Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[N:5][C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(O)(C)C>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:2][C:3]2[N:4]=[N:5][C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[CH2:27][CH2:26]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cccc(-c2cc(-c3ccccc3)nnc2CBr)c1
Solvent: CC(C)O
Product: CN1CCN(Cc2nnc(-c3ccccc3)cc2-c2cccc([N+](=O)[O-])c2)CC1
Yield: 50.7 %

Procedure:
A mixture of 3-bromomethyl-4-(3-nitrophenyl)-6phenylpyridazine (0.6 g), 1-methylpiperazine (0.36 g) in isopropyl alcohol (6 ml) was refluxed for 30 minutes. After evaporating the solvent, the residue was dissolved in methylene chloride (50 ml), washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to a column chromatography on silica gel (50 g) and eluted with a mixture of chloroform and methanol (20:1 V/V). The fractions containing the desired compound were combined and concentrated under reduced pressure. The residue was recrystallized from ethanol to give 3-(4-methylpiperazine-1-ylmethyl)-4-(3-nitrophenyl)-6-phenylpyridazine (0.32 g).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19]3[CH:38]=[CH:37][C:22]([CH2:23][O:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:27]([F:36])[CH:26]=4)=[CH:21][C:20]=3[O:39][CH:40]([CH3:42])[CH3:41])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[Cl-].[Ca+2:46].[Cl-]>CO.O>[Ca+2:46].[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19]3[CH:38]=[CH:37][C:22]([CH2:23][O:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O-:35])=[O:34])=[C:27]([F:36])[CH:26]=4)=[CH:21][C:20]=3[O:39][CH:40]([CH3:42])[CH3:41])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19]3[CH:38]=[CH:37][C:22]([CH2:23][O:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O-:35])=[O:34])=[C:27]([F:36])[CH:26]=4)=[CH:21][C:20]=3[O:39][CH:40]([CH3:42])[CH3:41])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)Oc1cc(COc2ccc(CCC(=O)O)c(F)c2)ccc1Cn1nc(-c2ccccc2)cc1-c1ccccc1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)Oc1cc(COc2ccc(CCC(=O)[O-])c(F)c2)ccc1Cn1nc(-c2ccccc2)cc1-c1ccccc1
Yield: 82.6 %

Procedure:
3-[4-({4-[(3,5-Diphenyl-1H-pyrazol-1-yl)methyl]-3-isopropoxybenzyl)oxy)-2-fluorophenyl]propanoic acid (0.32 g, 0.56 mmol) was dissolved in methanol (3 mL), and 1 N aqueous sodium hydroxide solution (0.56 mL, 0.56 mmol) was added. Then, a solution of calcium chloride (31 mg, 0.28 mmol) in water (1 mL) was added, and the precipitated solid was collected by filtration, washed with water and methanol, and dried to give the title compound (0.27 g, yield 83%) as a colorless powder. MS (ESI+): 565 (M+H, as free form).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:31](O)=[O:32])[CH2:19][C:20]3[CH:29]=[C:28]([CH3:30])[C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[N:67]1([S:79]([NH2:82])(=[O:81])=[O:80])[CH2:72][CH2:71][CH:70]([CH:73]2[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]2)[CH2:69][CH2:68]1>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:29]=[C:28]([CH3:30])[C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)[C:31](=[O:32])[N:76]3[CH2:75][CH2:74][CH:73]([CH:70]4[CH2:71][CH2:72][N:67]([S:79](=[O:81])(=[O:80])[NH2:82])[CH2:68][CH2:69]4)[CH2:78][CH2:77]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[NH:3]1
Reactant: NS(=O)(=O)N1CCC(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2oc(=O)[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(S(N)(=O)=O)CC3)CC2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 73 mg (0.14 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydrobenz-oxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 51 mg (0.16 mmol) TBTU, 42 μL (0.3 mmol) triethylamine and 41 mg (0.14 mmol) [4,4′]bipiperidinyl-1-sulphonic acid amide (used as the hydrochloride salt) in 1.8 mL DMF was stirred overnight at RT. The reaction mixture was purified by HPLC, the fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:47]=[CH:48][CH:49]=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl>C(Cl)Cl.CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:47]=[CH:48][CH:49]=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2 g (3 mmol) of 4'-[(2-n-butyl-benzimidazol-1-yl)-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl are dissolved in a mixture of 10 ml of methylene chloride and 10 ml of methanol, treated with 10 ml of etherified hydrochloric acid and stirred at ambient temperature for 3 hours. The mixture is rotary evaporated to dryness in vacuum. The residue is dissolved in methanol, rendered alkaline using ammonia and rotary evaporated once again. The crude product is purified over a silica gel column (grain size: 0.063-0.2 mm, eluting agent: methylene chloride/ethanol/ammonia=19:1:0.1). The product is crystallised from ether and dried at 50° C. in vacuum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([CH2:51]OS(C)(=O)=O)[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([CH2:51][O:36][C:30]2[CH:29]=[C:28]3[C:33]([C:24]([O:23][C:20]4[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:11]5([C:9](=[O:10])[NH:8][C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[CH2:13][CH2:12]5)=[O:15])=[CH:18][C:19]=4[F:37])=[N:25][CH:26]=[N:27]3)=[CH:32][C:31]=2[O:34][CH3:35])[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 60.6 %

