Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]([CH3:10])([CH3:9])[C:7](=[O:11])[NH:6][C:5]1=[O:12].[ClH:13].[N:14]1([C:19](N)=[NH:20])C=CC=N1>CC#N>[ClH:13].[CH3:10][C:8]1([CH3:9])[N:4]([CH2:3][CH2:2][NH:1][C:19]([NH2:20])=[NH:14])[C:5](=[O:12])[NH:6][C:7]1=[O:11]
Reactant: N=C(N)n1cccn1
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Agent: Cl
Solvent: CC#N
Product: CC1(C)C(=O)NC(=O)N1CCNC(=N)N

Procedure:
1-(2-Amino-ethyl)-5,5-dimethyl-imidazolidine-2,4-dione (5.00 g., 29 mmol) and pyrazole-1-carboxamidine hydrochloride (4.28 g., 29 mmol) were added to MeCN (100 mL) and heated at reflux for 16 h. The mixture was cooled, the supernatent MeCN layer was decanted off, and the residual gum was washed with MeCN twice. The gum was dissolved in MeOH (100 mL) and concentrated to give the product as a foam. Yield=7.29 g., 100%.
Reaction SMILES: ClCCl.[Cl:4][C:5]1[CH:31]=[CH:30][C:8]([CH2:9][N:10]2[CH:15]=[N:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[N:12][C:11]2=[O:29])=[CH:7][C:6]=1[O:32]C.B(Br)(Br)Br>O>[Cl:4][C:5]1[CH:31]=[CH:30][C:8]([CH2:9][N:10]2[CH:15]=[N:14][C:13]([N:16]3[CH2:17][CH2:18][N:19]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH2:20][CH2:21]3)=[N:12][C:11]2=[O:29])=[CH:7][C:6]=1[OH:32]
Reactant: COc1cc(Cn2cnc(N3CCN(c4ccc(F)cc4)CC3)nc2=O)ccc1Cl
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)ncn1Cc1ccc(Cl)c(O)c1
Reaction time: 3 h
Yield: 62.2 %

Procedure:
To a dichloromethane solution (1.0 mL) of 1-(4-chloro-3-methoxybenzyl)-4-[4-(4-fluorophenyl)piperazin-1-yl]-1,3,5-triazin-2(1H)-one (10.0 mg, 0.0232 mmol) synthesized in Synthesis Example 141, 1M boron tribromide (1.00 mL, 1.00 mmol) was added at −78° C. and while elevating gradually the temperature of the resultant mixture to room temperature, the mixture was stirred for 3 hours. After the completion of the reaction, to the reaction solution, water was added and extraction with ethyl acetate from the reaction solution was performed. The organic layer was dried and was concentrated under reduced pressure and the resultant solid was washed with ethyl acetate to obtain the title compound (6.00 mg, yield: 62%).
Reaction SMILES: Br[C:2]1[C:29]([Cl:30])=[CH:28][C:5]([O:6][C:7]2[C:12]([C:13]([N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH:25]4[CH2:27][CH2:26]4)[CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([Cl:31])[CH:3]=1.C(N(C(C)C)C(C)C)C.[C:41]([O:45][CH2:46][CH3:47])(=[O:44])[CH:42]=[CH2:43].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:46]([O:45][C:41](=[O:44])[CH:42]=[CH:43][C:2]1[CH:3]=[C:4]([Cl:31])[C:5]([O:6][C:7]2[C:12]([C:13]([N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH:25]4[CH2:27][CH2:26]4)[CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:28][C:29]=1[Cl:30])[CH3:47]
Reactant: C=CC(=O)OCC
Reactant: O=C(c1cccnc1Oc1cc(Cl)c(Br)cc1Cl)N1CCN(C2CC2)c2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCOC(=O)C=Cc1cc(Cl)c(Oc2ncccc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 95 °C

