Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:19])[C:3]=1[C:4]([OH:6])=O.[F:20][C:21]1[CH:22]=[C:23]([C:27]2([CH2:33][CH2:34][N:35]3[CH:40]4[CH2:41][CH2:42][CH:36]3[CH2:37][CH:38]([N:43]3[C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=5[N:45]=[C:44]3[CH3:52])[CH2:39]4)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ClC1C(C(N2CCC(C3C=CC=C(F)C=3)(CCN3C4CCC3CC(N3C5C=CC=CC=5N=C3C)C4)CC2)=O)=C(Cl)C=CC=1S(NC)(=O)=O>>[Cl:1][C:2]1[C:3]([C:4]([N:30]2[CH2:29][CH2:28][C:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[CH:22]=3)([CH2:33][CH2:34][N:35]3[CH:36]4[CH2:42][CH2:41][CH:40]3[CH2:39][CH:38]([N:43]3[C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=5[N:45]=[C:44]3[CH3:52])[CH2:37]4)[CH2:32][CH2:31]2)=[O:6])=[C:7]([Cl:19])[CH:8]=[CH:9][C:10]=1[S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1Cl
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNS(=O)(=O)c1ccc(Cl)c(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3cccc(F)c3)CC2)c1Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)c2c(Cl)ccc(S(=O)(=O)NC(C)(C)C)c2Cl)CC1
Yield: 17 %

Procedure:
Prepared from a mixture of 2,6-dichloro-3-{[(1,1-dimethylethyl)amino]sulfonyl}benzoic acid 884-5a, 1-(8-{2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (100 mg, 0.16 mmol, 1 equiv), DIEA (117 μL, 0.66 mmol, 4 equiv) and HATU (62 mg, 0.16 mmol, 1 equiv) following the general procedure for 2,4-dichloro-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-N-methylbenzenesulfonamide (example 880). The crude product was purified by column chromatography on silica gel eluting with 10% 2M NH3 in methanol in ethyl acetate to afford 2,4-dichloro-N-(1,1-dimethylethyl)-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]benzenesulfonamide 5 as a white solid (21 mg, 17% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([S:9][CH2:10][C:11]#[N:12])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.[CH2:24](N)[CH2:25][NH2:26].ClC1C=CC=CC=1Cl.O>C(Cl)Cl>[C:13]1([CH3:23])[CH:14]=[CH:15][C:16]([S:19]([OH:22])(=[O:20])=[O:21])=[CH:17][CH:18]=1.[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([S:9][CH2:10][C:11]2[NH:26][CH2:25][CH2:24][N:12]=2)=[CH:8][C:2]=1[Cl:1]
Reactant: NCCN
Reactant: N#CCSc1ccc(N)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Product: Nc1ccc(SCC2=NCCN2)cc1Cl

Procedure:
The compound, 2-(((4-amino-3-chlorophenyl)-thio)methyl)-2-imidazoline p-toluenesulfonate was prepared by refluxing a mixture of 2-chloro-4-cyanomethylthioaniline (10 g), ethylenediamine p-toluenesulfonate (12 g) and 1,2-dichlorobenzene (150 ml). The reaction mixture was cooled and most of the 1,2-dichlorobenzene decanted off, leaving a viscous residue. Water and methylene chloride were added to the viscous residue and the mixture basified. The methylene chloride layer was separated and approximately 10 g of viscous residue obtained. The residue was dissolved in dimethoxyethane and 5 N hydrochloric acid in isopropanol added. Recrystallization from absolute ethanol containing HCl and then from dimethoxyethane gave 2-(((4-amino-3-chlorophenyl)thio)methyl)-2-imidazoline dihydrochloride, m.p. 195°-199° C.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])(=O)=O)=CC=1>CS(C)=O>[O:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)CCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Solvent: CS(C)=O
Product: COC(=O)CCCCCCCCCC=O
Temperature: 25 °C
Yield: 98.4 %

