Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[CH:8][CH:7]=1.[I-].[Na+].[CH3:19][CH:20]1[CH2:24][CH2:23][CH2:22][NH:21]1>C(#N)C>[CH3:19][CH:20]1[CH2:24][CH2:23][CH2:22][N:21]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[CH:8][CH:7]=1
Reactant: CC1CCCN1
Reactant: ClCCCOc1ccc(-c2nccs2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC1CCCN1CCCOc1ccc(-c2nccs2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
A solution of 2-[4-(3-chloropropoxy)phenyl]-1,3-thiazole i88 (120 mg, 1 eq, 0.47 mmol) in acetonitrile (1 ml) is added to a solution of sodium iodide (10 mg, 0.1 eq, 0.07 mmol) and 2-methylpyrrolidine (0.1 ml, 2 eq, 0.9 mmol) in acetonitrile (1 ml). The mixture is stirred at 85° C. overnight, filtered, washed with acetonitrile, and concentrated under reduced pressure. Purification of the residue by chromatography over silicagel (eluent: dichloromethane/methanol/ammonia 96/4/0.4) affords 40 mg of 2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-thiazole 83.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[OH:10].[Cl-].[Al+3].[Cl-].[Cl-].[C:15](Cl)(=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18].Cl>[N+](C1C=CC=CC=1)([O-])=O.O>[OH:1][C:2]1[C:3]([OH:10])=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[C:7]=1[C:15]([CH2:16][CH:17]([CH3:19])[CH3:18])=[O:20]
Reactant: CC(C)CC(=O)Cl
Reactant: Oc1cc(O)c(O)c(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: CC(C)CC(=O)c1c(O)cc(O)c(O)c1O
Reaction time: 5 h
Yield: 27.2 %

Procedure:
Under an atmosphere of argon, 4.28 g (30.14 mmol) of 1,2,3,5-tetrahydroxybenzene (3) was dissolved by stirring in 70 ml of nitrobenzene. The solution was cooled with water. To the cold solution, 16.1 g (120.56 mmol, 4.00 equivalents) of granular aluminum chloride was added piecemeal and stirred. To the stirred mixture, 3.67 ml (30.1 mmol, 1.00 equivalent) of isovaleryl chloride was added dropwise. After 5 hours, the reaction solution was poured into 100 ml of a cold.2 M hydrochloric acid solution, stirred for 20 minutes, and extracted from ether. The organic layer was washed with water, distilled to remove ether, combined with a large volume of water, and distilled under reduced pressure to remove nitrobenzene. The residue was extracted from ether, washed with saturated brine, dried over sodium sulfate, and distilled under a reduced pressure to obtain a crude reaction product. By purifying the crude product by silica gel column chromatography (300 g of Wako Gel C-200, hexane:ethyl acetate=2:1), 1.85 g (yield 27.2%) of the product (9) was obtained in the form of yellow powder crystals.
Reaction SMILES: [F:1][C:2]([F:21])([S:19][CH3:20])[C:3]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.ClC1C=CC=C(C(OO)=[O:30])C=1.O>C(Cl)Cl>[F:21][C:2]([F:1])([S:19]([CH3:20])=[O:30])[C:3]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: CSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CS(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
To a 10 ml solution of 150 mg (0.47 mmol) of 3,3-difluoro-2-(2',4'-difluorophenyl)-3-methylthio-1-(1H-1,2,4-triazol-1-yl)propan-2-ol [Compound (1a-1)] in methylene chloride, 114 mg (0.56 mmol) of m-chloroperbenzoic acid were added at room temperature, followed by stirring for 30 minutes. To the reaction mixture, water was added, followed by extraction with chloroform. The extract was then washed successively with a 10% aqueous solution of sodium thiosulfate and a 10% aqueous solution of sodium carbonate, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The oil so obtained was purified by chromatography on a silica gel column using chloroform : methanol (10:1), whereby 64 mg of the title Compound (1b-1) [diastereomers (1b-1A):(1b-1B)=2.5:1] were obtained in the form of colorless crystals (yield: 40%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:11]=[C:12]([C:13]([O:15]CC)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].C(O)C.[OH-].[Na+]>C1COCC1>[CH3:3][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:1]
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)nc2c1cnn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2cc(C(=O)O)c3cnn(C(C)C)c3n2)cc1

