Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:26]=1)[C:7]([C:9](=[CH:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].C1CCN2C(=NCCC2)CC1>CC(C)=O>[Br:1][C:2]1[CH:26]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH:15]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7]2=[O:8]
Reactant: CCOC(=O)C(=CNCc1ccc(OC)cc1)C(=O)c1cc(Br)ccc1F
Solvent: CC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(Cc2ccc(OC)cc2)c2ccc(Br)cc2c1=O
Temperature: 20 °C
Reaction time: 16.5 h
Yield: 81.8 %

Procedure:
On a larger scale, ethyl 2-(5-bromo-2-fluorobenzoyl)-3-[(4-methoxyphenyl)methylamino]prop-2-enoate (8434 g, (7730 g assumed active), 17.71 mol) was charged to the vessel with acetone (23.2 L) at 15° C. DBU (2.8 L, 18.72 mol) was added over 25 minutes with an observed exotherm from 18-23° C. over the addition. A precipitate formed after ˜25 minutes and the batch continued to exotherm reaching a maximum of 37° C. after 1 h. The reaction was stirred at 20° C. for 16.5 h at which point HPLC indicated consumption of starting material and 96.5% product. The resulting precipitate was collected by filtration washing with TBME (4×3.4 L). The solid was then dried under vacuum at 40° C. to give 6033 g of the desired material as a white solid (81.6% yield over 3 steps, 99.8% purity by HPLC). Analytical data was consistent with that obtained on previous batches.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.C(C1C=CC(OC2N=CC(N[C:33]([C@H:35]([NH:38][C:39](=O)[O:40]C(C)(C)C)[CH2:36][CH3:37])=[O:34])=CC=2)=CC=1C(C)C)#N.Cl>ClCCl.CN(C1C=CN=CC=1)C.CCOCC>[CH2:36]([C@H:35]1[NH:38][C:39](=[O:40])[N:14]([C:13]2[CH:15]=[CH:16][C:10]([O:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:11][CH:12]=2)[C:33]1=[O:34])[CH3:37]
Reactant: COc1cccc(Oc2ccc(N)cc2)c1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C#N)c(C(C)C)c2)nc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3cccc(OC)c3)cc2)C1=O
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To Boc-anhydride (138 mg, 0.631 mmol) in dichloromethane (1 mL) was added DMAP (55.1 mg, 0.451 mmol) followed by a solution of 4-{[3-(methyloxy)phenyl]oxy}aniline (97 mg, 0.451 mmol) in dichloromethane (1 mL). The mixture was stirred for 10 min. The brown solution thus obtained was added to Solution 1 via syringe with shaking at 35° C. and shaking was continued at this temperature for 2 hours. The solution was then kept at room temperature for ca. 64 hours. Conc. aq. HCl (ca. 0.8 mL) was added and the heterogenous mixture was heated at 100° C. for 2 hours with shaking, allowing the DCM to distill off through a glass capillary. After cooling to room temperature, the residue was diluted with water (ca. 3 mL) and extracted with dichloromethane (2 times ca. 2 mL). The dichloromethane extracts were concentrated under vacuum. The residue was purified by silica gel chromatography (Biotage system, 10 g column) eluting with a gradient cHex/EtOAc from 95/5 to 0/100 to give a brown viscous oil that was dissolved in Et2O (ca. 0.7 mL) and cHex (ca. 0.1 mL) and kept over night. The overstanding faint brown solution was decanted from a small quantity of a brown oil that had separated out. As the solvent was allowed to evaporate from this solution crystallisation initiated. The material thus obtained was allowed to dry and then triturated with Et2O (2 times ca. 0.5 mL) to afford, after drying, the title compound as a solid (28 mg).
Reaction SMILES: [Cl-].[Li+].C(OP([CH:11]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:21]1CCN2C(=NCCC2)CC1.C=O>C1COCC1.C(OCC)(=O)C>[CH2:17]([C:11](=[CH2:21])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:18]([CH3:19])[CH3:20]
Reactant: CCOC(=O)C(CC(C)C)P(=O)(OCC)OCC
Reactant: C1CCC2=NCCCN2CC1
Agent: C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(CC(C)C)C(=O)OCC
Yield: 62.8 %

