Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[CH2:9]Br)=[CH:4][CH:3]=1.C([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[CH2:9][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: CC(CBr)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(CN1CCNCC1)c1ccc(F)cc1
Yield: 58 %

Procedure:
A mixture of (±)-2-(4-fluorophenyl)propyl bromide (3.03 g, 13.96 mmol), N-Boc-piperazine (2.60 g, 13.96 mmol), potassium carbonate (3.86 g, 27.93 mmol) and sodium iodide (2.09 g, 13.96 mmol), in anhydrous isopropyl alcohol (100 ml) was refluxed for 16 h. The inorganics were filtered off and the solvent evaporated in vacuo. The resulting residue was partitioned between CH2Cl2 (3×150 ml) and water (50 ml). The combined extracts were dried (Na2SO4) and evaporated and the residue chromatographed on silica gel eluting with hexane to give 1.8 g (40%) of product. This material was dissolved in 99% formic acid (50 ml) and the solution stirred at room temperature for 16 h. The solvent was removed under vacuum and the residue basified by addition of saturated K2CO3 solution and then extracted with n-butanol (100 ml). The n-butanol was evaporated in vacuo and the residue chromatographed on silica gel eluting with CH2Cl2 /MeOH/NH3 (60:8:1) to give the title-product (0.34 g, 27%), δ(360 MHz, CDCl3) 1.24 (3H, d, J=7.0 Hz, Me), 2.30-2.46 (6H, m, 3 of CH2), 2.78-2.98 (5H, m, 2 of CH2 and CH), 6.94-7.00 (2H, m, Ar--H), 7.12-7.26 (2H, m, Ar--H).
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([CH:18]=[O:19])[NH:15][C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1([Mg]Br)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOCC.[Cl-].[NH4+]>O1CCCC1>[CH2:20]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([CH:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[OH:19])[NH:15][C:14]=12)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Temperature: -15 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of 7-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (Example 141) (1.7 g, 5.1 mmol) in tetrahydrofuran (25 mL) was added 3.0 M phenylmagnesium bromide in Et2O (2.0 mL, 6 mmol) dropwise at −78° C. under a nitrogen atmosphere. After stirring for ca. 2 h, additional 3.0 M phenylmagnesium bromide in Et2O (2.0 mL, 6 mmol) was added. The reaction mixture was stirred for another 1.5 h warming to −15° C. The reaction mixture was poured into a saturated ammonium chloride solution, and extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated sodium chloride, and dried over sodium sulfate. Filtration and concentration provided the crude material, which was purified by Biotage chromatography (10-30% ethyl acetate in hexanes) to provide [7-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl](phenyl)methanol (1.32 g, 62%) as a yellow foam: mp 53-61° C.; 1H NMR (500 MHz, CD3OD) δ4.60 (4H, q, J=23.2, 15.4 Hz), 5.95 (1H, s), 6.25 (1H, s), 7.05 (1H, d, J=5.7 Hz), 7.15-7.40 (15H, m), 7.62 (1H, d, J=5.7 Hz); ESI MS m/z 420 [C28H25N3O+H]+; HPLC (Method A) >99% (AUC), tR=19.2 min.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([C:16]2[C:17]([CH3:22])=[N:18][CH:19]=[CH:20][CH:21]=2)[N:13]=[N:12]1.[NH2:23][C:24]1[C:25]([O:39][CH3:40])=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1>>[C:30]([C:28]1[CH:27]=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:25]([O:39][CH3:40])=[C:24]([NH:23][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[CH:15]=[C:14]([C:16]4[C:17]([CH3:22])=[N:18][CH:19]=[CH:20][CH:21]=4)[N:13]=[N:12]3)[CH:4]=2)[CH:29]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1ccc(C(=O)O)cc1-n1cc(-c2cccnc2C)nn1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cccnc4C)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 9 was prepared by coupling 4-methyl-3-[4-(2-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzoic acid (5:3 mixture with 4-methyl-3-[5-(2-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzoic acid) with N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in the same manner as Example 1. Preparative HPLC was used to separate N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(2-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzamide from N-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[5-(2-methyl-pyridin-3-yl)-[1,2,3]triazol-1-yl]-benzamide. ESI MS m/z 549 [C28H32N6O4S+H]+.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[C:11]=1[C:12]#[N:13]>>[NH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([C:2]#[C:1][CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(N)cccc1Br
Reactant: C#CC1CCCCC1
Product: N#Cc1c(N)cccc1C#CC1CCCCC1