Procedure:
Cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy-quinazolin-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (325 mg, 0.64 mmol), 4-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester (193 mg, 0.66 mmol), K2CO3 (181 mg, 1.31 mmol) were combined in DMF (5 ml) and heated to 80° C. overnight. The reaction was not complete and more 4-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester (90 mg, 0.31 mmol) and K2CO3 (90 mg, 0.65 mmol) were added and heating at 80° C. continued for another night. The reaction mixture was allowed to cool to room temperature, then diluted with EtOAc and washed with H2O (3×), sat'd NaCl (1×), dried (Na2SO4) and concentrated in vacuo. The resulting crude material was purified by flash chromatography (1:1 hexanes:EtOAc, followed by 1:3 hexanes:EtOAc) to give 4-[4-(2-fluoro-4-{[1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl]-amino}-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (273 mg, 60%). LC/MS Calcd for [M+H]+ 704.3. found 704.4.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CO.[C:27]([O:34]C([O-])=O)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O>ClCCl.C(N(CC)CC)C>[C:30]([O:29][C:27]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13]1)=[O:34])([CH3:31])([CH3:32])[CH3:33]
Reactant: COC(=O)C1=CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 92.5 %

Procedure:
4.62 g of methyl 1-benzyl-1,2,3,6-tetrahydro-4-pyridinecarboxylate was dissolved in 30 ml of dichloromethane. Under ice-cooling, 4.29 g of 1-chloroethyl chloroformate was added thereto and the resulting mixture was heated under reflux for 2 hours. After adding 50 ml of methanol, the mixture was stirred at 70° C. for 1 hour and 20 minutes. Then triethylamine was added to the reaction mixture under ice-cooling until the pH value of the mixture exceeded 7. After further adding 4.37 g of tert-butyl dicarbonate, the resulting mixture was stirred at room temperature for 10 minutes. Then the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 4.46 g of the title compound as a yellow oily substance.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.CCOCC.[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20]>O>[C:1]([O:5][C:19](=[O:20])[CH:18]([Cl:22])[Cl:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)(C)O
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)C(Cl)Cl
Reaction time: 3 h
Yield: 76.4 %

Procedure:
74 g of t-butylalcohol, 79 g of pyridine and 250 ml of anhydrous ether were heated to boiling and 146 g of dichloroacetyl chloride were added dropwise to the reaction mixture at such a rate that the mixture continued to boil without further supply of heat. When all the dichloroacetyl chloride has been added, boiling was continued for 3 hours. Water was then added to the reaction mixture and the ethereal phase was separated off. The resulting reaction solution was processed in the usual manner to yield 140 g of α, α-dichloroacetic acid-t-butyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[C@@H:13]([CH2:33][S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[NH4+:44]>CCO>[NH2:44][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[C@@H:13]([CH2:33][S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=S(=O)(C[C@H]1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)c1ccccc1
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)[C@@H](CS(=O)(=O)c3ccccc3)C2)cn1
Temperature: 110 °C
Reaction time: 5 h
Yield: 22.9 %