Procedure:
333 mg of lithium chloride was suspended in 14 ml of dry THF. Then, 2.0 g of ethyl 2-diethylphosphono-4-methylpentanoate was added thereto under stirring. Then, 1.41 g of DBU was added thereto in the form of a dry THF solution. Then, a suspension of 348 mg of paraformaldehyde in dry THF was added thereto. The mixture was stirred at room temperature overnight. The reaction solution was subjected to filtration, and the collected substance was washed with a small amount of benzene. The filtrate and the washing solution were put together and concentrated under reduced pressure. The syrup thereby obtained was dissolved in 60 ml of ethyl acetate. The ethyl acetate layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, solvent was distilled off to obtain 700 mg of ethyl 2-isobutyl-2-propenoate as colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]([C:11](O)=[O:12])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].S(N)([NH2:20])(=O)=O.N1C=CC=CC=1>O>[CH3:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]([C:11]([NH2:20])=[O:12])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1c([N+](=O)[O-])cc(C(=O)O)c2nc[nH]c12
Reactant: NS(N)(=O)=O
Solvent: O
Solvent: c1ccncc1
Product: Cc1c([N+](=O)[O-])cc(C(N)=O)c2nc[nH]c12
Temperature: 25 °C
Yield: 85.3 %

Procedure:
A mixture of 7-Methyl-6-nitro-1H-benzimidazole-4-carboxylic Acid (23) (0.692 g, 3.12 mmol), sulfamide (0.600 g, 6.26 mmol), and pyridine (8 mL) is heated at reflux for about 16 hours. The resulting heterogeneous reaction mixture is cooled to ambient temperature, diluted with water (10 mL) and cooled to 0° C. for 1 hour. The solids that form are filtered, washed with water (10 mL) and methanol (10 mL), and dried to obtain 7-Methyl-6-nitro-1H-benzimidazole-4-carboxamide (25) as a cream colored solid (0.586 g, 85% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:9])=[N:6][C:7]=1[NH2:8].[C:20]1(C)[CH:25]=CC=[CH:22][CH:21]=1>O>[CH2:16]([NH:15][C:3]1[C:2]2[C:7](=[N:8][C:20]([CH3:25])=[C:21]([CH3:22])[N:1]=2)[N:6]=[C:5]([CH3:9])[C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:17][CH2:18][CH3:19]
Reactant: Cc1ccccc1
Reactant: CCCCNc1c(N)c(N)nc(C)c1C(=O)OCC
Solvent: O
Product: CCCCNc1c(C(=O)OCC)c(C)nc2nc(C)c(C)nc12
Reaction time: 5 h

Procedure:
26.6 g. of 5,6-Diamino-4-butylamino-2-methylpyridine-3-carboxylic acid, ethyl ester (0.1 Mol) are dissolved in 150 ml. of toluene. 9 g. of diacetyl are added and the mixture is refluxed while the water formed is removed by a water separator. After about 5 hours, the theoretical amount of water is separated and the solution is evaporated to dryness. The dark oily residue is extracted twice with 100 ml. portions of gasoline and addition of activated charcoal. The gasoline extracts are combined and concentrated to about 100 ml. 8-Butylamino-2,3,6-trimethylprido[2,3-b]pyrazine-7-carboxylic acid, ethyl ester crystallizes on cooling, yield 21 g. (66%); m.p. 97°-99°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[N:11]([C:17]=2[NH:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:12]=[CH:13][C:14]=3[C:15]#[N:16])=[CH:4][CH:3]=1.[OH2:24]>CS(C)=O.ClCCl>[NH2:9][C:10]1[N:11](/[C:17](=[N:18]/[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)/[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:24])[N:12]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1cnn2c(NC3CCCC3)c(-c3ccc(Br)cc3)[nH]c12
Reactant: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#Cc1cnn(/C(=N/C2CCCC2)C(=O)c2ccc(Br)cc2)c1N
Temperature: 25 °C
Yield: 21.7 %

Procedure:
A dilute solution of 2-(4-bromophenyl)-3-(cyclopentylamino)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile (500 mg, 1.35 mmol) in DMSO (100 mL) was stored at RT for more than 60 days. The yellow DMSO solution was poured into water (1 L) and the organic compound was extracted into ethyl acetate (2×75 mL). The combined extracts were washed with water and brine solution. The organic layer was dried over anhydrous MgSO4, filtered and concentrated to give the crude yellow solid which was not soluble in dichloromethane even at hot condition. Then, after cooling to RT, the solids were collected by filtration and washed with dichloromethane and the 1H NMR of this solid indicated that it is mostly starting material. Whereas, the mother liquor was removed under vacuum and the crude residue was purified using an ISCO (80 g) column eluting with 0-35% ethyl acetate in hexanes. The pure fractions were combined and the solvent was removed under vacuum to obtain 113 mg (21.7% yield) of (E)-5-amino-1-(1-(cyclopentylimino)-2-(4-bromophenyl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.40-1.80 (br m, 8H), 3.63 (p, 1H), 7.72 (s, 1H), 7.78 (d, J=6.1 Hz, 2H), 7.83 (d, J=6.2 Hz, 2H), 8.14 (br s, 2H). LC/MS calcd. for C17H16BrN5O (m/e) 386.25, obsd. 387.2 (M+H, ES+).
Reaction SMILES: [I:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.O=P(Cl)(Cl)[Cl:14].P(Cl)(Cl)(Cl)(Cl)Cl>O>[Cl:14][C:3]1[C:2]([I:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(I)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1cnc(Cl)c(I)c1
Temperature: 140 °C
Yield: 68.4 %