Procedure:
The title compound was prepared in the same manner as described for intermediate 58 using ethyl 1-(1-methylethyl)-6-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (200 mg, 0.589 mmol), Ethanol (4 mL) and THF (1 mL), and sodium hydroxide (0.982 mL, 2.95 mmol). The final product was collected as 181 mg (98%). LCMS E-S (M+H)=312.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.63 (m, 6 H), 3.85 (s, 3 H), 5.35 (m, 1 H), 7.11 (d, J=9.1 Hz, 2 H), 8.15 (s, 1 H), 8.18-8.25 (m, 2 H), 8.33 (s, 1 H), 13.95 (br. s., 1 H).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8](OC(=O)C)(=[O:10])[CH3:9]>O1CCCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[C:8](=[O:10])[CH3:9]
Reactant: OCCNCCO
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N(CCO)CCO

Procedure:
315 g of diethanolamine were dissolved in 500 g of tetrahydrofuran in a round-bottom flask. Then, 310 g of acetic anhydride were slowly added. The temperature was kept below 5° C. with the aid of a cooling bath. When, after the dropwise addition, exothermic heat was no longer detectable, heating was slowly carried out to 100° C. Tetrahydrofuran and acetic acid were removed under vacuum.
Reaction SMILES: Br[CH2:2][C:3]([C:5]([F:8])([F:7])[F:6])=O.[CH3:9][O:10][CH2:11][C:12]1[S:16][C:15]([NH2:17])=[N:14][N:13]=1.O>COCCOC>[CH3:9][O:10][CH2:11][C:12]1[S:16][C:15]2=[N:17][C:3]([C:5]([F:8])([F:7])[F:6])=[CH:2][N:14]2[N:13]=1
Reactant: COCc1nnc(N)s1
Reactant: O=C(CBr)C(F)(F)F
Solvent: O
Solvent: COCCOC
Product: COCc1nn2cc(C(F)(F)F)nc2s1
Temperature: 80 °C
Yield: 46.7 %

Procedure:
Bromotrifluoroacetone (478 g, 2.5 mol, 1.05 eq) is added on a suspension of 5-(methoxymethyl)-1,3,4-thiadiazol-2-amine a1 (346 g, 2.4 mol, 1 eq) in 1,2-dimethoxyethane (6 l) at 20° C. The reaction mixture is heated to 80° C. until maximum conversion (<24 h). Water (4 l) is added to the reaction mixture at 32° C. and the expected compound crystallized out of the reaction mixture. The crystalline suspension is cooled to 10° C. to complete the crystallization process, filtered and the crystalline precipitate is washed with water (1.5 l) to afford 266 g of pure 2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole a2.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][C@@H:11]2[CH2:13][C@H:8]1[C:9](=[O:14])[S:10]2)=[O:6])[CH:2]=[CH2:3].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][C@@H:11]([SH:10])[CH2:13][C@H:8]1[C:9]([N:19]1[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]1)=[O:14])=[O:6])[CH:2]=[CH2:3]
Reactant: CN1CCNCC1
Reactant: C=CCOC(=O)N1C[C@@H]2C[C@H]1C(=O)S2
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@@H](S)C[C@H]1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 33 h

Procedure:
To a solution of (1S,4S)-5-allyloxycarbonyl-2-thia-5-azabicyclo[2.2.1]heptan-3-one (30.6 mg) in tetrahydrofuran (1 ml) was added 4-methylpiperazine (15.8 mg). The mixture was stirred for 33 hours at room temperature. After the reaction was over, the mixture was diluted with ethyl acetate (2 ml). Distillation of the solvent gave oily 1-[(2S,4S)-1-allyloxycarbonyl-4-mercapto-2-pyrrolidinecarbonyl]-4-methylpiperazine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:4][C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[C:6]([C:13]([O:15]CC)=O)[C:7]=1[C:8]([O:10]CC)=O.O.[NH2:35][NH2:36]>C(O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:10])[NH:36][NH:35][C:13](=[O:15])[C:6]=2[C:5]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])=[N:4][C:3]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1c(S(=O)(=O)c2ccc(C)cc2)nc(-c2ccccc2)c(N)c1C(=O)OCC
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)c2nc(-c3ccccc3)c(N)c3c(=O)[nH][nH]c(=O)c23)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To 0.251 g of 3-amino-4,5-diethoxycarbonyl-2-phenyl-6-(p-tolylsulfonyl)pyridine were added 2 ml of hydrazine monohydrate and 2 ml of ethanol, and the mixture was stirred at 90° C. for 2 hours. After ethanol was added, the mixture was cooled. The resulting precipitate was collected by filtration and washed with ethanol. The thus obtained precipitate was suspended in 30 ml of water, and 2 ml of acetic acid was added thereto. After the mixture was heated, it was cooled. The resulting precipitate was collected by filtration, washed with water and dried to give 0.15 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[N:9][C:8]2[C:3]1=[N:4][C:5]([Cl:12])=[N:6][C:7]=2Cl.[CH2:13]([NH2:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:12][C:5]1[N:4]=[C:3]2[C:8]([N:9]=[CH:10][N:2]2[CH3:1])=[C:7]([NH:21][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:6]=1
Reactant: NCCc1ccccc1
Reactant: Cn1cnc2c(Cl)nc(Cl)nc21
Product: Cn1cnc2c(NCCc3ccccc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 4 from 9-methyl-2,6-dichloro-9H-purine and phenethyl-amine.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)=[O:11])[CH:7]=[CH:8][CH:9]=1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]2[N:26]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=3)[N:27]=[CH:28][C:21]=12>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([C:10]([N:12]2[CH2:13][CH2:14][CH:15]([O:18][C:20]3[N:25]=[CH:24][N:23]=[C:22]4[N:26]([C:29]5[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:33][CH:34]=5)[N:27]=[CH:28][C:21]=34)[CH2:16][CH2:17]2)=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)cc1
Reactant: O=C(c1cccc(F)c1)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCN(C(=O)c5cccc(F)c5)CC4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 16 mL reaction vial was placed sodium hydride (48 mg, 60% in oil, 1.2 mmol) and 5 mL of THF. (3-Fluoro-phenyl)-(4-hydroxy-piperidin-1-yl)-methanone (66 mg, 0.3 mmol) was added to the suspension and the mixture was stirred 60 min under N2 at room temperature, followed by the addition of 4-chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (60 mg, 0.2 mmol). After stir another 2 hrs under N2 at room temperature, all of the starting chloropyrozolepyrimidines was completely converted as indicated by LCMS. The reaction mixture was then filtered through a syringe filter and purified HPLC to give Compound A8. 1H NMR (CDCl3, 400MHz) δ 1.95 (m, 2H), 2.21 (m, 2H), 3.11 (s, 3H), 3.45 (m, 1H), 3.68 (m, 1H), 3.75 (m, 1H), 4.20 (s, 1H), 5.72 (m, 1H), 7.12 (m, 1H), 7.16 (m, 1H), 7.22 (m, 1H), 7.41 (m, 1H), 8.11 (d, 2H), 8.27 (s, 1H), 8.62 (d, 2H), 8.67 (s, 1H). Exact mass calculated for C24H22FN5O4S 495.14, found 496.3 (MH+)
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[O:6]=[C:7]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[C:11]([CH2:28][CH2:29][CH3:30])[N:10]2[N:31]=[CH:32][N:33]=[C:9]2[N:8]1[CH:34]1CCC(=O)[CH2:36][CH2:35]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:4]=[C:3]1[CH2:36][CH2:35][CH:34]([N:8]2[C:7](=[O:6])[C:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][CH:19]=3)=[C:11]([CH2:28][CH2:29][CH3:30])[N:10]3[N:31]=[CH:32][N:33]=[C:9]23)[CH2:1][CH2:2]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCC(n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution (15 mL) of methyltriphenylphosphonium bromide (1.2 g) in tetrahydrofuran was added n-butyllithium (1.6M hexane solution, 2 mL) at 0° C., and the mixture was stirred at the same temperature for 30 min. The reaction mixture was warmed to room temperature, and further stirred for 30 min. A solution (5 mL) of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1 g) in tetrahydrofuran was added, and the mixture was stirred at 70° C. for 3 hr. The insoluble material was filtered off, and the obtained filtrate was extracted with ethyl acetate and 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.8 g, 80%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=2)[CH2:5]1)(=[O:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:13][CH:12]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(=O)N1CCCC(C(=O)c2ccc(F)cc2)C1
Product: CC(=O)N1CCCC(C(=O)c2ccc(N3CCCCC3)cc2)C1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture consisting of 3.73 g of 1-acetyl-3-(4-fluorobenzoyl)piperidine and 5 ml of piperidine was stirred at 100° C. for 24 hours and the reaction mixture was then worked up in the same manner as Example 1. The residue was recrystallized from ethyl ether-n-hexane to give 3.2 g of colorless crystals melting at 116°-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([S:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2C(=O)C3C(=CC=CC=3)C2=O)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.NN>C(O)C>[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:11]([S:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]#[N:13]
Reactant: COc1ccc(C(C#N)(CCCCCN2C(=O)c3ccccc3C2=O)Sc2ccc(C)cc2)cc1OC
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(C(C#N)(CCCCCN)Sc2ccc(C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 112.6 %