Procedure:
Dimethylsulfoxide, 178 ml, was heated to 150° C. as nitrogen was bubbled through it. Sodium bicarbonate, 23.7 grams (0.282 mole), was added portionwise while maintaining the reaction mixture temperature at 140°-160° C. Upon completion of addition, 13.6 grams (0.037 mole) of methyl 11-(4-methylphenylsulfonyloxy)undecanoate was added portionwise during a ten minute period. Upon completion of addition the reaction mixture was allowed to cool to ambient temperature, and then it was poured into 600 ml of ice-water. The mixture was stirred until the ice melted, and then it was extracted with three portions of heptane. The combined extracts were washed with three portions of water followed by two portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure yielding 7.8 grams of methyl 11-oxoundecanoate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:12]3[O:13][CH2:14][CH2:15][O:16][C:11]=3[C:10]=2[S:19]([NH2:22])(=[O:21])=[O:20])[CH:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=1[NH:31][CH3:32].Cl>C(O)(C)C>[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][C:12]4[O:13][CH2:14][CH2:15][O:16][C:11]=4[C:10]=3[S:19]([NH2:22])(=[O:21])=[O:20])[CH:5]=[CH:4][N:3]=2)=[CH:26][C:25]=1[NH:31][CH3:32]
Reactant: NS(=O)(=O)c1c(Nc2ccnc(Cl)n2)ccc2c1OCCO2
Reactant: CNc1cc(N)ccc1C
Agent: Cl
Solvent: CC(C)O
Product: CNc1cc(Nc2nccc(Nc3ccc4c(c3S(N)(=O)=O)OCCO4)n2)ccc1C

Procedure:
To a suspension of 2.9 g (7.2 mmol) 6-(2-chloro-pyrimidin-4-ylamino)-2,3-dihydro-benzo[1,4]dioxine-5-sulfonic acid amide and 2.0 g 4,N3-dimethyl-benzene-1,3-diamine (compound of Example 102f)) in 50 ml isopropanol is added 5 ml conc. HCl and the reaction mixture is heated to reflux for 2 hours. Then the reaction mixture is partitioned between 1 l ethyl acetate and 1 l water. The aqueous layer is adjusted to slightly basic pH by adding NaHCO3. The water layer is extracted a second time with 300 ml ethyl acetate, the combined organic phases are dried with Na2SO4 and evaporated. The crude product is purified by chromatography on silica gel eluting with ethyl acetate to give in the order of elution a mixture of the two starting materials and the title compound. The mixture of starting materials is again subjected to the reaction conditions and workup giving another 1.21 g (37% yield) of desired product.
Reaction SMILES: [CH3:1][CH:2]([S:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:3].C(O)(C)C.[OH-].[Na+].Br[CH2:19][CH2:20][CH2:21][Cl:22]>O>[Cl:22][CH2:21][CH2:20][CH2:19][O:11][C:8]1[CH:7]=[CH:6][C:5]([S:4][CH:2]([CH3:1])[CH3:3])=[CH:10][CH:9]=1
Reactant: CC(C)Sc1ccc(O)cc1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Sc1ccc(OCCCCl)cc1
Yield: 20 %

