Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]([NH2:14])=[O:13].[F:15]C(F)(F)C1C=CC=C2C=1C=CN2CC(N)=O>>[F:15][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]([NH2:14])=[O:13]
Reactant: NC(=O)Cn1ccc2c(C(F)(F)F)cccc21
Reactant: NC(=O)Cn1ccc2c(Cl)cccc21
Product: NC(=O)Cn1ccc2c(F)cccc21

Procedure:
2-(4-chloro-1H-indol-1-yl)acetamide 2 (MS (LC-MS, MH+): 209/211)) and 2-[4-(trifluoromethyl)-1H-indol-1-yl]acetamide 2a can be synthesized according to the same method.
Reaction SMILES: Cl.CN(C)S([N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][N:13]([CH2:26][C:27]1[CH:51]=[CH:50][C:30]([CH2:31][N:32]2[C:36](=[O:37])[CH2:35][C:34]3([CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38]3)[CH2:33]2)=[CH:29][CH:28]=1)[CH2:14][C:15]1[N:16](S(N(C)C)(=O)=O)[CH:17]=[CH:18][N:19]=1)(=O)=O.[OH-].[Na+]>>[NH:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][N:13]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][N:32]2[C:36](=[O:37])[CH2:35][C:34]3([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[CH2:33]2)=[CH:50][CH:51]=1)[CH2:14][C:15]1[NH:19][CH:18]=[CH:17][N:16]=1
Reactant: CN(C)S(=O)(=O)n1ccnc1CN(Cc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)CC2=O)cc1)Cc1nccn1S(=O)(=O)N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CC2(CCNCC2)CN1Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A 2N-hydrochloric acid (5 mL) solution of the compound (480 mg) obtained in Example 45 was stirred at 80° C. for 3 hours. After the reaction solution was cooled to room temperature, the pH was adjusted to 12 with an aqueous 2N-sodium hydroxide solution. The aqueous layer was extracted four times with dichloromethane. The combined organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:10%-saturated aqueous ammonia-methanol=1:0→7:3) to obtain the title compound (277 mg) having the following physical properties.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=C(C(=O)C)[O:10][N:9]=2)=[CH:4][CH:3]=1.FC1C=CC(C#N)=CC=1.Cl.NO>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:12])[NH:9][OH:10])=[CH:4][CH:3]=1
Reactant: CC(=O)c1nc(-c2ccc(F)cc2)no1
Agent: Cl
Agent: N#Cc1ccc(F)cc1
Agent: NO
Product: N=C(NO)c1ccc(F)cc1

Procedure:
In another embodiment, intermediate compounds I-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethanol and 1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethanone may be prepared as described in Scheme 10D. In this route, 4-fluoro-benzonitrile is reacted with hydroxylamine hydrochloride to provide 4-fluoro-N-hydroxybenz-imidamide. In one embodiment, the reaction is performed at refluxing temperatures. In another embodiment, the reaction is performed in the presence of a lower alkyl alcohol such as ethanol, and a base such as sodium hydroxide or potassium hydroxide. The resultant compound is then reacted with 2-hydroxy-propionic acid to provide 1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethanol. In one embodiment, the reaction is performed in the presence of DMSO, DCC, and HOBt. 1-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)ethanol is then oxidized to 1-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)ethanone. In one embodiment, the oxidation is performed using manganese dioxide in dioxane.
Reaction SMILES: Cl[P:2]1[S:6][CH2:5][CH2:4][O:3]1.[CH:7]([NH:10][CH:11]([CH3:13])[CH3:12])([CH3:9])[CH3:8]>CCCCC>[CH:7]([N:10]([P:2]1[S:6][CH2:5][CH2:4][O:3]1)[CH:11]([CH3:13])[CH3:12])([CH3:9])[CH3:8]
Reactant: ClP1OCCS1
Reactant: CC(C)NC(C)C
Solvent: CCCCC
Product: CC(C)N(C(C)C)P1OCCS1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 1 (0.2 mol) is dissolved in n-pentane (300 mL) and diisopropylamine (0.4 mol) is added dropwise. The reaction mixture is stirred at room temperature for 30 minutes, after which dhisopropylamine hydrochloride is filtered off, solvent is evaporated under reduced pressure and crude product is purified by vacuum distillation. Product 2 is obtained as the fraction boiling at 70° C./0.1 mm Hg and is characterized by 31P NMR arid mass spectroscopy.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]2[CH:6]=[N:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.N1C=CC=CC=1.[Cl:28][CH2:29][C:30]1[S:31][CH:32]=[C:33]([C:35](Cl)=[O:36])[N:34]=1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[C:4]([NH:21][C:35]([C:33]2[N:34]=[C:30]([CH2:29][Cl:28])[S:31][CH:32]=2)=[O:36])[CH:3]=1
Reactant: O=C(Cl)c1csc(CCl)n1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(N)cc(Br)cc32)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ncc3c(NC(=O)c4csc(CCl)n4)cc(Br)cc32)cc1
Temperature: -10 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
A three necked rounded bottomed flask was charged with 6-bromo-1-[(4-methylphenyl)sulfonyl]-1H-indazol-4-amine (12.7 g), anhydrous DCM (100 ml) and pyridine (7.5 ml) then placed under a nitrogen atmosphere and cooled to −10° C. A suspension of 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (9.39 g) in anhydrous DCM (75 ml) was added in one portion. The reaction mixture was stirred at room temperature for ˜4 hrs. Additional 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (1.36 g) in anhydrous DCM was added in one portion and the reaction was stirred overnight. The suspension was filtered, washing sparingly with DCM, then dried on the vacuum pump to give title compound (15.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=3[C:10]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:9]2[Cl:32])[CH:5]=[CH:6][CH:7]=1.C=O.[BH3-][C:36]#N.[Na+]>C1COCC1>[Cl:32][C:9]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH3:36])[CH:3]=2)[C:12]2[N:13]=[CH:14][N:15]=[C:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[C:11]=2[C:10]=1[C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1c(-c1ccc(Cl)cc1)c(Cl)n2-c1cccc(N)c1
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1cccc(-n2c(Cl)c(-c3ccc(Cl)cc3)c3c(NC(=O)OC(C)(C)C)ncnc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
A mixture of tert-butyl 7-(3-aminophenyl)-6-chloro-5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylcarbamate (21) (421 mg, 0.89 mmol), aqueous HCHO (109 mg, 1.34 mmol) and 4 Å MS (3.0 g) in dry THF (5.0 mL) was stirred at r.t. overnight. NaBH3CN (56 mg, 0.89 mmol) was added and stirred at r.t. for 1 hr before the reaction was quenched with sat. NaHCO3 solution (10.0 mL), and was extracted with DCM (20.0 mL×2). The combined organic phases was washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatographic (silica gel, 0 to 40% EA in PE) to afford tert-butyl 6-chloro-5-(4-chlorophenyl)-7-(3-(methylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylcarbamate (22) (82 mg, 19% yield) as a yellow solid. LC-MS (ESI): m/z (M/M+2) 483.1/485.8.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:9]2[C:10](=[O:14])[CH2:11][CH2:12][O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3].[Br:24]Br.O>C(Cl)(Cl)Cl>[Br:24][CH:11]1[C:10](=[O:14])[C:9]2[CH:15]=[C:16]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[O:13][CH2:12]1
Reactant: CS(=O)(=O)Nc1cc2c(cc1Oc1ccccc1)C(=O)CCO2
Reactant: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1cc2c(cc1Oc1ccccc1)C(=O)C(Br)CO2
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
In 300 ml of chloroform was dissolved 33.3 g of 2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. To this solution being maintained at 25°-30° C. was dropwise added 16.3 g of bromine in 30 minutes. After the completion of the dropwise addition, the mixture was stirred for 30 minutes at 25°-30° C. 100 ml of water was added thereto. The organic layer was separated, washed with a 5% aqueous sodium thiosulfate solution, water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 40.1 g (yield: 97.3%) of 3-bromo-2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1.O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)c1ccc([N+](=O)[O-])c(O)c1
Yield: 53.6 %

Procedure:
3-Hydroxy-4-nitro-benzoic acid 1a (10 g, 54.60 mmol) was dissolved in 125 mL of toluene followed by the addition of benzyl alcohol (9 g, 83.20 mmol) and p-toluenesulfonic acid (1 g, 5.30 mmol). The reaction solution was heated to reflux for 16 hours in water segregator. The resulting solution was added with 50 mL of ethyl acetate, washed with water (50 mL) and saturated sodium chloride solution (50 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound benzyl 3-hydroxy-4-nitro-benzoate 29a (8 g, yield: 53.7%) as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:6][CH:5]=1.C([O-])=O.[NH4+]>C(O)C.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][N:12]2[C:13](=[O:22])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]2=[O:21])=[CH:8][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1C=Cc1ccc(CCO)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCc1ccc(CCO)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-{2-[4-(2-Hydroxy-ethyl)-phenyl]-vinyl}-isoindole-1,3-dione (Preparation 9, 10 g) in ethanol and ethyl acetate (350 mL each) was added 30% palladium hydroxide on carbon (1.44 g) followed by ammonium formate (21.5 g). The reaction was heated to 80° C. for 4 hours. Additional palladium hydroxide on carbon (1.44 g) and ammonium formate (21.5 g) were added and the reaction was stirred at 80° C. for 18 hours. The reaction was cooled, filtered through a pad of Arbocel® and rinsed with methanol. The solvent was removed under reduced pressure and the resulting white solid was partitioned between dichloromethane (200 ml) and water (100 ml). The aqueous layer was separated and extracted with further dichloromethane (2×50 mL). The combined organic layers were dried (sodium sulphate) and the solvent removed in vacuo to give the title compound as an off-white solid, 9.11 g.
Reaction SMILES: [C:1]12([C:11]3[C:12]([O:21][CH3:22])=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=3)[C:16](O)=[O:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>>[C:1]12([C:11]3[C:12]([O:21][CH3:22])=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=3)[C:16]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)=[O:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NCCc1ccc(O)cc1
Reactant: COc1cc(O)c(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Product: COc1cc(O)c(C(=O)NCCc2ccc(O)cc2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
0.15 g of the target compound is obtained as solid of a light color in substantially the same manner as in (2) of Example 1, except for using 5-adamantan-1-yl-2-hydroxy-4-methoxybenzoic acid instead of 5-adamantan-1-yl-2,4-dihydroxybenzoic acid and using tyramine instead of dopamine.
Reaction SMILES: [CH:1](=[C:8]1[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.Cl>CO>[CH2:1]([CH:8]1[C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C(=Cc2ccccc2)C(=O)N1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1NC(=O)C(Cc2ccccc2)C(=O)N1

Procedure:
To a suspension of 5-benzylidenebarbituric acid (4 g) in 200 ml of methanol are added portionwise 1.4 g of sodium borohydride. After 10 minutes from the end of the addition, 100 ml of water are added and the mixture is acidified with 1 N hydrochloric acid to pH=2. The solvent is evaporated off and the aqueous phase is extracted with ethyl acetate. The pooled extracts are dried over sodium sulfate and concentrated to dryness. 3.6 g of the product crystallize, m.p. 207-209° C.
Reaction SMILES: Cl[Sn]Cl.[CH3:4][C:5]1[C:13]2[S:12][CH:11]=[N:10][C:9]=2[CH:8]=[C:7]([N+:14]([O-])=O)[CH:6]=1.[OH-].[Na+]>Cl>[CH3:4][C:5]1[C:13]2[S:12][CH:11]=[N:10][C:9]=2[CH:8]=[C:7]([NH2:14])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])cc2ncsc12