Procedure:
A mixture of 3-iodo-5-nitropyridin-2-ol (37.6 mmol, 10 g), POCl3 (86.47 mmol, 7.94 ml) and PCl5 (48.87 mmol, 10.2 g) was heated at 140° C. for 1 h, under argon atmosphere. The crude mixture was poured into a mixture of ice and water and extracted with DCM. The solid residue was purified by chromatography over SiO2 eluting with hexane/dichloromethane mixtures affording 2-chloro-3-iodo-5-nitropyridine (7.32 g, yield 69%) of the expected product.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)=O.[SH2]=N.[C:14]1([NH:20][C:21](C2C=CC=CC=2C(O)=O)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[C:1]1([NH:7][C:21]([NH:20][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccccc1C(=O)Nc1ccccc1
Reactant: NC1CCCCC1
Agent: N=[SH2]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccccc1)NC1CCCCC1
Yield: 88.7 %

Procedure:
A mixture of 1.0 g cyclohexylamine and 5 ml aceton was added dropwise to a suspension of 1.5 g phenylcarbamoyl-benzoic acid sulfimide with 20 ml aceton, under stirring. The reaction mixture was stirred for 80 minutes at room temperature, then diluted with 150 ml water. The precipitated solid product was cooled, filtered, washed with water and dried. 1.0 g 1-phenyl-3-cyclohexylurea was obtained with a melting point of from 182° to 184° C.
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][CH:5]=1.CCN(C(C)C)C(C)C.[CH3:21][C:22]([CH3:26])([CH3:25])[C:23]#[CH:24]>O1CCOCC1.[Cu](I)I>[CH3:21][C:22]([CH3:26])([CH3:25])[C:23]#[C:24][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:11])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: C#CC(C)(C)C
Agent: I[Cu]I
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C#Cc1ccc(C(=O)O)cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
6-Chloronicotinic acid methyl ester (500 mg; 2.93 mmol) was suspended in 1,4-dioxane (3 ml) in a 5 ml reaction vial. To the vessel was added dichlorobis(triphenylphosphine) palladium(ii) (70 mg; 3 mol %), copper iodide (12 mg), n,n-diisopropylethylamine (0.63 ml; 3.5 mmol) and 3,3-dimethylbut-1-yne (0.44 ml; 3.5 mmol). The vessel was sealed and the mixture was heated at 80° C. for 24 hrs. The solvents were evaporated to dryness and 20 ml of tetrahydrofuran and 20 ml of 10N NaOH was added. The mixture was stirred at room temperature for 30 minutes and the solvent was evaporated. The basic layer was acidified with concentrated HCl and extracted three times with EtOAc. The organic layers were washed with brine and dried over Na2SO4, filtered and evaporated to give the desired product as a brown powder (590 mg; 99%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[C:9](Cl)=[CH:8][C:7]([C:11]2[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][CH3:20])=[N:6][CH:5]=1.B(CC)(CC)[CH2:23][CH3:24].C([O-])([O-])=O.[Na+].[Na+].CCCCCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[C:9]([CH2:23][CH3:24])=[CH:8][C:7]([C:11]2[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:19][CH3:20])=[N:6][CH:5]=1
Reactant: CCc1cccc(CC)c1-c1cc(Cl)c(C(=O)OC)cn1
Reactant: CCB(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCc1cc(-c2c(CC)cccc2CC)ncc1C(=O)OC
Temperature: 80 °C

