Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[C@@H:10]([CH2:18][N:19]([CH:36]([CH3:38])[CH3:37])[C:20](=[O:35])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[CH2:9]1)C1C=CC=CC=1.[CH3:39][O:40][CH2:41][CH2:42][CH2:43][O:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][C:53]=1[O:54][CH3:55])[C:48](O)=[O:49].CC#N.O.CC#N>O>[CH:36]([N:19]([CH2:18][C@@H:10]1[C@H:11]([CH2:13][N:14]([CH:15]([CH3:17])[CH3:16])[C:48](=[O:49])[C:47]2[CH:51]=[CH:52][C:53]([O:54][CH3:55])=[C:45]([O:44][CH2:43][CH2:42][CH2:41][O:40][CH3:39])[CH:46]=2)[CH2:12][NH:8][CH2:9]1)[C:20](=[O:35])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=1)([CH3:38])[CH3:37]
Reactant: COCCCOc1cc(C(=O)N(C[C@H]2CN(Cc3ccccc3)C[C@H]2CNC(C)C)C(C)C)ccc1OC
Reactant: COCCCOc1cc(C(=O)O)ccc1OC
Solvent: O
Solvent: CC#N
Product: COCCCOc1cc(C(=O)N(C[C@H]2CNC[C@H]2CN(C(=O)c2ccc(OC)c(OCCCOC)c2)C(C)C)C(C)C)ccc1OC

Procedure:
The title compound is prepared analogously as described in Example 361 by coupling N-[(3R*,4R*)-1-benzyl-4-(isopropylamino-methyl)-pyrrolidin-3-ylmethyl]-N-isopropyl4-methoxy-3-(3-methoxy-propoxy)-benzamide and 3-(3-methoxy-propoxy)-4-methoxy-benzoic acid in step J. MS (LC-MS): 658.3 [M+H]+; tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/2.5 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 5.20 min.
Reaction SMILES: C[O-].[Na+].C([O:6][C:7](=O)[CH:8]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[C:9](OCC)=[O:10])C.Cl.[CH:23]([NH2:25])=[NH:24]>CO>[C:17]1([CH3:20])[CH:18]=[CH:19][C:14]([C:8]2[C:9]([OH:10])=[N:24][CH:23]=[N:25][C:7]=2[OH:6])=[CH:15][CH:16]=1
Reactant: N=CN
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-c2c(O)ncnc2O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium methylate (17 g) was dissolved in methanol (600 ml) at 0° C. 2-p-Tolyl-malonic acid diethyl ester (24.5 ml, commercially available from Aldrich), dissolved in 150 ml methanol, was added within 30 min. Stirring was continued for 1 h while slowly warming the mixture to rt. Formamidine hydrochloride (9.9 g, commercially available from Fluka) was added and stirring was continued for 16 h. The solvent was evaporated and 2 M hydrochloric acid (200 ml) was added to the residue followed by slow addition of 10 M sodium hydroxide to adjust the pH to 5. The precipitated product was filtered off and washed subsequently with water and diethylether and dried to give 5-p-tolyl-pyrimidine-4,6-diol (17.7 g). 1H-NMR (d6-DMSO): 8.0(s, 1H); 7.4(d, 2H); 7.1(d, 2H); 2.25(s, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[CH3:14][S:15][C:16]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[CH:21][C:17]=1[C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[CH3:14][S:15][C:16]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=2)=[CH:21][C:17]=1[C:18]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:19]
Reactant: CSc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1C(=O)Cl
Reactant: OC1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CSc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1C(=O)OC1CCOC1
Reaction time: 8 h