Procedure:
Prepared as in Example 21c from ethynylcyclohexane and 2-amino-6-bromobenzonitrile as a brown oil (100%). 1H NMR (400 MHz, DMSO-d6) δ 1.24-1.77 (m, 10H), 2.70 (m, 1H), 6.13 (s, 2H), 6.64 (d, J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H). MS 225 (MH+).
Reaction SMILES: [OH-].[K+].N1C=CC=CC=1C1C=CC=CN=1.[C:15]([CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)([CH3:18])([CH3:17])[CH3:16].[H][H]>CC(O)C>[C:15]([C@H:19]1[CH2:20][CH2:21][C@H:22]([OH:25])[CH2:23][CH2:24]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: [H][H]
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CC(C)O
Product: CC(C)(C)[C@H]1CC[C@H](O)CC1
Reaction time: 18 h

Procedure:
RuClCp* (cod) (3.8 mg, 0.01 mmol), KOH (0.04 mmol), 2,2′-bipyridyl (3.1 mg, 0.02 mmol) and 4-t-butylcyclohexanone (385.63 mg. 2.5 mmol) were dissolved into 10 ml of 2-propanol. and deaerated by argon substitution, after which the total amount of the resulting mixture was transferred into a 100-milliliter metallic autoclave. Hydrogen was then charged to a predetermined pressure (4 atm), and the reaction was started at room temperature (28° C.) After the reaction solution was stirred for 18 hours, the reaction pressure was brought back to atmospheric pressure, and the reaction products, cis-4-t-bucylcyclohexanol (yield 23.2 and trans-4-t-butylcyclohexanol (yield 38.2%), were identified and quantitatively determined by TLC monitor (silica gel: n-hexane/ethyl acetate=4/1) and gas chromatography of the reaction solution,
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]1[CH:10]=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]=[C:7]([NH2:34])[CH:6]=1)[CH3:2].N1C=CC=CC=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44].O>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:3][C:4](=[O:35])[C:5]1[CH:10]=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]=[C:7]([NH:34][S:43]([CH3:42])(=[O:45])=[O:44])[CH:6]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1cc(N)cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc(NS(C)(=O)=O)cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)c1
Yield: 81.9 %

Procedure:
5-{2-[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl)-3-aminobenzoic acid ethyl ester (60 mg, 0.12 mmol), pyridine (11 μL, 0.137 mmol), methane sulphonyl chloride (11 μL, 0.137 mmol), and a catalytic amount of DMAP in 2 mL of dichloromethane were stirred at room temperature for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (MgSO4), filtered and concentrated. Purification was carried out on a SPE using iso-hexane containing a gradient of ethyl acetate (5–30%) to give the required product as yellow oil (55 mg, 78%). 1H NMR (CDCl3):1.32 (3H,t,J=7.1), 2.06–2.13 (2H,m), 2.60(3H,s), 2.88 (2H,t,J=7.4), 2.92–296(2H,m), 4.31 (2H,q,J=7.1), 5.11 (2H,s), 6.42 (1H,s), 7.04 (1H,d,J=8.6), 7.11 (1H,s), 7.23–7.30 (5H,m), 7.33(1H,d), 7.54 (1H,s), 7.66 (1H,s). LC/MS[MH−]=558 Rt=4.11.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O.O.NN>Cl>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][NH2:7]
Reactant: O=C1c2ccccc2C(=O)N1CCOc1ccccc1Cl
Agent: Cl
Agent: NN
Solvent: O
Product: NCCOc1ccccc1Cl
Reaction time: 0.75 h

Procedure:
21.0 grams (0.071 ml) of N-[2-(2-chlorophenoxy)ethyl]phthalimide and 3.55 grams (0.071 mol) of hydrazine hydrate are dissolved in 70 ml of moisture-free alcohol for heating and diffusing over 45 minutes. And stirred with 20 ml 18% HCl heat for diffusing over 1.0 hour. Upon cooling, after filtrating the extracted solids, 20% NaOH is added to alkalize. The mixed solution's organic layer is extracted with chloroform and filtrating the extracted solids with potassium carbonate solution. The generated product is filled into silica gel columns utilizing the ratio of ethyl acetate as the diluent; upon purification, 2-(2-chlorophenoxy) ethylamine is obtained.
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14].C(=O)=O.Cl.ClC1C(Cl)=C(Cl)C=CC=1.[OH-].[Na+]>O>[Cl:13][C:10]1[CH:9]=[C:8]([Cl:14])[C:7]([Cl:6])=[CH:12][C:11]=1[S:2]([OH:5])(=[O:4])=[O:3]
Reactant: Clc1ccc(Cl)c(Cl)c1
Reactant: O=S(=O)(O)Cl
Agent: Cl
Agent: Clc1cccc(Cl)c1Cl
Agent: O=C=O
Solvent: O
Product: O=S(=O)(O)c1cc(Cl)c(Cl)cc1Cl
Temperature: 120 °C
Reaction time: 3 h