Procedure:
A mixture of 4-chloro-6-(2,6-diethyl-phenyl)-nicotinic acid methyl ester (2.5 g, 8.2 mmol), Et3B (1M in Hexane, 49 mL, 49 mmol), Na2CO3 (2M in H2O, 12.3 mL) and Pd(PPh3)4 (500 mg) in toluene (36 mL) is heated at 80° C. under argon for 2 days. On cooling, hexane (50 mL) is added and the organic layer separated. The organic layer is washed with saturated Na2CO3 and water, dried (Na2SO4), and concentrated. The residue is purified by silica gel chromatography (hexane/EtOAc 4:1) to give 6-(2,6-diethyl-phenyl)-4-ethyl-nicotinic acid methyl ester. 1H NMR (CDCl3) 9.15 (s, 1H), 7.30 (m, 1H), 7.21 (s, 1H), 7.15 (d, 2H), 3.97 (s, 3H), 3.06 (q, 2H), 2.31 (m, 4H), 1.26 (t, 3H), 1.03 (t, 6H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=[C:11]2[NH:10][C:9]1=[O:20].[CH3:21][N+:22]([CH3:24])=[CH2:23].[I-]>CN(C)C=O.CCOC(C)=O>[CH3:21][N:22]([CH2:24][C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]3[NH:10][C:9](=[O:20])[N:8]([C@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]4[CH3:1])[C:12]3=2)[NH:17][CH:18]=1)[CH3:23]
Reactant: C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc3[nH]cc(CN(C)C)c3c21
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 53.3 %

Procedure:
To a solution of 1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (30 mg, 0.111 mmol) in N,N-dimethylformamide (0.6 mL) was added N,N-dimethylmethyleneiminium iodide (26.7 mg), and stirred at 85° C. for 1.5 hours. To the mixture was added Eschenmoser's salt (12.3 mg), and stirred at 80° C. for 30 minutes. The mixture was diluted with EtOAc, washed with saturated aqueous sodium hydrogencarbonate, 10% NaCl solution (×5), and brine, dried over MgSO4, evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1 to 10:1) to give 8-[(dimethylamino)methyl]-1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (11.6 mg) as a pale yellow amorphous solid.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=O.Cl.[NH2:14]O.C([O-])(=O)C.[Na+]>C(O)C>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:14]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc2ccccc2c1

Procedure:
2-Cyanonaphthalene is prepared by refluxing 2-formylnaphthalene with hydroxylamine hydrochloride and sodium acetate in ethanol to furnish the corresponding oxime which is refluxed with acetic anhydride in the presence of an acid catalyst to furnish 2-cyanonaphthalene.
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1>[CH3:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[N:1][C:15]([NH:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16]
Reactant: O=C=Nc1ccccc1
Reactant: CN1CCCC1=N
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1ccccc1

Procedure:
After dissolving 4.9 g. (0.05 mole) of 2-imino-1-methylpyrrolidine in anhydrous benzene, 5.96 g. (0.05 mole) of phenylisocyanate is added dropwise with stirring (heat evolves). The reaction mixture is stirred for one-half hour. The solid product which is formed, 1-(1-methyl-2-pyrrolidylidene)-3-phenylurea, is collected (m.p. = 140°-144° C); recrystallized from methanol to give the pure product, m.p. = 146°-147.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=4)[CH2:16][NH:15][C:14]3=[O:25])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][CH2:36][O:37]C1CCCCO1.O>C(#N)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:35][CH2:36][OH:37])[CH:19]=4)[CH2:16][NH:15][C:14]3=[O:25])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C1NC[C@H](c2cccc(O)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: O=C1NC[C@H](c2cccc(OCCO)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (S)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-hydroxyphenyl)-imidazolidin-2-one (26 mg, 0.068 mmol) in acetonitrile (2 mL) is added Cs2CO3 (50 mg, 0.15 mmol) followed by 2-(2-bromoethoxy)tetrahydro-2H-pyran (30 mg, 0.14 mmol). The resulting mixture is stirred at room temperature for 24 h and is then treated with water (5 mL) and extracted with EtOAc (3×3 mL). The combined organic layers are concentrated and the residue is dissolved in MeOH (1 mL). To the MeOH solution is added catalytic amount of pTSA (˜1 mg). The resulting mixture is stirred at room temperature for 1 h and is then treated with sat. NaHCO3 solution (3 mL). After extracting with EtOAc (3×3 mL), the combined organic layers are concentrated and purified by preparative thin layer chromatography (silica gel, 85% EtOAc/hexane) to provide the title compound as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.33 (d, J=9.2 Hz, 2H), 7.22-7.27 (m, 3H), 6.89 (d, J=7.6 Hz, 1H), 6.81-6.88 (m, 6H), 5.23 (dd, J=8.8, 6.0 Hz, 1H), 4.90 (br s, 1H), 3.92-4.08 (m, 5H), 2.34 (dd, J=8.8, 6.4 Hz, 1H), 2.03 (t, J=5.6 Hz, 1H); HPLC-MS calculated for C23H21ClN2O4 (M+H+) 425.1, found 425.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[NH:12][C:11]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][O:33][CH2:34][CH2:35][NH:36][CH2:37][CH3:38])=[C:10]1[C:39]([O:41][CH3:42])=[O:40].[C:43](=O)([O:49]C(C)(C)C)[O:44][C:45]([CH3:48])([CH3:47])[CH3:46].C(N(CC)CC)C>ClCCl>[CH3:42][O:41][C:39]([C:10]1[CH:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[NH:12][C:11]=1[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][O:33][CH2:34][CH2:35][N:36]([C:43]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:49])[CH2:37][CH3:38])=[O:40]
Reactant: CCNCCOCc1ccccc1CCC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CC(=O)OC)N1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CCOCc1ccccc1CCC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CC(=O)OC)N1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To an ice-cooled stirred solution of dimethyl 4-(2,6-dichlorophenyl)-2-[2-(2-{[2-(ethylamino)ethoxy]methyl}phenyl)ethyl]-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate (700 mg/1.13 mmol) in dichloromethane (50 ml) was added di-t-butyl carbonate (297 mg/1.36 mmol) and triethylamine (172 mg/1.70 mmol). The reaction mixture was warmed to room temperature and stirred for 1.5 h. The reaction mixture was quenched with water. The separated organic layer was washed with water, dried over MgSO4, filtered and concentrated to give a crude mixture. This crude was purified by column chromatography on silica gel (CH2Cl2:MeOH=40:1) to afford a yellow amorphous (813 mg/quant.).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:20]=[C:19]([NH:21][S:22]([CH:25]=[CH2:26])(=[O:24])=[O:23])[CH:18]=[C:17]([C:27]([F:30])([F:29])[F:28])[CH:16]=1)=[O:13].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(Cl)Cl>C(O)(C)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:16]=[C:17]([C:27]([F:29])([F:30])[F:28])[CH:18]=[C:19]([NH:21][S:22]([CH2:25][CH2:26][N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)(=[O:24])=[O:23])[CH:20]=1)=[O:13]
Reactant: C1CCNCC1
Reactant: C=CS(=O)(=O)Nc1cc(NC(=O)c2c[nH]c3ccccc3c2=O)cc(C(F)(F)F)c1
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(Nc1cc(NS(=O)(=O)CCN2CCCCC2)cc(C(F)(F)F)c1)c1c[nH]c2ccccc2c1=O
Temperature: 75 °C