Procedure:
A mixture of 4.72 g of α-(3,4-dimethoxyphenyl)-1,3-dihydro-α-[(4-methylphenyl)thio]-1,3-dioxo-2H-isoindole-2-heptanenitrile, 100 mL of ethyl alcohol, and 7.0 mL of hydrazine hydrate is heated under reflux. In about a 30 minutes, a heavy precipitate forms. After 1.33 hours, the reaction is cooled to room temperature and concentrated in vacuo. The residue is warmed on a steam bath with 2N hydrochloric acid for 10 minutes. Diatomaceous silica and chloroform are added, the mixture is shaken thoroughly and then filtered through more diatomaceous silica. The organic phase is washed first with aqueous ammonia, then brine, and, after drying (sodium sulfate), it is concentrated in vacuo to give 3.97 g of the desired product as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[N:46]=[C:47]=[O:48]>CN(C)C=O>[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[NH:46][C:47]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:13]2)[CH2:5][CH2:6]1)=[O:48]
Reactant: O=C=Nc1ccccc1F
Reactant: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCNCC4)CC3)cccc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCN(C(=O)Nc5ccccc5F)CC4)CC3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
2-Isopropyl-1H-benzoimidazole-4-carboxylic acid (1-piperidin-4-ylmethylpiperidin-4-ylmethyl)amide (220 mg, 0.55 mmol) was dissolved in N,N-dimethylformamide (2.0 mL) at room temperature. To this solution was added N,N-diisopropylethylamine (143.2 mg, 1.1 mmol) followed by o-fluorophenylisocyanate (75.4 mg, 0.55 mmol). The resulting mixture was stirred at room temperature overnight, concentrated in vacuo and the residue purified by preparative reverse-phase HPLC to afford the bis trifluoroacetate salt of the title compound as a white solid (92.6 mg, 0.12 mmol, 22%). (m/z): [M+H]+ calcd for C30H39FN6O2 535.32; found 535.2. Retention time (anal. HPLC: 2-65% MeCN/H2O over 4 min)=2.09 min.
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH2:4][CH2:5]O)[CH3:2].S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH2:4][CH2:5][Cl:18])[CH3:2]
Reactant: CCN(CCO)c1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCN(CCCl)c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 91.7 %

Procedure:
To a solution of 3.0 g (14.3 mmol) of 4-[N-ethyl,N-(2-hydroxyethyl)amino]nitrobenzene in 20 ml of chloroform, 2.1 ml (28.8 mmol) of thionyl chloride were added. After the resultant mixture was stirred under heat at 80° C. for 2 hours, the solvent was distilled out under reduced pressure. The residue was purified by chromatography on a silica gel column (ethyl acetate/n-hexane=1/1), whereby 3.0 g of yellow powder were obtained (yield: 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](O)=[O:10])=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([Cl:17])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)C(C(=O)O)c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)C(C(=O)Cl)c1ccc(F)cc1
Reaction time: 0.75 h