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: Cc1cc(N)cc2ncsc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 570.9 %

Procedure:
To a solution of SnCl2 (1.5 g, 1.9 mmol) in 5.0 mL of HCl was added 7-methyl-5-nitrobenzothiazole (65 mg, 0.32 mmol) in a portion and resulting reaction mixture was stirred for 1 h at 25° C. The reaction mixture was basified with aqueous NaOH and extracted with EtOAc and CHCl3. Combined organic layers were dried over Na2SO4 and concentrated in vacuo, yielding an oil (0.30 g, >95%) which was identified as the desired amine (>95% pure) and subjected to the following reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][SiH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:11][C:12]1[CH:13]=[C:14]([N:19]([C:28]2[CH:35]=[CH:34][C:31]([CH:32]=[CH2:33])=[CH:30][CH:29]=2)[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]>[Pt].[Pt].C[Si](C)(C)O[Si](C)(C=C)C=C.C[Si](C)(C)O[Si](C)(C=C)C=C.C[Si](C)(C)O[Si](C)(C=C)C=C.C1(C)C=CC=CC=1>[CH3:27][C:22]1[CH:21]=[C:20]([N:19]([C:28]2[CH:29]=[CH:30][C:31]([CH2:32][CH2:33][Si:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[CH:34][CH:35]=2)[C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([CH3:11])[CH:13]=2)[CH:25]=[CH:24][C:23]=1[CH3:26]
Reactant: C=Cc1ccc(N(c2ccc(C)c(C)c2)c2ccc(C)c(C)c2)cc1
Reactant: CCO[SiH](OCC)OCC
Agent: [Pt]
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccc(N(c2ccc(C)c(C)c2)c2ccc(C)c(C)c2)cc1)(OCC)OCC
Temperature: 25 °C

Procedure:
40 mL of toluene, 6.0 g of triethoxysilane, and 0.54 mmol of a toluene solution of tris-(tetramethyldivinyldisiloxane) diplatinum (0) were placed in a three-neck flask. While stirring at room temperature, 20 mL of a toluene solution of 9.9 g of 4-[N,N-bis-(3,4-dimethylphenyl)amino]styrene was dropped into the flask. Upon completion of addition of drops, the mixture was stirred for 3 hours at 70° C. The solvent was removed under reduced pressure, and a lemon-yellow oil of 4-[N,N-bis-(3,4-dimethylphenyl)amino][2-(triethoxysilyl)ethyl]benzene was obtained. The yield was 13.4 g (yield rate of 90.1%). This refined material was subjected to the same process as in Practical Example 1, and platinum was measured in the same manner. The platinum concentration of this refined material was 1.9 ppm.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1)([CH3:18])[CH3:17].[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:27][CH2:26][C:23]3[CH:24]=[CH:25][C:20]([NH:19][CH:16]([CH3:17])[CH3:18])=[N:21][CH:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(NC(C)C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(NC(C)C)nc2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, N-isopropyl-5-vinylpyridin-2-amine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:14]([C:43]([O:45]C(C)(C)C)=[O:44])=[N:15][C:16]([N:19]3[CH2:28][CH2:27][C:26]4[C:21](=[C:22]([C:29](=[O:42])[NH:30][C:31]5[S:32][C:33]6[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:34]=6[N:35]=5)[CH:23]=[CH:24][CH:25]=4)[CH2:20]3)=[CH:17][CH:18]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:14]([C:43]([OH:45])=[O:44])=[N:15][C:16]([N:19]3[CH2:28][CH2:27][C:26]4[C:21](=[C:22]([C:29](=[O:42])[NH:30][C:31]5[S:32][C:33]6[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:34]=6[N:35]=5)[CH:23]=[CH:24][CH:25]=4)[CH2:20]3)=[CH:17][CH:18]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5cc(F)c(F)cc5s4)c3C2)ccc1-c1cnn(Cc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1nc2cc(F)c(F)cc2s1)c1cccc2c1CN(c1ccc(-c3cnn(Cc4ccccc4)c3)c(C(=O)O)n1)CC2
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 7D (0.085 g) in dichloromethane (0.5 mL) was added TFA (0.5 mL) and the reaction was stirred overnight. The reaction mixture was concentrated and dried to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 12.98 (s, 1H), 8.20 (dd, 1H), 7.93-7.83 (m, 2H), 7.70 (d, 1H), 7.58 (dd, 2H), 7.47-7.19 (m, 7H), 6.94 (d, 1H), 5.32 (s, 2H), 4.93 (s, 2H), 3.86 (t, 2H), 2.99 (t, 2H).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]>Cl>[Cl:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: OCCCCCl