Procedure:
A solution of 4-(1-methylethylthio)phenol (16.83 g., 0.1 mole) in 150 ml. of isopropyl alcohol is treated with 5.2 ml. of 50% sodium hydroxide solution (0.10 mole) and 2 ml. of water. To this mixture is added in one portion 1-bromo-3-chloropropane (16.5 g., 0.105 mole) and the mixture stirred and refluxed for a period of 20 hrs. After cooling, the reaction mixture is concentrated under reduced pressure and the resulting residue extracted with ether. The ethereal extract is filtered, concentrated under reduced pressure and the oily residue distilled affording 4.8 g. (20% yield) of 1-chloro-3-[4-(1-methylethylthio)phenoxy]propane, b.p. 136°-140° C. at 0.6 mm Hg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]=[C:15]([O:17][CH:18]4[CH:22]5[O:23][CH2:24][CH:25]([OH:26])[CH:21]5[O:20][CH2:19]4)[NH:16][C:11]3=[CH:10][C:9]=2[Cl:27])=[CH:4][CH:3]=1.[C:28]([CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)#[CH:29].C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I>[Cl:27][C:9]1[CH:10]=[C:11]2[NH:16][C:15]([O:17][C@H:18]3[C@H:22]4[O:23][CH2:24][C@@H:25]([OH:26])[C@H:21]4[O:20][CH2:19]3)=[N:14][C:12]2=[N:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:29]#[C:28][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:3][CH:4]=1
Reactant: OC1COC2C(Oc3nc4nc(-c5ccc(Br)cc5)c(Cl)cc4[nH]3)COC12
Reactant: C#CC1CCNCC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(C#CC4CCNCC4)cc3)c(Cl)cc2[nH]1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
3R,3aR,6R,6aR)-6-((5-(4-bromophenyl)-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol (25 mg, 0.055 mmol), 4-ethynylpiperidine (10.5 mg, 0.072 mmol), copper (I) iodide (2.1 mg, 0.011 mmol), chloro(tri-tert-butyl)-2-[-(2′amino-1,1′-biphenyl)]palladium (II) (5.7 mg, 0.011 mmol, prepared by a procedure analogous to procedures described in J. AM. CHEM. SOC. 2010, 132, 14073-14075), and cesium carbonate (54.0 mg, 0.166 mmol) were placed under nitrogen in dry, degassed toluene (138 μl) and dimethylacetamide (138 μl). The mixture was stirred at 50° C. for 2 hours. The resulting residue was diluted with dimethylformamide (0.7 mL), then filtered through a filter disc (0.45 micron). The material was purified by reverse phase HPLC purification using 0-100% acetonitrile in water over 10 minutes. The desired product fraction was concentrated under reduced pressure to afford the title compound as an off-white solid. LC-MS: calculated for C25H25ClN4O4 480.16 observed m/e: 481.14 (M+H)+ (Rt 1.43/4 min). 1H NMR δ (ppm) (CD3OD): 7.80 (1H, s), 7.62 (2H, d, J=8.5 Hz), 7.49 (2H, d, J=8.5 Hz), 5.53 (1H, m), 4.95 (1H, t, J=5.5 Hz), 4.46 (1H, t, J=5.0 Hz), 4.27 (1H, m), 4.15 (1H, dd, J=9.5, 6.0 Hz), 4.09 (1H, dd, J=10.0, 4.9 Hz), 3.88 (1H, dd, J=8.0, 7.0 Hz), 3.58 (1H, t, J=8.5 Hz), 3.42 (2H, m), 3.18 (2H, m), 3.09 (1H, m), 2.17 (2H, m), 1.96 (2H, m)
Reaction SMILES: [CH2:1]1[O:23][C:4]2([CH2:9][CH2:8][C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)([N:10]=[C:11]=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.ClC1C=CC(C2(N=C=O)CCC(=O)CC2)=CC=1>>[CH2:2]1[O:3][C:4]2([CH2:5][CH2:6][C:7]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:17][CH:18]=3)([NH:10][CH3:11])[CH2:8][CH2:9]2)[O:23][CH2:1]1
Reactant: CC(C)(C)c1ccc(C2(N=C=O)CCC3(CC2)OCCO3)cc1
Agent: O=C=NC1(c2ccc(Cl)cc2)CCC(=O)CC1
Product: CNC1(c2ccc(C(C)(C)C)cc2)CCC2(CC1)OCCO2
Yield: 94 %