Procedure:
50 g of 2-(p-fluorophenyl)-3-methylbutyric acid were dissolved in 200 ml of benzene and treated with 54.2 g of thionyl chloride. The mixture was stirred at 60° for 45 minutes and subsequently heated to reflux for 2 hours. After evaporation of the solvent the residue was distilled, whereby 2-(4-fluorophenyl)-3-methyl-butyryl chloride, b.p. 70°/93 Pa, was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]3[C:19](=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24](C#N)[CH:23]=4)[N:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:30][O:31]C1C=C(C2N=C(OS(C(F)(F)F)(=O)=O)C=C3C=2N=CC=C3)C=CC=1>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:13]=[C:14]3[C:19](=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:31][CH3:30])[CH:23]=4)[N:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(c2cc3cccnc3c(-c3cccc(C#N)c3)n2)CC1
Reactant: COc1cccc(-c2nc(OS(=O)(=O)C(F)(F)F)cc3cccnc23)c1
Product: CCOC(=O)C1CCC(c2cc3cccnc3c(-c3cccc(OC)c3)n2)CC1

Procedure:
This compound is prepared in an analogous way to compound 4-[8-(3-Cyano-phenyl)-[1,7]naphthyridin-6-yl]-cyclohexanecarboxylic acid ethyl ester from trifluoromethanesulfonic acid 8-(3-methoxy-phenyl)-[1,7]naphthyridin-6-yl ester. Purification is by chromatography followed by trituration with ether to yield a white solid. MS (AP+) 391.0
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[CH3:45][C:46]([O:49][C:50]([NH:52][C:53]1[CH:54]=[CH:55][CH:56]=[C:57]2[C:61]=1[NH:60][C:59]([C:62](O)=[O:63])=[CH:58]2)=[O:51])([CH3:48])[CH3:47].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:62]([C:59]2[NH:60][C:61]3[C:57]([CH:58]=2)=[CH:56][CH:55]=[CH:54][C:53]=3[NH:52][C:50](=[O:51])[O:49][C:46]([CH3:47])([CH3:45])[CH3:48])=[O:63])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc2cc(C(=O)O)[nH]c12
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc2cc(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
HATU (0.055 g, 0.145 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.030 g, 0.096 mmol), 7-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylic acid (0.026 g, 0.096 mmol) and DIPEA (0.025 mL, 0.145 mmol) in DMF (1 mL). The mixture was stirred at RT overnight then extracted with water and ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (hexane/EtOAc) to give the title compound (0.027 g, 44%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.59 (s, 1H), 9.32 (s, 1H), 9.07 (t, 1H), 7.81 (s, 1H), 7.67-7.77 (m, 1H), 7.44-7.57 (m, 3H), 7.39 (t, 1H), 7.27 (d, 1H), 7.17 (d, 1H), 6.96 (t, 1H), 4.57 (d, 2H), 1.5 (s, 9H). MS: m/z 569 (M).
Reaction SMILES: [CH2:1](OC1C=CC=CC=1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:17]([NH:24][CH:25]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:29]([O:28][C:26](=[O:27])[C@H:25]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[N:24]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:1]/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:30]
Reactant: CCOC(=O)C(Cc1ccccc1)NCc1ccccc1
Reactant: C(=Cc1ccccc1)COc1ccccc1
Product: CCOC(=O)[C@H](Cc1ccccc1)N(C/C=C/c1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.1 %

Procedure:
Following the general procedure using cinnamyloxybenzene (105 mg, 0.50 mmol) and ethyl 2-(benzylamino)-3-phenylpropanoate (212 mg, 0.75 mmol), the reaction was stirred for 2.5 h at rt. Column chromatography on silica gel (eluting with 10% EtOAc/hexanes) afforded the product as a pale yellow liquid (190 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH:11](Cl)Cl)[CH:3]=1.O.[NH2:15][NH2:16]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:7])[NH:16][N:15]=[CH:11]2
Reactant: NN
Reactant: O=C(O)c1ccc(Cl)cc1C(Cl)Cl
Solvent: CCO
Solvent: O
Product: O=c1[nH]ncc2cc(Cl)ccc12
Yield: 63.1 %

Procedure:
A solution of 23.9 g (0.1 mole) of 4-chloro-2-dichloromethylbenzoic acid and 16 g (0.32 mole) of hydrazine hydrate in 200 ml of ethanol was heated under reflux for 3 hours. The ethanol was evaporated under reduced pressure, and the residue recrystallized from ethanol to give 11.4 g (yield: 63%) of 6-chloro-1-phthalazinone having a melting point of 272°-273° C.