Procedure:
119 g (1.0 mol) of technical grade chlorosulfonic acid were added dropwise, under stirring, to 218 g (1.2 mol) of technical grade 90% strength 1,2,4-trichlorobenzene over a period of time of about one hour. The reaction was permitted to proceed at 150° to 160° C. for three hours. During the reaction a slow stream of dried air or dried carbon dioxide was passed through the reaction mixture. The resulting hydrogen chloride of reaction was transferred with the gas stream into a receiving flask containing water. The hydrochloric acid trapped in the receiving flask constituted about 96% of theoretical. The reaction mixture, after being cooled to 120° C., was mixed with 200 ml of water. Steam was then charged therein to remove excess trichlorobenzene. 37 g (0.2 mol) of trichlorobenzene were recovered. Water was added to the reaction mixture to provide a total volume of 700 g which was then titrated with sodium hydroxide solution.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH3:7])[CH2:2]1.Cl.[C:9]1([CH3:16])[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1>>[CH3:16][C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][C:14]=1[CH:3]([CH2:4][CH2:5][CH2:6][CH3:7])[CH2:2][OH:1]
Reactant: Cc1cccc(C)c1
Reactant: CCCCC1CO1
Agent: Cl
Product: CCCCC(CO)c1ccc(C)cc1C
Temperature: 3 °C
Reaction time: 0.5 h

Procedure:
To a stirred, 0° C. mixture of m-xylene 173g (1.63 mole) and anhydrous stannic chloride 78.0g (0.30 mole) which is constantly swept with nitrogen, is added dropwise, 1,2-epoxyhexane, 30.0g (0.30 mole) in 50 g m-xylene. The exothermic temperature is maintained at 3° C. by the rate of addition. After the addition is completed, the reaction which now contains 223 g (2.0 mole) m-xylene is stirred for 30 minutes at 0° C. then poured into iced concentrated hydrochloric acid. The aqueous and organic layers are separated. After extracting the aqueous portion with ethyl ether, this organic layer is combined with the previous organic fraction. This combined organic material is washed successively with water, sodium bicarbonate and again water. The dried organic solvent mixture of ethyl ether and excess unreacted m-xylene is then removed on rotary evaporator. The concentrated residue is fractionally distilled in vacuo. The third fraction, 112° C./0.5 mm, is shown to be the desired product by spectral and analytical data. The yield is 35.6g (57.6% theory).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[Se](=O)=[O:13].CCCCC.CCOC(C)=O>CO>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:1]=[O:13])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2ncccc2c1
Reactant: O=[Se]=O
Solvent: CCOC(C)=O
Solvent: CCCCC
Solvent: CO
Product: O=Cc1ccc2ncccc2c1
Temperature: 100 °C
Yield: 21.5 %

Procedure:
6-Methyl-quinoline (Aldrich Chemical Co.) (1 g, 7.0 mmol) and selenium dioxide (2.32 g, 21.0 mmol) were combined in the absence of solvent and heated at 100° C. under a nitrogen atmosphere for 16 h. The reaction mixture was allowed to cool to room temperature, taken up in MeOH and presorbed onto silica gel. Chromatography using a 3:1 mixture of pentane: EtOAc provided the title product (236 mg, 21%); 1HNMR (400 MHz, CDCl3) δ: 7.46-7.52 (m, 2H), 7.98 (d, 1H), 8.33-8.37 (m, 2H), 9.03 (d, 1H), 10.18 (s, 1H); m/z (ES+) 315 (2MH+).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1[C:20]([CH3:21])=[CH:19][P:18](C2C=CC=CC=2)[CH:17]=1>C1(C)C=CC=CC=1>[CH3:21][C:20]1[C:16]2([CH3:15])[CH2:17][P:18]([C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[C:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:19]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(#Cc1ccccc1)c1ccccc1
Reactant: Cc1cp(-c2ccccc2)cc1C
Solvent: Cc1ccccc1
Product: CC1=C(c2ccccc2)P2CC1(C)C(c1ccccc1)=C2c1ccccc1