Procedure:
A 2-mL vial was charged with 2-(4-((2R)-4-((6-chloro-3-pyridinyl)sulfonyl)-2-((phenylsulfonyl)methyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.026 g, 0.039 mmol) and ammonium hydroxide (30 wt %, 0.50 mL, 3.9 mmol) and EtOH (0.5 mL). The vial was sealed and the reaction mixture was stirred at 110° C. for 5 h. The reaction mixture was concentrated and purified by column chromatography (10 g of silica, 0-5% (2 M NH3 in MeOH) in DCM) to afford 2-(4-((2R)-4-((6-amino-3-pyridinyl)sulfonyl)-2-((phenylsulfonyl)methyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.0057 g) as a white solid.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[N:14]=[C:13]([CH2:15]OS(C)(=O)=O)[CH:12]=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[N+:21]([C:24]1[NH:28][N:27]=[CH:26][CH:25]=1)([O-:23])=[O:22].C([O-])([O-])=O.[K+].[K+].[I-]>CC(C)=O>[CH3:3][C:4]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:15][N:27]3[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[N:28]3)[N:14]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2cccc(COS(C)(=O)=O)n2)OCCO1
Reactant: O=[N+]([O-])c1ccn[nH]1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: CC1(c2cccc(Cn3ccc([N+](=O)[O-])n3)n2)OCCO1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methanesulfonic acid 6-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-2-ylmethyl ester (273 mg, 1.00 mmol) in acetone (4.0 mL) was added, under inert atmosphere (N2) to a solution of 5-nitro-1H-pyrazole (115 mg, 1.00 mmol) in acetone (4.0 mL). K2CO3 (698 mg, 5.00 mmol) and TBA iodide (64 mg, 0.20 mmol) were added and the reaction mixture was stirred at rt for 5 h. The solvent was removed under reduced pressure. Water (10 mL) and EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (30:10 to 50:50 hept-EA) gave the title compound as a light brown solid. TLC: rf (50:50 hept-EA)=0.16. LC-MS-conditions 02: tR=0.87 min; [M+H]+=291.35.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[O-][Si]([O-])=O.[Mg+2]>C(Cl)Cl.CCOCC>[CH:2]([CH2:3][CH2:4][CH2:5][C@H:6]([N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:1]
Reactant: O=C(OCc1ccccc1)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Agent: O=[Cr](=O)([O-])Cl
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCCC[C@@H](C(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O
Reaction time: 4 h
Yield: 79.4 %

Procedure:
Benzyl 6-hydroxy-2(S)-phthalimidohexanoate (4.0 g) was dissolved in CH2Cl2 and treated with pyridinium chlorochromate (3.64 g). The reaction mixture was stirred under nitrogen for 4 hours and then diluted with 160 ml of ether. The mixture was filtered through a celite pad and concentrated to give an oil. This oil was passed through a short florisil column with ether as eluent. Concentration and drying in vacuo yielded pure benzyl 5-formyl-2(S)-phthalimidopentanoate (3.16 g); [α]D25° =-18.6° (CH2Cl2, c=4.1); I.R. (neat): 2730 cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([Cl:18])=[CH:13][N:12]=1.[I-].[K+]>CC(N(C)C)=O>[Cl:10][C:11]1[N:16]=[C:15]([NH:9][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=2)[C:14]([Cl:18])=[CH:13][N:12]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Cc1cc(C)nc(N)c1
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)nc(Nc2nc(Cl)ncc2Cl)c1