Procedure:
To a degassed solution of [2-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone (500 mg, 0.96 mmol, 1.0 equiv; Example 163) in propionitrile (10 mL) under Ar was added N-ethyldiisopropylamine (373 mg, 491 μL, 2.89 mmol, 3.0 equiv; [CAS RN 7087-68-5]), ethyl acrylate (0.58 g, 0.63 mL, 5.78 mmol, 6.0 equiv; [CAS RN 140-88-5]), palladium(II) acetate (22 mg, 0.10 mmol, 0.1 equiv; [CAS RN 3375-31-3]) and tri-o-tolyl-phosphane (59 mg, 0.19 mmol, 0.2 equiv; [CAS RN 6163-58-2]). The reaction mixture was heated to 95° C. over night. The crude reaction was filtered over Celite®, a sat. solution of NaCl (50 mL) added and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over Na2SO4 and the product purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate affording 320 mg (62%) of the title compound as a yellow foam. MS (ISN): 538.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[CH2:18]1[C:26]2[C:21](=[C:22]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:23]=[CH:24][CH:25]=2)[CH2:20][O:19]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[CH2:18]1[C:26]2[C:21](=[C:22]([N:27]3[CH2:32][CH2:31][N:30]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]4[N:9]=[C:10]5[C:5]([CH2:4][CH2:3][C:2](=[O:1])[NH:11]5)=[CH:6][CH:7]=4)[CH2:29][CH2:28]3)[CH:23]=[CH:24][CH:25]=2)[CH2:20][O:19]1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Reactant: c1cc2c(c(N3CCNCC3)c1)COC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5c4COC5)CC3)nc2N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.8 %

Procedure:
To a suspension of 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.278 g, 1.186 mmol, 1.1 eq) and 1-(1,3-dihydro-isobenzofuran-4-yl)-piperazine (0.217 g, 1.064 mmol, 1 eq) in dichloroethane (5 mL) was added NaBH(OAc)3 (0.469 g, 4.425 mmol, 3.73 eq). The slurry was allowed to stir overnight at room temperature (18 h). The mixture was diluted with EtOAc and quenched with saturated NaHCO3. The organic phase was then washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. Purification by silica gel chromatography (2% MeOH/CH2Cl2) followed by formation of the HCl salt using 1 N HCl in ether provided the title compound (0.143 g, 26%). CHN Found: C, 64.37; H, 6.54; N, 12.13. This calculates out for C24H30N4O3×1.00 HCl.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1.[N:17]#[C:18]Br>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][CH:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[C:18]([NH2:17])=[N:16][C:4]=2[CH:3]=1
Reactant: N#CBr
Reactant: Nc1cc(Cl)ccc1NCC1CCOCC1
Solvent: CCO
Product: Nc1nc2cc(Cl)ccc2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-N1-(tetrahydro-pyran-4-ylmethyl)-benzene-1,2-diamine (1.026 g; 4.261 mmol) is dissolved in ethanol (65 mL) and cyanogen bromide (0.903 g; 8.522 mmol) is added. The reaction is stirred at room temperature overnight. After this time the mixture is concentrated in vacuo to afford title compound as a tan solid which was used without further purification. ESI m/z 266 [M+H]+/264 [M−H]−
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[C:18]([C:8]1[S:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc2c(-c3ccccc3)csc2c1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc2c(-c3ccccc3)c(C(=O)c3ccccc3)sc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To 100 ml. of 1,2-dichloroethane were added 5.0 g. (0.021 mole) of 3-phenyl-6-methoxybenzothiophene and 2.81 g. (0.021 mole) of benzoyl chloride. The mixture was cooled to 0° C., and 2.93 g. (0.022 mole) of aluminum chloride were added. The mixture was stirred for one hour, and ice then was added. The resulting organic layer was separated, washed with water, and evaporated. To the residue were added 250 ml. of methanol and 10 ml. of 5N sodium hydroxide. The mixture was refluxed for 30 minutes, evaporated, and ether and water were added to the residue. The ether layer was separated, washed with 1N sodium hydroxide, 1N hydrochloric acid, and aqueous soidum chloride. The ether layer then was dried over magnesium sulfate, filtered, and evaporated. The residue was crystallized from methanol to obtain 3.77 g. (52 percent) of the title compound, m.p. 94°-95.5° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[CH:15]=[C:14]([Cl:16])[N:13]=[C:12](Cl)[N:11]=3)[NH:7][N:8]=2)[CH2:3][CH2:2]1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[SH:28].C(N(CC)CC)C>C(O)(C)(C)C>[Cl:16][C:14]1[N:13]=[C:12]([S:28][C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[N:11]=[C:10]([NH:9][C:6]2[NH:7][N:8]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[CH:5]=2)[CH:15]=1
Reactant: Clc1cc(Nc2cc(C3CC3)n[nH]2)nc(Cl)n1
Reactant: Sc1ccc2ccccc2c1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: Clc1cc(Nc2cc(C3CC3)n[nH]2)nc(Sc2ccc3ccccc3c2)n1
Temperature: 25 °C