Procedure:
A solution of 27.94 g (158 mmol) of diphenylacetylene and 29.50 g (158 mmol) of 3,4-dimethyl-1-phenylphosphole in 100 ml of toluene are refluxed for 3 days. The reaction mixture is then evaporated to dryness under vacuum generated by an oil pump, and the residue is washed three times, each time using 70 ml of pentane. The product can be recrystallized from methylene chloride.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:9][C:10]([NH:12]C(=O)C2C=CC=CC=2)=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[OH-].[Na+]>CCO>[NH2:2][C:1]1[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][C:4]=2[NH:9][C:10](=[O:11])[N:12]=1
Reactant: N#Cc1cccnc1NC(=O)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(=O)[nH]c2ncccc12
Temperature: 25 °C
Yield: 54.8 %

Procedure:
A solution of N-(3-cyanopyridin-2-ylcarbamoyl)benzamide (example 53a) (360 mg, 1.35 mmol) and NaOH (2 N, 1.85 mL) in EtOH (5 mL) was stirred at 100° C. under nitrogen for half an hour. After cooling to room temperature, the clear reaction solution was filtered and the filtrate was carefully neutralized with 10% AcOH with vigorous stirring at 0° C. The resultant precipitate was collected by filtration, and washed with warm 20% EtOH in water to give the final product 4-aminopyrido[2,3-d]pyrimidin-2(1H)-one (120 mg, 55%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ7.22 (dd, J=4.4 Hz, 4.8 Hz, 1H), 7.29 (dd, J=4.8 Hz, 1H), 8.24 (dd, J=2 Hz, 1.6 Hz, 1H), 8.59 (dd, J=2 Hz, 1.6 Hz, 1H), 8.66-8.71 (m, 2H), 8.70 (d, J=1.2 Hz, 1H). MS 162 (MH+).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.C([O:40][C:41](=[O:45])[C@H:42]([CH3:44])[NH2:43])C>CCOCC>[CH2:15]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:43][C@H:42]([C:41]([OH:45])=[O:40])[CH3:44])=[O:11])=[CH:13][CH:14]=1)[CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCOC(=O)[C@H](C)N
Reactant: CCCCCCCCCC=CCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)N[C@@H](C)C(=O)O)cc1

Procedure:
A solution of 4.75 g. of N-trifluoroacetyl-4-(4-tetradecenylamino)benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the combined filtrate and washings are evaporated. After treatment of the residue with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product a white, crystalline solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([Cl:17])[N:14]=[N:15][CH:16]=[C:11]2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19]Br>ClCCl>[CH2:1]([N:8]1[C:12]2=[C:13]([Cl:17])[N:14]=[N:15][CH:16]=[C:11]2[C:10]([Br:19])=[C:9]1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Cc1cc2cnnc(Cl)c2n1Cc1ccccc1
Solvent: ClCCl
Product: Cc1c(Br)c2cnnc(Cl)c2n1Cc1ccccc1
Yield: 83 %

Procedure:
8.0 g (31 mmol) of 1-benzyl-7-chloro-2-methylpyrrolo[2,3-d]pyridazine and 1.59 ml (31 mmol) of bromine are reacted in a total of 150 ml of dichloromethane as described for Example 3a. Yield: 83%, m.p.: 138°-140° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH2:18]([S:20]([C:23]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:24]=1[NH2:25])(=[O:22])=[O:21])[CH3:19]>>[CH2:18]([S:20]([C:23]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:24]=1[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1)(=[O:22])=[O:21])[CH3:19]
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Reactant: CCS(=O)(=O)c1ccc(O)cc1N
Product: CCS(=O)(=O)c1ccc(O)cc1Nc1cc(C(F)(F)F)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyridinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol) and 2-ethylsulfonyl-5-hydroxyaniline (46 mg, 0.231 mmol) similar to Example 186 and was isolated as a yellow solid (35 mg, 54%). 1H NMR (CDCl3): 8.88 (s, 1H), 8.60 (brt, 2H), 8.01 (t, 1H), 7.52 (m, 2H), 7.01 (m, 2H), 3.02 (q, 2H), 1.22 (t, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:21]=[C:20]([CH3:22])[C:19]3[C:14](=[CH:15][C:16]([N:23]([S:30]([C:33]4[CH:34]=[CH:35][CH:36]=[C:37]5[C:42]=4[N:41]=[CH:40][CH:39]=[CH:38]5)(=[O:32])=[O:31])[CH2:24][C:25]([O:27]CC)=[O:26])=[CH:17][CH:18]=3)[N:13]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[OH-].[Na+]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:21]=[C:20]([CH3:22])[C:19]3[C:14](=[CH:15][C:16]([N:23]([S:30]([C:33]4[CH:34]=[CH:35][CH:36]=[C:37]5[C:42]=4[N:41]=[CH:40][CH:39]=[CH:38]5)(=[O:32])=[O:31])[CH2:24][C:25]([OH:27])=[O:26])=[CH:17][CH:18]=3)[N:13]=2)=[CH:6][CH:5]=1)(=[NH:2])[NH2:3]
Reactant: CCOC(=O)CN(c1ccc2c(C)cc(CNc3ccc(C(=N)N)cc3)nc2c1)S(=O)(=O)c1cccc2cccnc12
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(CNc2ccc(C(=N)N)cc2)nc2cc(N(CC(=O)O)S(=O)(=O)c3cccc4cccnc34)ccc12

