76 (s, 2 H), 3.30 (s, 2 H), 3.07 (s, 3 H), 2.84 (s, 6 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[OH-:11].[Na+].O.[C:14]1([CH3:20])C=CC=C[CH:15]=1>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:15][C:14](=[O:11])[CH3:20]
Reactant: Cc1ccccc1
Reactant: [OH-]
Reactant: COc1ccccc1C=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccccc1C=CC(C)=O
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
2-Methoxy-benzaldehyde (5 g, 36 mmol) was suspended in a mixture of acetone/water (5 ml/5 ml). A 1% aqueous solution of sodium hydroxide (10 ml) was slowly added to the reaction mixture. The reaction mixture was heated to 65° C. and stirred for 1.5 h. The reaction mixture was cooled to ambient temperature, water (20 ml) and toluene (20 ml) were added to the flask. The organic phase was separated, washed with brine and dried with MgSO4. The solution was filtered and the solvent removed in vacuo to give the required product as a yellow powder. The title compound was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[CH:28]=[CH2:29].O>C1COCC1>[CH2:29]([O:14][C@@H:13]1[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12]1)[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a solution of 26 g (77 mmol) of benzyl 3-[(tert-butoxycarbonyl)amino]-4-hydroxypyrrolidine-1-carboxylate in 120 mL of THF was added 5 g (211 mmol) of sodium hydride at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then 10 mL (115 mmol) of allyl bromide was added. The reaction mixture was warmed up to room temperature and continuously stirred at room temperature overnight. Water (50 mL) was added to quench the reaction. The organic phase was separated, and the aqueous layer was extracted with ethyl acetate twice (100 mL×2). The combined extracts were washed with brine, dried over Na2SO4, evaporated under reduced pressure. Chromatography on silica gel column with 25% EtOAc-hexane provided the title compound (21.3 g, 73%). MS (M+H)+377.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][S:30][CH2:31][C@@H:3]12.[CH2:32]([N:34](C(C)C)C(C)C)C.Cl.CN>CN(C=O)C>[CH3:32][NH:34][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][S:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
In a vial equipped with a stir bar was charged (R)-4-(4-((6-oxo-5,6,6a,7,9,10-hexahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (50 mg, 0.114 mmol) was taken up in DMF (1.14 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (59 μl, 0.34 mmol), O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (64.9 mg, 0.171 mmol), and methanamine hydrochloride (8.45 mg, 0.125 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (55-90% acetonitrile in water, ammonium bicarbonate buffer). The fractions were collected and lyophilized to yield 25.1 mg (49%) of the product as a white solid. 1H NMR (CHLOROFORM-d) δ: 8.37 (br. s., 1H), 7.58-7.89 (m, 3H), 7.15 (br. s., 1H), 6.87 (d, J=8.8 Hz, 2H), 6.07 (d, J=4.5 Hz, 1H), 5.06 (dt, J=13.6, 2.5 Hz, 1H), 4.42 (dd, J=10.1, 3.8 Hz, 1H), 3.55 (br. s., 2H), 3.36 (br. s., 4H), 3.08-3.24 (m, 1H), 2.56-3.08 (m, 8H), 2.40 (dd, J=13.5, 1.1 Hz, 1H), 1.74 (br. s., 2H). [M+H] calc'd for C23H28N6O2S, 453. found, 453.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[CH3:6][N:7]1[C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=[N:8]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O.CN(C)C=O>[CH3:5][O:4][N:3]([CH3:2])[C:12]([C:11]1[N:7]([CH3:6])[N:8]=[CH:9][CH:10]=1)=[O:14]
Reactant: Cn1nccc1C(=O)O
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccnn1C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