Procedure:
A mixture of 4-oxo-N-[3-(trifluoromethyl)-5-(vinylsulfonamido)phenyl]-1,4-dihydroquinoline-3-carboxamide (50 mg, 0.11 mmol), piperidine (18 μL, 1.6 eq) and LiClO4 (20 mg, 1.7 eq) was suspended in a 1:1 solution of CH2Cl2:isopropanol (1.5 mL). The mixture was refluxed at 75° C. for 18 h. After this time, LCMS analysis showed >95% conversion to the desired product. The crude mixture was purified by reverse-phase HPLC to provide 4-oxo-N-[3-[2-(1-piperidyl)ethylsulfonylamino]-5-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide (318) as a yellowish solid (15 mg, 25%). 1H-NMR (d6-Acetone, 300 MHz) δ 8.92 (br s, 1H), 8.4 (d, J=8.1 Hz, 1H), 8.05 (br s, 1H), 7.94 (br s, 1H), 7.78 (br s, 2H), 7.53-751 (m, 1H), 7.36 (br s, 1H), 3.97 (t, J=7.2 Hz, 2H), 3.66 (t, J=8 Hz, 2H), 3.31-3.24 (m, 6H), 1.36-1.31 (m, 4H); ESI-MS 481.1 m/z (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[S:5]1(=[O:22])=[O:21].[CH3:23][NH2:24]>C(O)C>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:6]1[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH2:9][N:4]([CH2:3][CH2:2][NH:24][CH3:23])[S:5]1(=[O:22])=[O:21]
Reactant: O=S1(=O)N(CCBr)Cc2ccccc2N1c1ccccc1F
Reactant: CN
Solvent: CCO
Product: CNCCN1Cc2ccccc2N(c2ccccc2F)S1(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
3-(2-bromoethyl)-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.96 g, 0.25 mmol) was dissolved in an 8 M solution of methylamine in ethanol (4 ml) and was stirred in a capped vial at room temperature for two hours. The reaction mixture was evaporated and the residue purified by flash chromatography (SiO2, 0-5% 7 M NH3-methanol/dichloromethane). The purified free-base was dissolved in dichloromethane (3 mL) and treated with hydrogen chloride (1.0 mL of a 2 M solution in ethyl ether), resulting in a white precipitate that was evaporated and dried under vacuum to afford 2-[1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylethanamine (0.071 g, 85%) as a white solid: