Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[Br:31][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(CCCO)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(CCCBr)cc1
Reaction time: 3 h
Yield: 84.8 %

Procedure:
Compound 13-1 (690 mg) was dissolved in methylene chloride (30 ml), triphenylphosphine (1.33 g) and N-bromosuccinimide (899 mg) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (830 mg) as a colorless oil.
Reaction SMILES: CN([CH:4]=[O:5])C.[CH3:6]/[C:7](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])=[CH:8]\[CH2:9][C:10]1[C:15]([OH:16])=[CH:14][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][C:11]=1[OH:22].Cl.C(Cl)(Cl)Cl.C[OH:35]>>[CH3:21][CH2:20][CH2:19][CH2:18][CH2:17][C:13]1[CH:14]=[C:15]([OH:16])[C:10]([CH2:9]/[CH:8]=[C:7](/[CH2:23][CH2:24][CH:25]=[C:26]([CH3:27])[CH3:28])\[CH3:6])=[C:11]([OH:22])[C:12]=1[C:4]([OH:5])=[O:35]
Reactant: CN(C)C=O
Reactant: CO
Reactant: CCCCCc1cc(O)c(C/C=C(\C)CCC=C(C)C)c(O)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCCCc1cc(O)c(C/C=C(\C)CCC=C(C)C)c(O)c1C(=O)O
Temperature: 120 °C

Procedure:
6-carboxylic acid-2-[(2E)-3,7-dimethylocta-2,6-dienyl]-5-pentyl-benzene-1,3-diol, Cannabigerolic Acid (CBGA) was prepared as follows. To a 10 mL conical flask was added 1 mL of a DMF solution of MMC. To this solution was added 2-[(2E)-3,7-dimethylocta-2,6-dienyl]-5-pentyl-benzene-1,3-diol (120 mg, 0.379 mmol). The flask was heated at 120° C. for 1 hour, following which the reaction mixture was dissolved in 100 mL of chloroform:methanol (2:1) solution. The pH of this solution was adjusted with dilute HCl to pH 2.0, and then partitioned using 50 mL H2O.
Reaction SMILES: C[N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)N.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH2:18][C:19]([CH3:21])=O)=[CH:13][CH:12]=1.O.[C:23](#N)C>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:23])[CH:8]=3)[NH:2][C:19]=2[CH3:21])=[CH:13][CH:12]=1
Reactant: CN(N)c1ccccc1
Reactant: CC(=O)CSc1ccc(Cl)cc1
Reactant: CC#N
Solvent: O
Product: Cc1ccc2[nH]c(C)c(Sc3ccc(Cl)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methylphenylhydrazine (7 g) in acetonitrile (100 ml) was added 1-[(4-chlorophenyl)thio]acetone (8.84 g) and water (10 ml). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue dissolved in dichloromethane. The solution was washed with sodium hydrogen carbonate, brine, dried (MgSO4) and concentrated in vacuo. The residue was recrystallised (methanol) to give the sub-title compound (6 g).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([C:17]#N)[CH:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1.Cl.[OH-:20].[Na+]>C(OCC)C.C(OCC)(=O)C>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([C:17](=[O:20])[CH3:1])[CH:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1
Reactant: [OH-]
Reactant: N#Cc1ccnc(-c2ccc(F)cc2)c1
Reactant: C[Mg]Br
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(=O)c1ccnc(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methylmagnesium bromide (1.85 g) was added to a suspension of 2-(4-fluorophenyl)pyridine-4-carbonitrile (1.0 g) in diethyl ether (10 mL), and the mixture was stirred at room temperature overnight. After adding ice and 2M hydrochloric acid and stirring, the resulting mixture was made basic with 2M aqueous sodium hydroxide solution. After exracting with ethyl acetate, the organic phase was separated out and the solvent was distilled off The resulting residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=98:2-80:20) to afford 1-[2-(4-fluorophenyl)pyridin-4-yl]ethanone (350 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1.Br[C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:19]2[CH:20]=[C:21]([NH2:22])[CH:23]=[CH:24][CH:25]=2)[CH:6]=[N:5][CH:4]=1
Reactant: Nc1cccc(Br)c1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cncc(-c2cccc(N)c2)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
3-methoxypyridine-5-boronic acid pinacol ester (0.205 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in DME (3 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.610 mL, 1.22 mmol) and Pd(PPh3)4 (0.02 g, 0.017 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (0-5% MeOH/CH2Cl2). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.067 g in 58% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[CH:8][CH:7]=[CH:6]2.[CH:14]([N:17]1[CH2:20][CH:19]([OH:21])[CH2:18]1)([CH3:16])[CH3:15].[OH-].[K+].[ClH:24]>>[ClH:24].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][CH2:20][CH:19]([OH:21])[CH2:18][NH:17][CH:14]([CH3:16])[CH3:15])=[CH:8][CH:7]=[CH:6]2
Reactant: CC(C)N1CC(O)C1
Reactant: COc1ccc2c(O)cccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COc1ccc2c(OCC(O)CNC(C)C)cccc2c1
Temperature: 140 °C
Yield: 57.5 %

Procedure:
A mixture of 9.5 parts of 6-methoxy-1-naphthol, 5.8 parts of 1-(iso-propyl)-3-azetidinol and 0.3 part of potassium hydroxide was heated under nitrogen gas at 140° C. for 8 hours with agitation. The reaction mixture was treated in the same manner as in Example 1, and when the resulting hydrochloride was recrystallized from iso-propyl alcohol, there was obtained 17.7 parts of 1-(6'-methoxy-1-naphthoxy)-3-(iso-propylamino)-2-propanol hydrochloride melting at 165°-167° C. The yield was 57.5%.
Reaction SMILES: [OH:1][C@H:2]1[CH2:8][CH2:7][C@@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:5][C:3]1=[O:4].[CH2:15]([O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].N(C(O)=O)=NC(O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH2:15]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:1][C@H:2]2[CH2:8][CH2:7][C@@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:5][C:3]2=[O:4])=[O:29])=[CH:31][CH:32]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC[C@@H]1CC[C@H](O)C(=O)O1
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Agent: O=C(O)N=NC(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCCCCCCCOc1ccc(C(=O)O[C@H]2CC[C@@H](CCCCCC)OC2=O)cc1
Reaction time: 8 h
Yield: 41.7 %

Procedure:
In dehydrated benzene were dispersed 200 mg of (2S,5R)-hydroxy-5-hexyl-δ-valerolactone synthesized in the same manner as described in Referential Example 4, 250 mg of p-octyloxybenzoic acid and 200 μl of azodicarboxylic acid, and 270 mg of triphenylphosphine was added to the dispersion and reaction was carried out with stirring overnight. The reacted solution was concentrated, and the concentrate was separated and purified by the silica gel column chromatography using n-hexane/benzene as the developing solvent. The obtained product was recrystallized from methanol to obtain 180 mg of (2S,5R)-2-(4-octyloxybenzoyloxy)-5-hexyl-δ-valerolactone. The NMR spectrum of the obtained compound is shown in FIG. 1. The results of the measurement of the phase transition behavior by a differential thermal scanning calorimeter and a polarization microscope are shown below: ##STR23##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])O[C:5]2=[O:12].[CH3:13][O:14][C:15](=[O:21])[C@H:16]([CH:18]([CH3:20])[CH3:19])[NH2:17].C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:17]([CH:16]([CH:18]([CH3:20])[CH3:19])[C:15]([O:14][CH3:13])=[O:21])[C:5]2=[O:12]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: COC(=O)[C@@H](N)C(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(C(C)C)N1C(=O)c2ccc(Br)cc2C1=O
Temperature: 80 °C

Procedure:
5-bromoisobenzofuran-1,3-dione (3 g, 13.21 mmol), L-valine methyl ester (3.31 g, 19.82 mmol) and triethyl amine (2.75 mL, 19.82 mmol) were taken in acetonitrile and heated at 80° C. for 24 h. The solvent was removed by distillation and the crude material obtained was purified using column chromatography (silicagel, 20% dichloromethane in petroleum ether) to afford the title compound.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][C:11]1([CH3:38])[CH2:16][CH:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:14][C:13]([CH3:37])([CH3:36])[NH:12]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1>[Cl:3][C:2]1[N:1]=[C:8]([N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:15]2[CH2:14][C:13]([CH3:37])([CH3:36])[NH:12][C:11]([CH3:38])([CH3:10])[CH2:16]2)[N:7]=[C:5]([N:17]([CH:15]2[CH2:16][C:11]([CH3:38])([CH3:10])[NH:12][C:13]([CH3:36])([CH3:37])[CH2:14]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[N:4]=1
Reactant: CCCCCCCCCCCCCCCCCCNC1CC(C)(C)NC(C)(C)C1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCCCCCCCN(c1nc(Cl)nc(N(CCCCCCCCCCCCCCCCCC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1

Procedure:
A solution of 12.0 g of cyanuric chloride in 100 ml of xylene was added dropwise at 20°-25° C. to a solution of 54.0 g of 2,2,6,6-tetramethyl-4-(octadecylamino)piperidine in 200 ml of xylene. The resulting mixture was then heated under reflux for 8 hours, after which it was neutralised with an aqueous solution of potassium carbonate and then extracted with benzene. The extract was dried over anhydrous potassium carbonate and then the solvent was distilled off. The resulting residue was purified by column chromatography through silica gel, eluted with a 20:1:1 by volume mixture of ethyl acetate, ethanol and triethylamine, to give the title compound in the form of crystals. These were recrystallised from ethyl acetate, giving the purified title compound in the form of colourless crystals melting at 68°-70° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:35]([O:36][CH3:37])=[CH:34][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[CH:6]=1)[N:14]=[CH:13][C:12]([C:17]#[N:18])=[C:11]3[NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:27]2[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=2)=[C:22]([Cl:33])[CH:21]=1.[NH:38]1[CH:42]=[CH:41][N:40]=[N:39]1.[OH-].[Na+]>CN(C)C=O>[Cl:33][C:22]1[CH:21]=[C:20]([NH:19][C:11]2[C:10]3[C:15](=[CH:16][C:7]4[CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:39]5[N:40]=[CH:41][CH:42]=[N:38]5)[C:35]([O:36][CH3:37])=[CH:34][C:8]=4[CH:9]=3)[N:14]=[CH:13][C:12]=2[C:17]#[N:18])[CH:25]=[CH:24][C:23]=1[S:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1
Reactant: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1OCCCl
Reactant: c1c[nH]nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1OCCn1nccn1
Temperature: 80 °C
Yield: 19.3 %

Procedure:
A mixture of 0.3 g (0.55 mmol) of 8-(2-chloroethoxy)-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.32 mL (5.5 mmol) of 1H-1,2,3-triazole and 0.1 g (2.5 mmol) of sodium hydroxide powder in 5 mL of N,N-dimethyl formamide is heated at 80° C. for 4.5 hours, then cooled and poured on to ice. The solid is collected by filtration, washed with water and dried. The two isomers are separated by silica gel chromatography, utilizing a 99:1 to 85:15 gradient of ethyl acetate/methanol. The less polar material, 0.062 g of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-(2-[1,2,3]triazol-2-yl-ethoxy)benzo[g]quinoline-3-carbonitrile is obtained as yellow solid, mp 235–237° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)=[O:4].Cl.C(N=C=NCCCN(C)C)C.O[N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=N1.NCC1C=CC=CN=1>CN(C)C=O.O>[N:31]1[CH:32]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:33][NH:29][C:11]([C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:15][CH:14]=1)=[O:13]
Reactant: On1nnc2ccccc21
Reactant: COC(=O)CCc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NCc1ccccn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(C(=O)NCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.1 %

Procedure:
To a solution of 4-[2-(methoxycarbonyl)ethyl]benzoic acid (200 mg) in N,N-dimethylformamide were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (221 mg), 1-hydroxybenzotriazole (169 mg) and 2-aminomethylpyridine (114 mg) in water bath, and the mixture was stirred for 24 hours at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by a preparative thin layer chromatography (dichloromethane:methanol=10:1, V/V) to give methyl 3-[4-(2-pyridylmethylcarbamoyl)phenyl]propionate (218 mg).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CCOCC.C([Li])CCC.[Cl:24][Si:25](Cl)([CH3:27])[CH3:26]>CCCCCC>[Cl-:24].[CH3:26][SiH:25]([CH3:27])[CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: C[Si](C)(Cl)Cl
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C[SiH](C)C1c2ccccc2-c2ccccc21
Product: [Cl-]
Temperature: -10 °C
Yield: 43 %