Procedure:
Prepared analogously to Example 3 from 2-[N-(4-amidinophenyl)-aminomethyl]-4-methyl-7-[N-(ethoxycarbonylmethyl)-quinoline-8-sulphonylamino]-quinoline and sodium hydroxide solution.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:26][CH3:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1COCC1.O[Li].O>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:26][CH3:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(Cc2ccc(CC(=O)OC)cc2)nc(-c2cccc(Cl)c2)n1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(Cc2ccc(CC(=O)O)cc2)nc(-c2cccc(Cl)c2)n1
Yield: 64.1 %

Procedure:
A 25-mL flask, with stirrer bar, was charged with methyl 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetate (64 mg, 0.17 mmol, 1.0 eq.) and THF (3 mL). Water (3 mL) and LiOH.H2O (21 mg, 0.50 mmol, 3.0 eq.) were added. The resulting mixture was stirred at room temperature for 17 hrs until the starting ester was consumed. The reaction mixture was diluted with water (10 mL) and acidified with 2N HCl. The mixture was extracted with ethyl acetate. The organic extract was washed with sat. sodium chloride (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (88 mg) was purified by chromatography on silica gel using dichloromethane/methanol (10:0 to 9:1) as eluent to afford 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetic acid (40 mg, 66% yield) as a white solid. MW=366.84. 1H NMR (DMSO-d6, 500 MHz) δ 12.31 (br s, 1H), 8.40-8.33 (m, 2H), 7.62-7.53 (m, 2H), 7.31 (d, J=8.0 Hz, 2H), 7.26 (s, 1H), 7.21 (d, J=8.0 Hz, 2H), 4.10 (s, 2H), 3.51 (s, 2H), 2.78 (q, J=7.5 Hz, 2H), 1.26 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[S:25][C:24](I)=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[C:36]([Cu])#[N:37]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[S:25][C:24]([C:36]#[N:37])=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C[Cu]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc(I)sc23)CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc(C#N)sc23)CC1
Yield: 68.8 %

Procedure:
To a solution of {1-(4-chlorobenzyl)-2-[4-(6-iodothieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (50 mg, 0.080 mmol) in Pyridine (5 mL) was added CuCN (20 mg, 0.223 mmol). The mixture was refluxed under N2 for 12 hours. The solvent was removed and the residue was subject to chromatography on silica gel to afford {1-(4-chlorobenzyl)-2-[4-(6-cyanothieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (29 mg, 69%). 1H NMR (CDCl3, 400 Hz) δ 8.65 (s, 1H), 7.95 (s, 1H), 7.28-7.26 (d, J=7.6 Hz, 2H), 7.18-7.16 (d, J=8.4 Hz, 2H). 5.35-5.33 (d, J=8.4 Hz, 1H), 4.85-4.80 (m, 1H), 3.91-3.56 (m, 7H, 3.24-3.19 (m, 1H), 3.01-2.99 (d, J=8.0 Hz, 2H), 1.44 (s, 9H). MS (ESI+) [M+H]+ 527.
Reaction SMILES: S1C=CC=C1CC(N1CCCC(C(O)=O)C1)=O.[C:18]([N:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([C:32]([O:34]CC)=[O:33])[CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>C(O)C>[C:18]([N:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([C:32]([OH:34])=[O:33])[CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)c2ccccc2)C1
Agent: O=C(O)C1CCCN(C(=O)Cc2cccs2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@H]1CCCN(C(=O)c2ccccc2)C1
Yield: 92.7 %

Procedure:
The reaction was run in the same manner as 1-(2-thiopeneacetyl)-3-piperidine carboxylic acid, starting with (S)-ethyl 1-benzoyl-3-piperidinecarboxylate (8.71 g; 33.31 mmol), 1N sodium hydroxide (100 ml) and absolute ethanol (100 ml), giving (S)-1-benzoyl-3-piperidinecarboxylic acid as a white solid (7.20 g). MS m/z (negative ion) 232 ([M-H]−; 100).