Procedure:
3-Hydroxytetrahydrofuran (0.04 mole), toluene (50 ml) and triethylamine (0.04 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. A solution of 2-methylthio-5-(4-trifluoromethylphenoxy)benzoyl chloride (0.04 mole) in toluene (20 ml) is slowly added at room temperature with stirring. After the addition is completed, stirring is continued for a period of about eight hours. After this time, the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure leaving a residue. This residue is purified by silica gel chromatography using toluene and ethyl acetate/toluene mixture as the eluant to yield the desired product 3-tetrahydrofuryl 2-methylthio-5-(4-trifluoromethylphenoxy)benzoate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[C:5]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[NH:14]C(=O)C1C=CC=CC=1)=[O:6].[CH3:27][NH:28][CH3:29].[OH-].[K+]>C(Cl)Cl.O>[NH2:14][C:8]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=1[C:5]([C:4]1[CH:23]=[CH:24][CH:25]=[CH:26][C:3]=1[CH2:2][N:28]([CH3:29])[CH3:27])=[O:6]
Reactant: O=C(Nc1ccc(Cl)cc1C(=O)c1ccccc1CBr)c1ccccc1
Reactant: CNC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CN(C)Cc1ccccc1C(=O)c1cc(Cl)ccc1N
Reaction time: 16 h

Procedure:
To a solution of N-[4-chloro-2-(2-methyl-benzoyl)-phenyl]-benzamide (5.1 g, 14.6 mmol) and N-bromosuccinimide (2.85 g, 16 mmol) in CCl4 (150 mL) was added 2,2′-azobisisobutrylnitrile (0.2 g, 1.5 mmol). The solution was refluxed for 4 h. The solution was then cooled to room temperature, diluted with CH2Cl2 (150 mL) and washed with H2O (3×50 mL). The organic portion was dried over Na2SO4 and evaporated to dryness in vacuo to provide N-[2-(2-bromomethyl-benzoyl)-4-chloro-phenyl]-benzamide (4.6 g, 74%). A solution of the benzamide (2.3 g, 5.4 mmol) in CH2Cl2 (50 mL) was saturated with dimethylamine, stirred for 16 h and evaporated to dryness in vacuo. The resulting residue was dissolved in MeOH (50 mL) and KOH (0.9 g, 16 mmol) in H2O (5 mL) was added. The solution was refluxed for 24 h. The solution was concentrated in vacuo and then diluted with EtOAc (150 mL) and H2O (50 mL). The organic portion was washed with H2O (3×50 mL), dried over Na2SO4 and purified by column chromatography (silica gel, 18:80.2 MeOH:CH2Cl2:NHOH) to provide lq (0.9 g, 53% yield) MS m/z=289 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:18])[CH2:16][Br:17])=[CH:11][C:10]=1[CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])[CH3:30]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si:32]([C:29]([CH3:31])([CH3:30])[CH3:28])([CH3:34])[CH3:33])[CH2:16][Br:17])=[CH:11][C:10]=1[CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCc1cc([C@H](CBr)O[Si](C)(C)C(C)(C)C)ccc1OCc1ccccc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 5. Excess TBSCl and a higher reaction temperature were used.
Reaction SMILES: [CH3:1][N:2]([N:4]=[N:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[Se:8][C:7]=1[C:15]([O:17]CC)=[O:16])[CH3:3].[OH-].[Na+].Cl>CO.O>[CH3:3][N:2]([N:4]=[N:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[Se:8][C:7]=1[C:15]([OH:17])=[O:16])[CH3:1]
Reactant: CCOC(=O)c1[se]c2ncccc2c1N=NN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)N=Nc1c(C(=O)O)[se]c2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3-[(dimethylamino)diazenyl]selenopheno[2,3-b]pyridine-2-carboxylate (170 mg, 0.52 mmol), prepared as described in Example 6 step b) in methanol (10 mL) was added a solution of sodium hydroxide (83 mg, 2.08 mmol) in water (2 mL) and stirred at room temperature (rt) for 2 h. The mixture was diluted with ice cold water and acidified with dil. HCl. The mixture was stirred for 30 min and extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (95:5) as eluents to give the product, which was recrystallized from chloroform-methanol-hexane as a light brown color solid (30 mg, 20%), mp 172-174° C. IR (KBr) νmax 3427, 3025, 2919, 1707, 1265, 1218, 1013, 863 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 13.09 (1H, br s, —COOH), 8.65-8.69 (2H, m, H-4,6), 7.53 (1H, dd, J=8.2, 4.6 Hz, H-5), 3.67 (3H, s, —NCH3), 3.29 (3H, s, —NCH3); LC-MS (positive ion mode): m/z 319, 321 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[F:11]F.C(=O)([O-])O.[Na+].C(OCC)(=O)C>FC(F)(F)C(O)=O>[NH2:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][C:5]([F:11])=[CH:6][N:7]=1
Reactant: NC(=O)c1nccnc1N
Reactant: FF
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: NC(=O)c1nc(F)cnc1N
Temperature: 0 °C

Procedure:
In 9 mL of trifluoroacetic acid was dissolved 0.3 g of 3-amino-2-pyrazinecarboxamide. At an ice-cooled temperature, 10% fluorine gas (a fluorine gas diluted with nitrogen gas) was introduced into the solution at a rate of 45 ml per minute for a period of 22 minutes. After stirring the mixture at an ice-cooled temperature for 17 minutes, the temperature was elevated to room temperature. The reaction mixture was added to a mixture of 30 mL of saturated aqueous solution of sodium hydrogen carbonate and 30 mL of ethyl acetate, and the organic layer was separated. The remaining aqueous layer was acidified with 6 mol/L hydrochloric acid and then extracted with 20 ml of ethyl acetate. The organic layers thus obtained were united, washed successively with 10 mL of water and 10 mL of saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=2:1] to obtain 0.015 g of 3-amino-6-fluoro-2-pyrazinecarboxamide as a light yellow-colored solid product.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1)([O-:19])=[O:18]>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([C:9]2[CH2:10][C:11]3[C:16]([CH:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: C1=Cc2ccccc2C1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(C2=Cc3ccccc3C2)cc1
Temperature: 25 °C
Yield: 40.9 %

Procedure:
20 ml of triethylamine, 2.2 g (20 mmole) of indene, 4.98 g (20 mmole) of para-nitro iodo-benzene and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled to room temperature and treated with 100 ml of ethanol. The crystalline yellow precipitate was isolated, recrystallized from ethanol, washed with cold ethanol and dried under vacuum to obtain 1.94 g (41%) of 2-(4-nitro-phenyl)-indene.
Reaction SMILES: C([O:8][C:9](=[O:44])[C@@H:10]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[CH2:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[S:20]2(=[O:35])=[O:34])[CH:13]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.CCO.[Pd]>[C:40]([O:39][C:37]([NH:36][C@@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[CH2:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[S:20]2(=[O:34])=[O:35])[CH:13]=1)[C:9]([OH:44])=[O:8])=[O:38])([CH3:41])([CH3:43])[CH3:42]
Reactant: [H][H]
Reactant: COc1ccc(CN2C(=O)CN(Cc3cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc4ccccc4)c3)S2(=O)=O)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)CN(Cc3cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c3)S2(=O)=O)cc1
Reaction time: 0.5 h

Procedure:
The title D compound, (S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-propionic acid benzyl ester (127 mg, 0.20 mmol) is dissolved in EtOAc/EtOH (50:50) (56 mL) and 10% palladium on carbon (35 mg) is added and the mixture is treated with 45 psi of hydrogen on a Parr shaker apparatus. After two 90 min runs, starting material is not completely consumed, so another aliquot of 10% palladium on carbon (35 mg) is added and after shaking at 45 psi hydrogen for 30 min, the reaction is complete. The mixture is filtered through celite, the filtrate is concentrated and dried to give (S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-propionic acid as a white foam: [M+1]+=534.
Reaction SMILES: [C:1]1([CH2:11][C:12]([CH2:21][C:22]2[C:31]3[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)(C(OC)=O)[C:13]([O:15]C)=[O:14])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)CCC.O>[C:1]1([CH2:11][CH:12]([CH2:21][C:22]2[C:31]3[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)[C:13]([OH:15])=[O:14])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(Cc1cccc2c1CCCC2)(Cc1cccc2c1CCCC2)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: O=C(O)C(Cc1cccc2c1CCCC2)Cc1cccc2c1CCCC2
Yield: 78.7 %

Procedure:
A solution of 3.1 g (7.4 mmol) of dimethyl bis-(5,6,7,8-tetrahydro-1-naphthylmethyl)-malonate in 20 mL n-butanol was treated with a solution of 1.24 g (22 mmol) of potassium hydroxide (KOH) in 20 mL H2O and the solution heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in H2O and acidified with dilute HCl to the Congo red color change. The mixture was extracted with EtOAc and the EtOAc washed with 1N HCl, and then a saturated solution of NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure gave 2.03 g of the product. A small amount recrystallized from EtOAc/hexane had mp 144-146° C. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]([O:36][C:37]([N:39]1[CH2:42][CH2:41][C@H:40]1[CH2:43][OH:44])=[O:38])([CH3:35])([CH3:34])[CH3:33].[Br:45][C:46]1[CH:47]=[N:48][CH:49]=[C:50](O)[CH:51]=1>C1COCC1>[Br:45][C:46]1[CH:51]=[C:50]([O:44][CH2:43][C@@H:40]2[CH2:41][CH2:42][N:39]2[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH:49]=[N:48][CH:47]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: Oc1cncc(Br)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Reaction time: 0.17 h

Procedure:
Triphenylphosphine (4.01 g, 15.3 mmol) and DEAD (2.43 mL, 15.3 mmol) were dissolved in 30 mL of THF at 0° C., and the mixture was stirred for 10 minutes. Samples of 1-t-butyloxycarbonyl-2-(S)-azetidinemethanol (2.86 g, 15.3 mmol, Step 7c above) and 3-bromo-5-hydroxypyridine.(1.51 g, 10.2 mmol, Step 10c above) were added, and the mixture was stirred for 40 hours at room temperature. The volatile components were removed under vacuum, and the residue was triturated with hexane. The separated hexane fraction was concentrated, and the residue was chromatographed (silica gel; hexane/ether, 10:1 to 10:2) to afford 5-bromo-3-((1-t-butyloxycarbonyl-(2S)-azetidinyl)methoxy)pyridine as a colorless oil (1.669 g): 1H NMR (CDCl3, 300 MHz) δ1.42 (s, 9H), 2.31 (m, 2H), 3.89 (m, 2H), 4.12 (m, 1H), 4.322 (m, 1H), 4.52 (m, 1H), 7.43 (m, 1H), 8.29 (m, 2H); MS (CI/NH3) m/z 344 (M+H)+. The 5-bromo-3-(2-(1-BOC-2-(S)-azetidinyl)methoxy)pyridine was treated with with 4 M HCl in dioxane to give the free base of the title compound. This was converted to the dihydrochloride salt and recrystallized from methanol/ether to provide the title compound: mp 163-165° C.; [α]25D −5.1 (c 0.57, methanol); 1H NMR (D2O, 300 MHz) δ8.36 (d, J=1.8 Hz, 1H), 8.32 (d, J=2.6 Hz, 1H), 7.84 (dd, J=1.8, 2.6 Hz, 1H), 4.98-4.90 (m, 1H), 4.43 (d, J=4.0 Hz, 2H), 4.20-4.02 (m, 2H), 2.67 (q, J=8.5 Hz, 2H); MS (CI/NH3) m/z 243/246 (M+H)+, 260/262 (M+NH4)+. Anal. calcd for C9H13N2OBrCl2: C, 34.21; H, 4.15; N, 8.86. Found: C, 34.18; H, 4.17; N, 8.89.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:12]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[C:14]([O:22][CH3:23])[N:13]=1.O>CN(C)C=O>[CH3:23][O:22][C:14]1[N:13]=[C:12]([S:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(OC)nc1F
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC)nc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a stirred mixture of 0.8 g (0.0161 mol) of 50% sodium hydride (in mineral oil), which had been washed with hexanes, in 20 mL dry dimethylformamide cooled to -5° under nitrogen was added dropwise 1.9 mL (0.0161 mol) benzyl mercaptan The suspension was stirred at room temperature for 1 hour, cooled to 0°, and a solution of 3.2 g (0.0147 mol) of the product of Example 2 in 20 mL dry dimethylformamide was added dropwise. After warming to room temperature, the solution was poured into water and extracted with ether. The combined organic layers were washed with water and with brine, dried over magnesium sulfate, and evaporated to an oil which was purified by flash chromatography to afford 3.0 g (64%) of a yellow solid: m.p. 67°-71°; NMR (CDCl3, 200 MHz) 3.88 (3H, s), 3.96 (3H, s), 4.46 (2H, s), 6.44 (1 H, d, J=9 Hz), 7.2-7.5 (5H, m), 8.1 (1H, d, J=9 Hz); IR (nujol) 1700, 1580, 1305, 1255 cm-1.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.CCO[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:3]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(Br)nc1
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(Br)nc1)C(=O)OCC
Yield: 88.8 %