Procedure:
To a solution of (5-cyclopropyl-2H-pyrazol-3-yl)-(2,6-dichloropyrimidin-4-yl)-amine (211 mg, 0.781 mmol) and 2-naphthalenethiol (125 mg, 0.781 mmol) in tert-butanol (5 mL) was added triethylamine (174 μL, 1.25 mmol) and the resulting mixture was heated at reflux for 15 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, Hexane/AcOEt gradient) to afford [6-chloro-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[S:11]1[C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=2[N:13]=[C:12]1[NH2:20]>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][C:12]2[S:11][C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[N:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1nc2c(s1)CCCC2
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nc2c(s1)CCCC2)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 78.1 %

Procedure:
4-Bromobenzoyl chloride (1.5 g, 6.83 mmol) and 4,5,6,7-Tetrahydro-1,3-benzothiazol-2-amine (1.054 g, 6.83 mmol) were dissolved in Pyridine (15 ml) and stirred at 50° C. for 1.5 h. The reaction mixture was cooled to room temperature and poured in water. The solid formed was filtered, washed with water. The solids were co-evaporated with toluene twice to afford 1.8 g of 4-bromo-N-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzamide (78%) as a yellow solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][S:24][CH2:25][C@H:26]([NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][C:64]([P:67](=[O:74])([O:71][CH2:72][CH3:73])[O:68][CH2:69][CH3:70])([F:66])[F:65]>>[CH2:69]([O:68][P:67]([C:64]([F:66])([F:65])[CH2:63][CH2:62][O:61][CH2:60][CH2:59][O:58][CH2:57][CH2:56][NH:55][C:20](=[O:21])[C@@H:19]([NH:18][C:16]([O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:17])[CH2:23][S:24][CH2:25][C@H:26]([NH:41][C:42](=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=[O:74])[O:71][CH2:72][CH3:73])[CH3:70]
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCOCCN
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(=O)CCCCCCCCCCC
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCC(F)(F)P(=O)(OCC)OCC)NC(=O)CCCCCCCCCCC

Procedure:
The title compound was prepared from (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-((R)-2-dodecanamido-3-(dodecyloxy)propylthio)propanoic acid (1.0 eq, from example 26, step 8) and diethyl 3-(2-(2-aminoethoxy)ethoxy)-1,1-difluoropropylphosphonate (1.2 eq, from example 22, step 3) by following the procedure described for example 26, step 9.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([O:16][C@@H:17]([CH:21]=[CH2:22])[C@@H:18]1[O:20][CH2:19]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>C1COCC1.[Cu]I>[CH2:9]([O:16][C@@H:17]([CH:21]=[CH2:22])[C@H:18]([OH:20])[CH2:19][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=C[C@H](OCc1ccccc1)[C@H]1CO1
Reactant: Cl[Mg]C1CCCCC1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C[C@H](OCc1ccccc1)[C@H](O)CC1CCCCC1
Reaction time: 0.17 h

Procedure:
146 mg of copper (I) iodide was suspended in THF, and 3.85 ml of cyclohexyl magnesium chloride (2M diethyl ether solution) was added thereto under an argon atmosphere at -78° C. The mixture was stirred at the same temperature for ten minutes. Then, a THF solution (5 ml) of 969 mg of (2R,3S)-3-benzyloxy-1,2-epoxy-4-pentene was dropwise added thereto over a period of 10 minutes at -78° C. The mixture was stirred at -10° C. for two hours, and then poured into a saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The extract layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.2 g of (2R,3S)-3-benzyloxy-1-cyclohexyl-4-penten-2-ol as slightly brown oily substance. This alcohol was dissolved in DMF, and 923 mg of tert-butyldimethylsilyl chloride, 312 mg of 4 -dimethylaminopyridine and 923 μl of triethylamine were added thereto at 0° C. The mixture was stirred at room temperature overnight. Then, water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed sequentially with 1N hydrochloric acid, with 4% sodium hydrogencarbonate, with water and with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/benzene=10/1) to obtain 1.3 g of the above identified compound as colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[S:13].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:17]1[S:11][C:12](=[S:13])[NH:14][C:15]1=[O:16]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1cccc(Cl)c1Cl
Temperature: 0 °C
Yield: 40 %