Procedure:
Following the procedure of Example 1, Part G, but substituting an appropriate quantity of 4-(p-t-butylphenyl)-4-isocyanatocyclohexanone ethylene ketal for 4-p-chlorophenyl-4-isocyanatocyclohexanone there is obtained 4-(p-t-butylphenyl)-4-methylaminocyclohexanone ethylene ketal which as a m.p. 118.5°-121° C. (94% yield).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][C:9]=3[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:28][CH2:29][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C=O)C>[CH:1]1([C:7]2[C:8]3[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][C:9]=3[N:10]([CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cc2[nH]c(-c3ccccc3)c(C3CCCCC3)c2s1
Reactant: ClCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccccc1)n2CCN1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution (0.1 M) of methyl 6-cyclohexyl-5-phenyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in DMF at 0° C. was treated with NaH (1.5 eq., 60% dispersion in mineral oil), and the suspension was stirred at RT for 30 min then it was treated with 1-(2-chloroethyl)pyrrolidine (3 eq.). The mixture was heated to 80° C. for 16 h then it was quenched with ammonium chloride (saturated solution), basified with aqueous NaOH (1 N) and extracted with AcOEt. The combined organic phase was washed with brine and dried. Evaporation of the solvent gave a residue that was purified by flash chromatography on silica gel (5:95 MeOH/DCM) to afford methyl 6-cyclohexyl-5-phenyl-4-(2-pyrrolidin-1-ylethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylate as a solid that was dissolved in MeOH. The resulting solution (0.06 M) was treated with aqueous NaOH (2 N solution, 16 eq.) then the mixture was heated to reflux for 2 h. After cooling down, the mixture was concentrated and the residue was purified by RP-HPLC (Conditions: Waters X-TERRA MS C18, 5 micron, 10×100 mm; flow: 5 mL/min; Gradient: A: H2O+0.05% TFA; B: MeCN+0.05% TFA; 60% A isocratic for 2 min, linear to 60% A in 3 min, linear to 50% in 2 min then linear to 40% A in 3 min) to afford the title compound (62%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:16]>CCOCC.CO>[NH2:16][C:6]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: N
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(-c2c(N)ncnc2Cl)cc1

Procedure:
To a solution of 4,6-dichloro-5-(4-methylphenyl)pyrimidine (4.14 g) in ether (20 ml) is added 27% ammonia in methanol solution (30 ml), and the mixture is reacted at room temperature for three days in a sealed tube. The mixture is evaporated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=10:1~ethyl acetate only) to give 4-amino-6-chloro-5-(4-methyl-phenyl)pyrimidine (1.89 g).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6]Cl)[CH2:2]Cl.[Na].[C:9]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[O:4]1[CH2:5][CH2:6][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:9]([O:17][CH2:18][CH3:19])=[O:16])[CH2:2][CH2:1]1
Reactant: ClCCOCCCl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Product: CCOC(=O)C1(C(=O)OCC)CCOCC1

Procedure:
From J. Chem. Soc. 1930, pages 2525 to 2530, a process for preparing tetrahydropyran-4-carboxylic acid esters is known in which β,β'-dichlorodiethyl ether is reacted with the sodium salt of diethyl malonate to give diethyl tetrahydropyran-4,4-dicarboxylate, and this is converted to tetrahydropyran-4-carboxylic acid via tetrahydropyran-4,4-dicarboxylic acid and finally esterified to give the desired tetrahydropyran-4-carboxylic acid ester.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10]/[CH:11]=[C:12](/[CH2:14][CH2:15][C:16]([OH:18])=[O:17])\[CH3:13])[C:5]([OH:19])=[C:4]2[C:20]([O:22][CH2:23][C:3]=12)=[O:21].C[O-].[Na+:26]>ClCCl>[CH3:1][C:2]1[C:3]2[CH2:23][O:22][C:20](=[O:21])[C:4]=2[C:5]([OH:19])=[C:6]([CH2:10]/[CH:11]=[C:12](/[CH2:14][CH2:15][C:16]([O-:18])=[O:17])\[CH3:13])[C:7]=1[O:8][CH3:9].[Na+:26]
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)[O-])C(=O)OC2

Procedure:
Mycophenolic acid (3.20 g, 10 mmol) was dissolved in dichloromethane (64 ml). To this solution sodium methoxide (9 mmol, 1.67 ml of its 30% methanolic solution) was added under stirring. The formed suspension was diluted with 256 ml of dichloromethane. After 2 hours stirring at room temperature the solid was filtered off, dried at normal pressure at room temperature. Polymorphism was determined by X-ray diffraction. The obtained material was form M22.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O-])=[S:7])([O-:3])=[O:2].[NH2:13][C:14]([NH2:16])=[NH:15].C(O)C>O1CCCC1>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:15][C:14]([NH2:16])=[NH:13])=[S:7])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1C([O-])=S
Reactant: N=C(N)N
Solvent: C1CCOC1
Solvent: CCO
Product: N=C(N)NC(=S)c1ccccc1[N+](=O)[O-]