Procedure:
A 1 liter four-neck flask equipped with a reflux tube, a thermometer and a dropping funnel was thoroughly purged with nitrogen and dried. To the flask, fluorene (5.00 g, 30 mmol) and dehydrated ether (100 ml) were introduced. Under stirring at -10° C., a hexane solution of n-butyllithium (30 mmol) was dropwise added over a period of 30 minutes. After the dropwise addition, the temperature of the system was allowed to spontaneously and slowly rise to room temperature, followed by stirring at room temperature for 4 hours. The reaction liquid became a yellow slurry. The slurry was dropwise added to a dichlorodimethylsilane (18.24 ml, 150 mmol)/dehydrated ether (100 ml) solution under stirring at -10° C. over a period of 1 hour. After the temperature of the system was allowed to spontaneously rise to room temperature, the reaction mixture was stirred over night. Lithium chloride was removed by means of pressure filteration of the resulting solution using a glass filter (G-5). Further the solvent and the unreacted dichlorodimethylsilane remained in the filtrate were removed under reduced pressure. The resulting filtrate was reslurried with dehydrated hexane (100 ml) and subjected to pressure filteration using a glass filter (G-5) to obtain a white powder (3.30 g, yield: 43%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8]Cl)[CH:7]=1.[C-:10]#[N:11].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:10]#[N:11])[CH:5]=[N:4][CH:3]=1
Reactant: [C-]#N
Reactant: ClCc1cncc(Br)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
3-Bromo-5-chloromethyl-pyridine (0.45 g; 2.2 mmol) was dissolved in DMF (10 mL). Potassium cyanide (0.21 g, 3.27 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The organic phases were washed with water, brine and dried over Na2SO3 filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 7% EtOAc in Hexanes to provide 2-(5-bromopyridin-3-yl)acetonitrile (200 mg, 46.5%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.68 (d, 1H, J=2 Hz), 8.51 (d, 1H, J=2 Hz), 7.88 (t, 1H, J=2 Hz), 3.77 (s, 2H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]=[CH:28][C:27]([CH2:30][C:31]([NH2:33])=[O:32])=[C:26]([NH:34][CH2:35][C:36]4[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=4)[CH:25]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=O)(C)(C)C.Cl.C(OCC)(=O)C>C(Cl)(Cl)Cl>[NH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]=[CH:28][C:27]([CH2:30][C:31]([NH2:33])=[O:32])=[C:26]([NH:34][CH2:35][C:36]4[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=4)[CH:25]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCN1CCN(c2ccc(Nc3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)cc2)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: NCCN1CCN(c2ccc(Nc3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
18 mg of 6-[(4-{4-[2-(tert-butoxycarbonyl)aminoethyl]piperazin-1-yl}phenyl)amino]-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (the compound of Example 247) was dissolved in 0.5 mL of chloroform, to which, under ice cooling, 0.5 mL of 4 mol/L hydrochloric acid-ethyl acetate was added, and stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=10:1) to obtain 15 mg (95%) of the title compound as a slight yellow crystalline powder.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].C([N:8]([CH2:11]C)[CH2:9]C)C.C1[CH2:17][O:16][CH2:15][CH2:14]1>>[CH3:17][O:16][CH2:15][CH2:14][CH2:4][N:2]1[CH2:1][CH2:9][NH:8][CH2:11][CH2:3]1
Reactant: CN(C)C=O
Reactant: C1CCOC1
Reactant: CCN(CC)CC
Product: COCCCN1CCNCC1

Procedure:
In a similar manner to Step 1 of Example 224, bromide was obtained from (E)-{4-[2-(1H-indazol-3-yl)vinyl]-3-nitrophenyl}methanol (0.30 g, 1.0 mmol) obtained in Step 1 of Example 306, carbon tetrabromide (1.0 g, 3.1 mmol) and triphenylphosphine (0.80 mg, 3.1 mmol). Further, in a similar manner to Step 2 of Example 224, a crude product was obtained from DMF (6.0 mL) and 1-(3-methoxypropyl)piperazine (0.48 g, 3.1 mmol), triethylamine (0.43 mL, 3.1 mmol) and THF (6.0 mL), and the product was used for next step without isolation. In a similar manner to Example 2, the crude product was treated with tin (0.39 g, 3.3 mmol), concentrated hydrochloric acid (1.4 mL) and ethanol (8.9 mL), to obtain (E)-2-[2-(1H-indazol-3-yl)vinyl]-5-[4-(3-methoxypropyl)piperazin-1-ylmethyl]phenylamine (0.34 g, 81%).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3][CH:2]=1.[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]2[N:22]=[C:21]([NH2:23])[NH:20][N:19]=2)[CH:13]=[C:14]([Cl:16])[CH:15]=1.ClC1C=C(N=C=S)C=C(Cl)C=1C#N>O>[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]2[N:22]=[C:21]([NH:23][CH2:7][C:5]3[CH:6]=[N:1][CH:2]=[N:3][CH:4]=3)[NH:20][N:19]=2)[CH:13]=[C:14]([Cl:16])[CH:15]=1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Reactant: O=Cc1cncnc1
Agent: N#Cc1c(Cl)cc(N=C=S)cc1Cl
Solvent: O
Product: Clc1cc(Cl)cc(Nc2n[nH]c(NCc3cncnc3)n2)c1
Yield: 76.2 %

Procedure:
A solution of pyrimidine-5-carbaldehyde (54 mg, 0.5 mmol) and N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (122 mg, 0.50 mmol) and picolineborane (54 mg, 0.5 mmol) was stirred at rt for 4 hours. The mixture was poured into water (20 mL) and extracted with EtOAc (3×10 mL). The extract was dried with sodium sulfate and the solvent was reduced to 2 mL. The remaining residue was loaded on a 25 g silica gel column and eluted with 5% MeOH in ethyl acetate to give 128 mg (76.2%) of desired product as a white solid. MS +m/z: 335.90 (M+H)+
Reaction SMILES: C(O)C.O.[OH-].[K+].[CH2:7]([O:9][CH:10]([N:12]1[C:16]2[S:17][C:18]([C:20]([O:22]CC)=[O:21])=[CH:19][C:15]=2[C:14]([NH:25][C:26]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[O:27])=[N:13]1)[CH3:11])[CH3:8]>O1CCCC1>[CH2:7]([O:9][CH:10]([N:12]1[C:16]2[S:17][C:18]([C:20]([OH:22])=[O:21])=[CH:19][C:15]=2[C:14]([NH:25][C:26]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[O:27])=[N:13]1)[CH3:11])[CH3:8]
Reactant: CCOC(=O)c1cc2c(NC(=O)c3cccs3)nn(C(C)OCC)c2s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C)n1nc(NC(=O)c2cccs2)c2cc(C(=O)O)sc21
Temperature: 85 °C
Yield: 29.7 %

Procedure:
1 cm3 of ethanol, 1 cm3 of water and 0.29 g (5.1 mmol) of potassium hydroxide are successively added with stirring to a solution of 1.0 g (2.3 mmol) of ethyl 1-(1-ethoxyethyl)-3-[(thiophene-2-carbonyl)amino]-1H-thieno[2,3-c]pyrazole-5-carboxylate in 8 cm3 of tetrahydrofuran. The reaction medium is heated at a temperature in the region of 85° C. for 2 hours and is then cooled to a temperature in the region of 25° C. and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. The residue is dissolved in water and extracted with diethyl ether. The aqueous phase is acidified to a pH of about 5-6 by adding solid citric acid, and is then extracted three times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 0.25 g of 1-(1-ethoxyethyl)-3-[(thiophene-2-carbonyl)amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid is thus obtained in the form of a yellowish solid. Acidification of the aqueous phase to a pH of about 3-4, followed by the same treatment allows a second fraction of 0.25 g of 1-(1-ethoxyethyl)-3-[(thiophene-2-carbonyl)amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid to be obtained in the form of a yellowish solid. (Rf=0.15, thin-layer chromatography on silica gel, eluent: dichloromethane/methanol (90/10 by volume)).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][C:17]1[O:21][N:20]=[C:19]([CH2:22][CH2:23][CH3:24])[N:18]=1)(C)(C)C>C(Cl)Cl>[CH2:22]([C:19]1[N:18]=[C:17]([CH2:16][CH2:15][NH2:14])[O:21][N:20]=1)[CH2:23][CH3:24]
Reactant: CCCc1noc(CCNC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1noc(CCN)n1

Procedure:
TFA (6 ml) is added to a stirred solution of [2-(3-propyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamic acid tert-butyl ester (0.67 g, 2.62 mmol) in DCM (10 ml). After 1 hor the solvents are removed to afford the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1.[I:20]C1C=CC2N(C=C(C(OCC)=O)N=2)C=1>>[I:20][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1
Reactant: O=C(Nc1ccccc1)c1cn2cc(Br)ccc2n1
Reactant: CCOC(=O)c1cn2cc(I)ccc2n1
Product: O=C(Nc1ccccc1)c1cn2cc(I)ccc2n1

Procedure:
By working in the same manner as for the preparation of Intermediate 1, replacing the ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate with ethyl 6-iodoimidazo[1,2-a]pyridine-2-carboxylate, 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide is obtained in the form of a beige-coloured solid.