Procedure:
A mixture of 2,3-dichlorobenzaldehyde (4.6 g, mmoles), rhodanine (3.5 g, 25 mmoles), sodium acetate (7.5 g, 91 mmoles), and acetic acid (40 ml) is stirred under an inert atmosphere and heated to reflux. After 2.5 hours the mixture is stirred into ice-water (250 ml) and the precipitate is filtered off, rinsed three times with water and dried. Recrystallization from methanol gave the pure product (2.9 g), mp 203°-204° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:7]([C:9]1[C:18]2[C:13](=[C:14]([Br:19])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=O)[CH3:6].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].O.S>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]([C:7]([C:9]1[C:18]2[C:13](=[C:14]([Br:19])[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[S:22])[CH3:6]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)CN(C)C(=O)c1cccc2c(Br)cccc12
Agent: S
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)CN(C)C(=S)c1cccc2c(Br)cccc12
Temperature: 25 °C

Procedure:
To a stirred solution of N-[(5-bromo-1-naphthalenyl)carbonyl]-N-methylglycine methyl ester (35.5 g, 106 mmoles, described in Example 2) in dry pyridine (100 ml), phosphorus pentasulfide (44.5 g, 200 mmoles) was added portionwise. The mixture was stirred and refluxed for 1.5 hr and then poured into a liter of water at 50° to 80° C. (caution: evolution of copious quantities of H2S). The mixture was allowed to cool to 20° to 22° C. (room temperature), filtered and the filtrate was extracted with ethyl acetate. The extract was washed with 1 N aqueous HCl solution, brine, a saturated solution of sodium carbonate and brine, dried (MgSO4), filtered and evaporated to dryness. The residue was recrystallized from ethanol-water (4:1) to give the title compound; mp 85°-86° C.; NMR (CDCl3) δ3.0 (s, 3H), 3.85 (s, 3H), 4.58 & 5.37 (2d, J=17, 2H), 7.1-8.3 (m, 6H); UVλmax (EtOH) 281 nm (ε14,480), 218 (14,480).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:11]=2[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13])=[C:5]([F:25])[CH:4]=1)#[CH:2]>C1COCC1.CO.[Pd]>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:11]=2[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13])=[C:5]([F:25])[CH:4]=1)[CH3:2]
Reactant: C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Reaction time: 14.8 h

Procedure:
A mixture of the product of Example 7A, 2-[(4-ethynyl-2-fluorophenyl)amino]-3,4-difluoro-N-(2-hydroxy-ethoxy)benzamide (11.0 g, 31.40 mmol), Pd—C (10%, 1.0 g) in THF (100 mL) and MeOH (100 mL) was subject to hydrogenation (25 psi) for 14.8 hrs (The reaction was followed by HPLC until all SM peak disappeared.). The mixture was filtered through Celite® and the filtrates were concentrated to give a light yellow solid. The solid was recrystallized from heptane-EtOAc to give the title compound as a white solid, 6.97 g, 62.8%, mp 112–112.5° C. Anal.: C, 58.00 (57.63); H, 4.99 (4.84); N, 7.59 (7.91); F, 15.55 (16.09).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([O:12][C:13](=[O:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2].[CH:16]([C@H:18]1[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[N:19]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:17].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:28]([O:27][C:25]([N:19]1[C@@H:18]([C@@H:16]([OH:17])[C@@H:4]([N+:1]([O-:3])=[O:2])[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13](=[O:15])[CH3:14])[CH:7]=2)[CH2:22][O:21][C:20]1([CH3:24])[CH3:23])=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Reactant: CC(=O)Oc1cccc(CC[N+](=O)[O-])c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)Oc1cccc(C[C@@H]([C@H](O)[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)[N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 42.9 %