Procedure:
The mixture 4,6-dimethylpyridin-2-amine (61 mg, 0.50 mmol), 2,4,5-trichloropyrimidine (57 μL, 0.5 mmol), and potassium iodide (166 mg, 1.0 mmol) in 3 mL of DMA is heated at 90° C. overnight. The mixture is concentrated in vacuo and the resulting crude product is partitioned between EtOAc and brine. The collected organic extracts are dried (Na2SO4) and concentrated in vacuo to afford 2,5-dichloro-N-(4,6-dimethylpyridin-2-yl)pyrimidin-4-amine; ESMS m/z 269.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([N:14]2[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][C:22]([C@@H:24]([NH:28][C:29]([C:31]3[O:32][C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[CH:35]=3)=[O:30])[CH2:25][CH2:26][CH3:27])=[O:23])[C:16](=[O:40])[CH2:15]2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.COC1C=C(S(Cl)(=O)=O)C=CC=1OC.CO>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([N:14]2[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][C:22]([C@@H:24]([NH:28][C:29]([C:31]3[O:32][C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[CH:35]=3)=[O:30])[CH2:25][CH2:26][CH3:27])=[O:23])[CH:16]([OH:40])[CH2:15]2)(=[O:12])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCC[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCN(S(=O)(=O)c2ccc(OC)c(OC)c2)CC1=O
Agent: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCN(S(=O)(=O)c2ccc(OC)c(OC)c2)CC1O
Yield: 119.6 %

Procedure:
To a solution of benzofuran-2-carboxylic acid {(S)-1-[1-(3,4-dimethoxy-benzenesulfonyl)-3-oxo-azepan-4-ylcarbamoyl]-butyl}-amide of Example 78c (0.175 g) in dichloromethane was added triethylamine (0.1 mL) and 3,4-dimethoxy-benzenesulfonyl chloride (0.12 g). The reaction was stirred until complete. Workup and column chromatography (5% methanol:dicloromethane) provided the title compound (0.21 g): MS(EI) 587 (M+).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:25]2[C:26]3[C:22](=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=3[Cl:17])[CH2:23][CH2:24]2)[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1cc(Cl)c2c(c1)CCN2
Reactant: CC[C@@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Agent: Cl
Product: CC[C@@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-chloro-5-methoxyindoline hydrochloride as the starting materials. mp 128–130° C.; 1H NMR (300 MHz, CDCl3): δ 6.93 (s, 1 H), 6.71 (s, 2 H), 4.34–4.24 (m, 2 H), 4.11–3.99 (m, 1 H), 3.75 (s, 3 H), 3.08 (t, J=7.9 Hz, 2 H), 1.93–1.73 (m, 2 H), 1.06–0.99 (m, 1 H), 0.92 (t, J=7.3 Hz, 3 H), 0.79–0.72 (m, 1 H), 0.54–0.43 (m, 2 H), 0.34–0.24 (m, 1 H); HRMS (ESI) calcd for C19H22N3O2Cl2 (M+H)+: 394.1089; found m/z 394.1088.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[N:20]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:28]3[CH2:29][CH2:30][CH:25]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:26][CH2:27]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: C1CCN(C2CCNCC2)C1
Product: O=C(N1CCC(N2CCCC2)CC1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 65 %