Reactant: C1=COCCC1
Agent: Cl
Product: ClCCCCOC1CCCCO1
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
Dihydropyran (15.5 g) was added dropwise to a mixture of 4-chlorobutanol (20 g) and hydrochloric acid (18M, 1 drop) at RT. The mixture was stirred for 30 min and washed with H2O (100 ml), aqueous NaHCO3 (1M, 50 ml) and BR (50 ml). The dried liquid was heated under reduced pressure to leave the title compound as a colourless liquid (31.9 g). T.l.c. [L] Rf 0.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([NH:8][C:9]([NH:11][C:12]2[C:13]([CH3:19])=[N:14][N:15]([CH3:18])[C:16]=2[CH3:17])=[S:10])[CH:7]=1.[CH3:21]I>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([NH:8]/[C:9](=[N:11]\[C:12]2[C:13]([CH3:19])=[N:14][N:15]([CH3:18])[C:16]=2[CH3:17])/[S:10][CH3:21])[CH:7]=1
Reactant: CI
Reactant: Cc1ccc(Cl)cc1NC(=S)Nc1c(C)nn(C)c1C
Solvent: CC(C)=O
Product: CS/C(=N/c1c(C)nn(C)c1C)Nc1cc(Cl)ccc1C
Yield: 73.5 %

Procedure:
Under anhydrous conditions, a solution of 1-(5-Chloro-2-methyl-phenyl)-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-thiourea (2.3 g, 7.5 mmol) produced in example 8 and methyl iodide (0.94 mL, 15 mmol) in 70 mL of acetone was stirred at ambient temperature for 64 hours. The reaction mixture was concentrated in vacuo and partitioned between CH2Cl2 and saturated aqueous NaHCO3 solution. The organic phase was washed with dilute Na2S2O3 and dried (Na2SO4). Removal of solvent and crystallization of the residue from Et2O provided 1.78 g of title compound as a white solid (74% of theory, m.p. 134-135° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7]([Cl:12])[N:6]=1)=[O:4].[S:13]1(=[O:19])(=[O:18])[CH2:17][CH2:16][CH2:15][NH:14]1.N1C=CC=CC=1C(=O)CC(C1C=CC=CN=1)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]I.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:14]2[CH2:15][CH2:16][CH2:17][S:13]2(=[O:19])=[O:18])=[C:7]([Cl:12])[N:6]=1)=[O:4]
Reactant: O=S1(=O)CCCN1
Reactant: COC(=O)c1ccc(Br)c(Cl)n1
Agent: [Cu]I
Agent: O=C(CC(=O)c1ccccn1)c1ccccn1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(N2CCCS2(=O)=O)c(Cl)n1
Yield: 40 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-bromo-6-chloro-pyridine-2-carboxylic acid methyl ester (Example 9 c, 1 g, 4 mmol), isothiazolidine 1,1-dioxide (730 mg, 06 mmol), copper(I) iodide (150 mg, 0.8 mmol), 1,3-di(pyridin-2-yl)propane-1,3-dione (CAN 10198-89-7, 180 mg, 0.8 mmol) and potassium carbonate (1.1 g, 8 mmol) in DMF (20 mL) was reacted for 24 h at 110° C. The reaction mixture was poured into water, and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 4 g, 10% ethyl acetate in petroleum ether) to yield the title compound (0.048 g, 1.6 mmol, 41.4%) as yellow solid; MS (EI): m/e=291.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.[Cl-].[NH4+]>C1COCC1.CO.CCOC(C)=O.[Zn]>[NH2:14][C:10]1[C:9](=[O:17])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=c1c([N+](=O)[O-])cccn1-c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of 1-(4-fluorophenyl)-3-nitropyridin-2(1H)-one (610 mg, 2.6 mmol) in THF (50 mL) and MeOH (50 mL), were added ammonium chloride (695 mg, 13.0 mmol, EMD) and Zn dust (850 mg, 13.0 mmol, Aldrich). The reaction mixture was stirred at room temperature for 3 h, diluted with 200 mL of EtOAc and filtered through a pad of Celitee. The filtrate was concentrated in vacuo to give the desired product (530 mg, 100% yield) as a brown solid. MS(ESI+) m/z 205.29 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][N:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:28][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=[N:2][CH:3]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1cncc2ccccc12
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: CCOC(=O)C1(NC(=O)c2cncc3ccccc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a solution of isoquinoline-4-carboxylic acid (211 mg, 1.22 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (250 mg, 1.22 mmol), HATU (696 mg, 1.83 mmol) in anhydrous DMF (8 mL) is added DIPEA (302 μL, 1.83 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (51) as white solid (359 mg, 82%).