Procedure:
6-bromopyridin-3-amine (40.3 g, 0.233 mol) and diethyl ethoxymethylene malonate (56.5 g, 0.261 mol) were added in 400 mL of ethanol, and reacted under reflux for 5 h, cooled and precipitated a solid. The reaction mixture was suction filtered and the resulting solid was washed with petroleum ether to give 71 g of a pale yellow solid.
Reaction SMILES: CN([C:4]([O:8][N:9]1N=NC2C=CC=[N:15][C:10]1=2)=[N+:5](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]([N:28]([CH2:32][CH3:33])[CH:29]([CH3:31])C)([CH3:27])C.N1CCCC(C(O)=O)C1>CN(C)C=O>[CH2:33]1[CH:31]2[CH:27]([C:4]3[O:8][N:9]=[C:10]([NH2:15])[N:5]=3)[CH2:25][N:28]([CH2:29]2)[CH2:32]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)C1CCCNC1
Solvent: CN(C)C=O
Product: Nc1noc(C2CN3CCC2C3)n1
Temperature: 25 °C

Procedure:
Under argon and at RT, HATU (1.2 eq.), N,N-diisopropylethylamine (2.2 eq.) and the appropriate N′-hydroxyimidamide (1.1 eq.) are added to a solution of the appropriate piperidine-3-carboxylic acid in dimethylformamide (10 ml/mmol). The reaction mixture is stirred at RT until the formation of the intermediate has gone to completion and then stirred further at 120° C. until the desired product is formed from this intermediate. The reaction mixture is then purified by preparative HPLC.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:15]1([NH:20][S:2]([C:5]2[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=2)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCC1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cc(S(=O)(=O)NC2CCCC2)ccc1F
Yield: 90 %

Procedure:
5-Chlorosulfonyl-2-fluoro-benzoic acid (A, 0.506 g, 0.0021 mol), cyclopentylamine (B, 0.1806 g, 0.00212 mol) and diisopropylethyl amine (DIEA, 1.1 mL, 0.00636 mol) in CH2Cl2 were stirred at room temperature overnight. The solvent was evaporated and the crude product was purified by silica gel chromatography (MeOH containing 10% AcOH)/CH2Cl2) to give 5-cyclopentylsulfamoyl-2-fluoro -benzoic acid (C, 0.55 g, 90%). After drying overnight under vacuum, C (0.48 g, 0.0016 mol) in SOCl2 (5 mL) was heated at 80° C. for 3 hours, after which the SOCl2 was evaporated and the residue was dried overnight. The residue was then dissolved in tetrahydrofuran (5 mL), 3,4-Difluoro-phenylamine (D, 0.216 g, 0.00167 mol) was added followed by diisopropylethyl amine (0.5 mL). The mixture was heated to 70° C. overnight. The solvent was evaporated, followed by ethyl acetate extraction. After purification by silica gel chromatography (ethyl acetate/hexane), 0.3 g (45%) of 5-cyclopentylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide (DVR-56) was obtained.
Reaction SMILES: C12(COC3C(Cl)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[C:24]12([CH2:34][O:35][C:36]3[CH:44]=[CH:43][C:39]([C:40]([OH:42])=O)=[CH:38][C:37]=3[C:45]([F:48])([F:47])[F:46])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2.[N:49]1([S:55]([NH2:58])(=[O:57])=[O:56])[CH2:54][CH2:53]OC[CH2:50]1.N1(S(N)(=O)=O)CCC1>>[C:24]12([CH2:34][O:35][C:36]3[CH:44]=[CH:43][C:39]([C:40]([NH:58][S:55]([N:49]4[CH2:54][CH2:53][CH2:50]4)(=[O:57])=[O:56])=[O:42])=[CH:38][C:37]=3[C:45]([F:47])([F:48])[F:46])[CH2:25][CH:26]3[CH2:32][CH:30]([CH2:29][CH:28]([CH2:27]3)[CH2:33]1)[CH2:31]2
Reactant: NS(=O)(=O)N1CCOCC1
Reactant: O=C(O)c1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C(F)(F)F)c1
Agent: NS(=O)(=O)N1CCC1
Agent: O=C(O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C(F)(F)F)c1