Procedure:
The title compound of Example 2 (1.0 g, 3.4 mmol) was reacted with 4-(1-pyrrolidinyl)piperidine (0.77 g, 3.4 mmol) and the reaction was carried out by the method of Example 4. Following chromatographic purification, 0.91 g of the title product was obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([CH:18]=[O:19])[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O)=[O:6])[CH:2]=[CH2:3].C([O-])(=O)C.[Na+].[NH2:25][NH:26][C:27]([NH2:29])=[O:28]>CO>[CH2:1]([O:4][C:5]([NH:7][C@H:8]([CH:18]=[O:19])[CH2:9][CH2:10][C:11](=[N:25][NH:26][C:27]([NH2:29])=[O:28])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N[C@H](C=O)CCC(=O)OC(C)(C)C
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N[C@H](C=O)CCC(=NNC(N)=O)OC(C)(C)C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a solution of (207a) (2.39 g, 8.8 mmol), in MeOH (20 ml) was added sodium acetate (0.72 g, 8.8 mmol) and semicarbazide (0.98 g, 8.8 mmol) stirred overnight, concentrated and diluted with CH2Cl2 (100 ml), washed with water, dried and concentrated. Flash chromatography (2% MeOH in CH2Cl2) afforded (208a) (2.10 g, 73%) as an oil: [α]D20 -21 (c 2.55°, CH2Cl2); 1H NMR (CDCl3) δ 9.98 (1H, s), 7.27 (1H, d), 5.8 (1H, m), 5.5 (1H, d), 5.35-5.19 (2H, m), 4.58 (2H, m), 4.14 (1H, m), 2.37 (2H, t), 2.09 (1H, m), 2.0-1.75 (2H, m); Anal. Calcd for C14H24N4O5 : C, 51.21; H, 7.37; N, 17.06. Found: C, 50.2; H, 7.3; N, 16.1
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH:15]1([NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([CH3:40])=[C:25]([NH:27][C:28](=[O:39])[C:29]3[CH:34]=[C:33](F)[CH:32]=[CH:31][C:30]=3[N+:36]([O-:38])=[O:37])[CH:26]=2)=[O:20])[CH2:17][CH2:16]1>>[CH:15]1([NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([CH3:40])=[C:25]([NH:27][C:28]([C:29]3[CH:34]=[C:33]([N:5]4[CH2:6][C@@H:1]5[CH2:7][C@H:4]4[CH2:3][N:2]5[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:32]=[CH:31][C:30]=3[N+:36]([O-:38])=[O:37])=[O:39])[CH:26]=2)=[O:20])[CH2:17][CH2:16]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (B) in the portion of Example 1, which is concerned with the preparation of starting materials, and tert-butyl(1S,4S)-(−)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give of tert-butyl(1S,4S)-5-{3-[({5-[(cyclopropylamino)carbonyl]-2-methylphenyl}amino)carbonyl]-4-nitrophenyl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; NMR Spectrum: (DMSOd6) 0.59 (m, 2H), 0.70 (m, 2H), 1.39 (d, 9H), 2.00 (m, 2H), 2.32 (s, 3H), 2.54 (s, 2H), 2.86 (m, 1H), 3.40 (m, 1H), 3.66 (t, 1H), 4.53 (d, 1H), 4.87 (s, 1H), 6.80 (s, 2H), 7.30 (d, 1H), 7.58 (m, 1H), 8.01 (s, 1H), 8.07 (d, 1H), 8.38 (d, 1H), 9.90 (s, 1H); Mass Spectrum: M+H+ 536.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH2:17]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[CH2:27]O)[C:22]#[N:23])[CH3:18]>>[C:22]([C:21]1[CH:24]=[CH:25][C:26]([CH2:27][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:19]([CH2:17][CH3:18])[CH:20]=1)#[N:23]
Reactant: COC(=O)c1ccnc(-n2nccc2O)c1
Reactant: CCc1cc(C#N)ccc1CO
Product: CCc1cc(C#N)ccc1COc1ccnn1-c1cc(C(=O)OC)ccn1

Procedure:
The title compound was prepared from methyl 2-(5-hydroxypyrazol-1-yl)pyridine-4-carboxylate (PREPARATION 6) and 3-ethyl-4-(hydroxymethyl)benzonitrile according to the procedure for the preparation of Example 125, part B. 1H NMR (400 MHz, CDCl3): δ 1.26 (3H, t, J=7.6 Hz), 2.73 (2H, q, J=7.6 Hz), 3.96 (3H, s), 5.28 (2H, s), 5.77 (1H, d, J=1.2 Hz), 7.53-7.67 (4H, m), 7.77 (1H, d, J=4.8 Hz), 8.31 (1H, s), 8.67 (1H, d, J=4.8 Hz). [M+H] Calc'd for C20H18N4O3, 363; Found, 363.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:2]=1.Br[CH2:14][C:15]#[CH:16]>>[CH2:16]([N:9]1[CH2:10][CH2:11][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:8]1=[O:12])[C:15]#[CH:14]
Reactant: C#CCBr
Reactant: O=C1NCCN1c1cccnc1
Product: C#CCN1CCN(c2cccnc2)C1=O

Procedure:
The starting material, 1-(2-propynyl)-3-(3-pyridyl)-2-imidazolidinone was synthesized similarly to Referential example 1, using 1-(3-pyridyl)-2-imidazolidinone as material and using 3-bromopropyne in place of 4-fluoronitrobenzene.