Procedure:
The reactions of Equation 57 above can be run by methods known in the art. Thus, in reaction 57a, a 2-nitrothiobenzoate of Formula (LXXV) is reacted with guanidine in a solvent such as ethanol or tetrahydrofuran at 0° to about 30° C. for 2 to 120 hours to form a 2-nitrothiobenzoylguanidine of Formula (LXXVI), according to the teachings of J. Goerdeler and A. Fincke, Chem. Ber., 89, 1033 (1956). In reaction 57b, LXXVI is cyclized by reaction with bromine in methanol at 0° to 60° C. for 0.5 to 3 hours to form a 3-amino-5-(2-nitrophenyl)-1,2,4-thiadiazole of Formula (LXXVII), according to the teachings of ibid. In reaction 57c, LXXVII is reacted with sodium nitrite in hydrochloric acid or hydrobromic acid, in the presence of copper powder, at -10° to 60° C. for 0.5 to 5 hours to form Xq' via Sandmeyer reaction, according to the teachings of F. Kurzer and S. Taylor, J. Chem. Soc., 3234 (1960). And in the last reaction, Xq' is reacted with sodium methoxide, sodium ethoxide or sodium methylmercaptide in a solvent such as methanol, ethanol or tetrahydrofuran at reflux for 0.5 to 5 hours to form Xq", according to the teachings of ibid.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[F:15][CH:16]([F:41])[C:17]1[C:21]([C:22]([NH:24][C:25]2[C:33]3[CH:32]([CH2:34][CH3:35])[O:31][C:30]([CH2:38][CH3:39])([CH2:36][CH3:37])[C:29]=3[CH:28]=[CH:27][CH:26]=2)=O)=[CH:20][N:19]([CH3:40])[N:18]=1>O1CCOCC1>[F:15][CH:16]([F:41])[C:17]1[C:21]([C:22](=[S:2])[NH:24][C:25]2[C:33]3[CH:32]([CH2:34][CH3:35])[O:31][C:30]([CH2:38][CH3:39])([CH2:36][CH3:37])[C:29]=3[CH:28]=[CH:27][CH:26]=2)=[CH:20][N:19]([CH3:40])[N:18]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCC1OC(CC)(CC)c2cccc(NC(=O)c3cn(C)nc3C(F)F)c21
Solvent: C1COCCO1
Product: CCC1OC(CC)(CC)c2cccc(NC(=S)c3cn(C)nc3C(F)F)c21
Yield: 61 %