Procedure:
Dissolve acetic acid 3-(2-nitroethyl)-phenyl ester (25.53 g, 121.6 mmol) and tert-butyl (R)-(+)-4-formyl-2,2-dimethyl-3-oxazolidinecarboxylate (Gardner's aldehyde) (22.38 g, 97.61 mmol) in dry tetrahydrofuran (200 mL). Cool in ice bath and add tetrabutylammonium fluoride (98 mL, 98 mmol, 1.0 M in tetrahydrofuran) and stir for 15 minutes. Pour into ice water (2.7 L), wash with 1 N hydrochloric acid (200 mL), saturated aqueous sodium chloride, dry (magnesium sulfate), filter through a pad of silica gel and concentrate. Purify using silica gel chromatography, eluting with 5:95 ethyl acetate:dichloromethane, followed by 2 separate crystallizations using hexanes/dichloromethane to give the desired compound (18.372 g, 43% total yield).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([N:7]2[NH:12][N:11]=[N:10][C:8]2=[O:9])[C:4]([Cl:13])=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH:20]1([N:26]([CH2:30][CH3:31])[C:27](Cl)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[CH3:31][CH2:30][N:26]([C:27]([N:10]1[N:11]=[N:12][N:7]([C:5]2[C:4]([Cl:13])=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:8]1=[O:9])=[O:28])[CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CCN(C(=O)Cl)C1CCCCC1
Reactant: O=c1nn[nH]n1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(C(=O)n1nnn(-c2ccccc2Cl)c1=O)C1CCCCC1
Yield: 84.9 %

Procedure:
1-(2-chlorophenyl)-5(4H)-tetrazolinone (2 g) and potassium carbonate (1.68 g) were suspended in acetonitrile (30 ml), followed by fifteen minutes heating under refluxing. After cooling, N-cyclohexyl-N-ethylcarbamoyl chloride (2.31 g) was added to the reaction mixture, followed by a further five-hour heating under refluxing. The resulting mixture was filtered and the filtrate was evaporated under reduced pressure, and the resulting residue was subjected to flush column chromatography (hexane:ethylacetate=5:2), to obtain the desired 1-(2-chlorophenyl)-4-(N-cyclohexyl-N-ethylcarbamoyl)- 5(4H)-tetrazolinone (3.02 g) having a m.p. in the range of from 77.5° to 79.5° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[NH2:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[OH:20]>>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH2:2][N:10]=[C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][CH:12]1[OH:20]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CC(=O)c1ccccn1
Product: O=[N+]([O-])C1=CC(=NCCc2ccccn2)C(O)C=C1
Yield: 30 %

Procedure:
Ligand L28 was prepared following the same procedure as that used to prepare ligand L27 except that 300 μL (2 mmol) of 2-acetylpyridine were used as reagent 1 and 321 mg (2 mmol) of 2-amino-4-nitrophenol as reagent 2. 156 mg of ligand L28 were obtained as dark yellow solid with a yield of 30%.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:20]([S:21](=[O:23])(=[O:24])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(Nc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Nc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Temperature: 25 °C

Procedure:
The mixture of 3.9 g of 4-(4-acetamidophenylamino)-3-benzylamino-5-sulfamoylbenzoic acid and 39 ml of 2N aqueous sodium hydroxide is refluxed for 1 hour under nitrogen. After cooling to room temperature it is filtered and the filtrate acidified with glacial acetic acid to pH = 4. The precipitate formed is filtered off and recrystallized from aqueous ethanol, to yield the 4-(4-aminophenylamino)-3-benzylamino-5-sulfamoylbenzoic acid melting at 244° with decomposition.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-:23].[K+].[K+]>O1CCOCC1.O>[O:23]=[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:4][NH:3]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc[nH]c(=O)n2)CC1
Temperature: 25 °C
Yield: 103.5 %

Procedure:
A mixture of tert-butyl 4-(2-chloropyrimidin-4-yloxy)piperidine-1-carboxylate (341.5 mg, 0.90 mmol), potassium carbonate (225.6 mg, 1.64 mmol, EMD) and 1,4-diazacyclo[2,2,2]octane (48.8 mg, 0.44 mmol, commercially available from Alfa Aesar) in dioxane/H2O (10 mL/10 mL) was heated at 70° C. for 6 h, cooled to room temperature and then evaporated. The residual was purified by flash chromatography (0 to 10% MeOH/CH2Cl2) to yield 275 mg (85%) of the product as an off-white solid.