Procedure:
Following the procedure as described in Example 98 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-3-(trifluoromethyl)benzoic acid and morpholine-4-sulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a colorless solid (0.05 g, 22%): 1H NMR (300 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.26-8.22 (m, 2H), 7.38-7.35 (m, 1H), 4.05 (t, J=7.7 Hz, 4H), 3.76 (s, 2H), 2.20-2.09 (m, 2H), 1.99 (br s, 3H), 1.75-1.63 (m, 12H); MS (ES−) m/z 471.3 (M−1); MS (ES+) m/z 473.2 (M+1).
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH2:2].ClCC=CC1C=CC=CC=1.C(N(CC)CC)C.[F:28][C:29]([F:48])([C:33]([F:47])([F:46])[C:34]([F:45])([F:44])[C:35]([F:43])([F:42])[C:36]([F:41])([F:40])[CH:37]([F:39])[F:38])[C:30](Cl)=[O:31]>C(C1C=CC=C(C(C)(C)C)C=1O)(C)(C)C.C(#N)C>[CH:1]([N:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:30](=[O:31])[C:29]([F:28])([F:48])[C:33]([F:46])([F:47])[C:34]([F:44])([F:45])[C:35]([F:42])([F:43])[C:36]([F:40])([F:41])[CH:37]([F:38])[F:39])=[CH2:2]
Reactant: C=CNCc1ccccc1
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: ClCC=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CN(Cc1ccccc1)C(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 0 °C
Yield: 65.1 %

Procedure:
300 ml of acetonitrile, 33.9 g (0.3 mol) of vinylbenzylamine (synthesized by the method described in "Kobunshi Gakkai Yokoshu", vol. 26, page 834 (G3 C-07) (1977) from chloromethylstyrene (meta:para=about 6:4); p.b.: 82° C./1.5 mm Hg), 30.3 g (0.3 mol) of triethylamine, and 0.5 g of 2,6-di-t-butylphenol were charged into a 500-ml three-necked flask equipped with a stirrer, and a calcium chloride tube, and the mixture was then cooled with ice water. 109.5 g (0.3 mol) of the 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoro-n-heptanoic acid chloride synthesized in Synthesis Example 1 was added dropwise, with stirring and ice-cooling. Next, the mixture was stirred for 1 hour at room temperature, and the deposited triethylamine hydrochloride was filtered off. The filtrate was distilled under reduced pressure to remove the acetonitrile, 200 ml of ethyl acetate was added to the remainder to be dissolved, and white insolubles were filtered off. The filtrate was distilled under reduced pressure to be condensed, and 300 ml of n-hexane was added to the remainder, followed by cooling. The deposited white crystals were filtered and dried in vacuo at room temperature, thus producing 90.1 g (yield: 65.2%; m.p.: 53° to 57° C.) of 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoro-n-heptanoic acid vinylbenzylamide.