Procedure:
In a microwave sealable tube, P2S5 (13 mg, 0.061 mmol, 0.5 eq) is added to a solution of 3-(difluoromethyl)-1-methyl-N-(1,1,3-triethyl-1,3-dihydro-2-benzofuran-4-yl)-1H-pyrazole-4-carboxamide (45 mg, 0.121 mmol, 1 eq) in 2 ml of dioxane. The tube is sealed and the reaction is microwaved 20 min at 130° C. The resulting solution is filtered through alumina and washed with dioxane. The solvent is evaporated and the residue purified by chromatography on silica gel to give pure material (61%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.[NH4+].[Cl-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][CH2:19][C:20]2[CH:27]=[CH:26][C:23]([CH3:24])=[CH:22][CH:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: Cc1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(COCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)piperidine (328 mg, 1.43 mmol) in anhydrous THF (10 mL) was cooled to 0° C., and NaH (60% dispersion in oil, 69 mg, 1.71 mmol, 1.2 equiv.) was added all at once. Alkoxide formation was effected by stirring at room temperature for 2 h under N2, then 4-methylbenzyl bromide (317 mg, 1.71 mmol, 1.2 equiv.) was added. The mixture was stirred at room temperature overnight. Saturated aqueous NH4Cl solution was added, and the product was extracted into EtOAc. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by CC (SiO2, EtOAc/hexane 1:4) to afford 1-(tert-butoxycarbonyl)-4-[2-(4-methylbenzyloxy)ethyl]piperidine (470 mg, 99%) after evaporation. 1H NMR (CDCl3, 400 MHz) δ 7.21 (d, 2H, J=8.0 Hz), 7.14 (d, 2H, J=8.0 Hz), 4.45 (s, 2H), 4.04 (d, 2H, J=13.6 Hz), 3.48 (t, 2H, J=6.4 Hz), 2.66 (t, 2H, J=13.6 Hz), 2.32 (s, 3H), 1.60 (m, 2H), 1.54 (m, 3H), 1.44 (s, 9H), 1.10(m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:7][C:5]([NH2:6])=[C:4]([N+:17]([O-])=O)[CH:3]=1.Cl>[Zn].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]([NH2:6])=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=1
Reactant: Nc1cc(Oc2ccc(F)cc2)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: CCO
Product: Nc1cc(Cl)c(Oc2ccc(F)cc2)cc1N
Temperature: 85 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
To a solution of 4-fluorophenol (1.63 g, 14.54 mmol) in DMSO (20 ml) was added 4,5-dichloro-2-nitroaniline (3 g, 14.49 mmol) and potassium carbonate (4 g, 28.94 mmol) with stirring overnight at 90° C. The reaction was then quenched by the addition of water (200 ml), extracted with ethyl acetate (3×100 ml) and dried over anhydrous magnesium sulfate. The solids were filtered out and the filtrate was concentrated under vacuum to give a residue, which was purified by a silica gel column with 2% to 10% ethyl acetate in petroleum ether to produce 4-chloro-5-(4-fluorophenoxy)-2-nitroaniline as a yellow solid (2.0 g, 49%). Next, to a solution of 4-chloro-5-(4-fluorophenoxy)-2-nitroaniline (2 g, 7.08 mmol) and hydrogen chloride (1.8 ml) and ethanol (25 ml) was added Zn powder (2.8 g) in portions at room temperature. The resulting solution was stirred for 4 h at 85° C. and then concentrated under vacuum. The residue was dissolved in water (300 ml), pH adjusted to 8 with aqueous sodium bicarbonate and extracted with ethyl acetate (3×80 ml). The combined organic layers were dried and concentrated under reduced pressure to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 4-chloro-5-(4-fluorophenoxy)benzene-1,2-diamine as red oil (1 g, 83%). Finally, a solution of 4-chloro-5-(4-fluorophenoxy)benzene-1,2-diamine (400 mg, 1.58 mmol) in 2,2-difluoro-3,3-dimethylbutanoic acid (4 ml) was stirred overnight at 95° C. in an oil bath. Then the solution was poured into water (100 ml), adjusted to pH 8 with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-(4-fluorophenoxy)-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a white solid (19.9 mg, 3%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=2)[C:4](=[O:16])[CH2:3]1.[Br:17]Br>ClCCl>[Br:17][C:3]1[C:2]([CH3:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=2)[C:4]=1[OH:16]
Reactant: BrBr
Reactant: CC1CC(=O)c2ccc(S(C)(=O)=O)cc2C1
Solvent: ClCCl
Product: Cc1cc2cc(S(C)(=O)=O)ccc2c(O)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methyl-6-(methylsulfonyl)-3,4-dihydronaphthalen-1(2H)-one (7.64 g, 32.06 mmol) in dichloromethane (200 mL) at room temperature was added a solution of bromine (3.38 mL, 65.72 mmol) in dichloromethane (5 mL) over 30 minutes to give an orange mixture. The reaction mixture was stirred at room temperature for 2 hours, then more bromine (0.3 mL) was added and stirring continued for 1 hour. The reaction mixture was concentrated and co-evaporated with dichloromethane and dried under house vacuum. The resulting off-white residue was suspended in acetonitrile and cooled to −40° C. 1,8-Diazabicyclo[5.4.0]dunde-7-ene (7.19 mL, 48.09 mmol) was added over 5 minutes and the reaction mixture was warmed to room temperature overnight. The reaction mixture was concentrated, diluted with ethyl acetate, washed with dilute acetic acid solution, brine and dried (MgSO4) and filtered. Concentration and purification by flash column chromatography (silica gel, 20-60% ethyl acetate/hexanes) gave an impure product. Repurification by flash column chromatography (silica gel, 40% ethyl acetate/hexanes) gave the desired product. LCMS-ESI+ (m/z): [M−H]− calcd for C12H10BrO3S: 314.2. Found: 313.2, 315.1.