N,O-dimethylhydroxylamine hydrochloride (1.30 g) was added to an dimethylformamide (32 mL) solution that contained 1-methyl-1H-pyrazol-5-carboxylic acid (1.21 g), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (4.38 g) and diisopropylethylamine (3.34 mL) at a room temperature, and the obtained solution was then stirred for 2 hours. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with water and a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, chloroform:methanol=100:0 to 95:5), so as to obtain the title compound (1.03 g) in the form of a yellow oily substance.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)[CH:23]=[C:22]([CH3:33])[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]2[CH:23]=[C:22]([CH3:33])[N:21]=[C:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[CH:19]=3)[N:25]=2)=[CH:31][CH:30]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2ccnc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 33.8 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-(4-chloro-phenyl)-6-methyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butylamide (0.12 g) in dichloromethane (4 mL) was added TFA (4 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried. Further purification by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (diethyl ether) yielded the title compound as a white solid (0.036 g, 12%). MS (ISP) 443.2 [(M+H)+]; mp 232.5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3](=[O:12])[C:4](=[N:10][OH:11])[C:5](=[N:7][O:8][CH3:9])[CH3:6].[H-].[Na+].[H][H].[CH2:18]([N:20]([CH2:24][CH3:25])[C:21](Cl)=[O:22])[CH3:19]>O1CCCC1>[CH3:13][N:2]([CH3:1])[C:3](=[O:12])[C:4](=[N:10][O:11][C:21](=[O:22])[N:20]([CH2:24][CH3:25])[CH2:18][CH3:19])[C:5](=[N:7][O:8][CH3:9])[CH3:6]
Reactant: [H][H]
Reactant: CON=C(C)C(=NO)C(=O)N(C)C
Reactant: CCN(CC)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)ON=C(C(=O)N(C)C)C(C)=NOC
Reaction time: 3 h

Procedure:
To a stirred mixture of 75 parts of N,N-dimethyl-2-hydroxyimino-3-methoxyiminobutyramide and 1500 parts of tetrahydrofuran was added portionwise over a fifteen-minute period 19 parts of 50% sodium hydride, mineral oil dispersion. The temperature was maintained in the range of 20° C. to 30° C. After about one-half hour, evolution of hydrogen gas ceased, and rapid addition of 55 parts diethylcarbamoyl chloride was begun. The temperature spontaneously rose to 33° C., and rapid thinning-out of the oxime salt slurry occurred. The mixture was refluxed and stirred for three hours. The inorganic solids were then removed by filtration and the product recovered by removal of the solvent under reduced pressure. The residue was twice triturated with hexane and the liquid decanted to remove the mineral oil. After drying, there was obtained 90 parts of N,N-dimethyl-2-[(diethylcarbamoyl)oxyimino]-3-methoxyiminobutyramide, m.p. 59°-61°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O.I[CH2:37][C:38]([NH2:40])=[O:39]>C(#N)C>[C:16]([C:10]1([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14][N:13]([CH2:37][C:38]([NH2:40])=[O:39])[CH2:12][CH2:11]1)#[N:17]
Reactant: NC(=O)CI
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CCNCC1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: N#CC1(c2ccc([N+](=O)[O-])cc2)CCN(CC(N)=O)CC1
Reaction time: 8 h
Yield: 109.9 %

Procedure:
4-(4-Nitro-phenyl)-piperidine-4-carbonitrile (0.795 g, 3.44 mmol) and MP-Carbonate resin (3.16 mmol/g loading; 2.18 g, 6.88 mmol) were combined in Acetonitrile (24.0 mL) and Iodoacetamide (0.720 g, 3.70 mmol) was then added and then stirred overnight. After 24 h, conversion was not complete, so additional MP-Carbonate resin (1.21 g, 3.82 mmol), Iodoacetamide (0.405 g, 2.08 mmol) and Acetonitrile (30.0 mL, 574 mmol) were added. After 8 h, the reaction was complete. Solubilize the precipitated product with DCM:MeOH, filter off resin and wash with DCM:MeOH. Conc. onto 10 g silica gel. ISCO (40 g, 0-20% MeOH:EtOAc) to afford 2-[4-Cyano-4-(4-nitro-phenyl)-piperidin-1-yl]-acetamide (1.09 g; Yield=100) as a white solid. 1H-NMR (DMSO-d6): 8.31 (d, 2H, J=8.7 Hz), 7.87 (d, 2H, J=8.7 Hz), 7.35 (br s, 1H), 7.18 (br s, 1H), 2.97 (m, 4H), 2.50 (m, 2H), 2.22 (m, 2H), 2.13 (m, 2H).