Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:11]3[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=3[O:9][CH2:8]2)[CH2:4][CH2:3]1.ClC1C=CC(O[CH2:25][C:26]#[N:27])=CC=1.CC(C)([O-])C.[K+].Cl>CN(C=O)C.O>[C:26]([CH2:25][C:14]1[C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]2[C:5]3([CH2:8][O:9][C:10]=2[CH:15]=1)[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)#[N:27]
Reactant: N#CCOc1ccc(Cl)cc1
Reactant: CN1CCC2(CC1)COc1ccc([N+](=O)[O-])cc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC2(CC1)COc1cc(CC#N)c([N+](=O)[O-])cc12
Reaction time: 6 h
Yield: 43.5 %

Procedure:
2,3-Dihydro-1'-methyl-5-nitrospiro[benzofuran-3,4'-piperidine] (D4, 0.70 g, 2.8 mmol) and 4-chlorophenoxyacetonitrile (0.90 g, 5.4 mmol) were dissolved in dry DMF (15 ml) and added to potassium t-butoxide (1.60 g, 14.3 mmol). The mixture was stirred under Ar for 6 h, diluted with water (150 ml), acidified (5M HCl) and washed with ethyl acetate. It was then basified (saturated K2CO3 solution) and extracted with ethyl acetate. This extract was dried (Na2SO4) and evaporated to give the title compound (0.35 g, 43%) still containing some spirocyclic starting material (ca 30%, NMR).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:5][CH2:4][CH2:3][CH2:2][N:19]1[CH2:18][CH2:17][N:16]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([O:7][CH3:6])[CH:9]=2)[CH2:21][CH2:20]1
Reactant: COc1ccc(N2CCNCC2)cc1OC
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(CCCCl)CC2)cc1OC
Reaction time: 0.5 h

Procedure:
The 1-(3-chloropropyl-4-(3,4-dimethoxyphenyl)piperazine is prepared in the following manner: 11.5 g (70.2 m. moles) of 1-bromo-3-chloropropane are added quickly with stirring to a mixture of 13 g (58.5 m. moles) of 1-(3,4-dimethoxyphenyl)piperazine [prepared according to P. C. Jain et coll. J. Med. Chem. 10, 812 (1967)] and 9.7 g (70.2 m. moles) of potassium carbonate in 60 cc of N,N-dimethylformamide. The stirring is continued for 4 hours 30 min at ambient temperature. The inorganic products are then filtered and the filtrate concentrated to dryness under reduced pressure. The residue is dissolved in ether and the solution obtained washed with water, then dried on sodium sulfate. After evaporation of the ether, there is obtained 14 g (yield) 80%) of 1-(3-chloropropyl)-4-(3,4-dimethoxyphenyl)piperazine that is used without any other purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[NH:23]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24]1.C([O-])([O-])=O.[K+].[K+].O>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>[NH:23]1[CH:27]=[C:26]([C:2]2[CH:3]=[C:4]([N:8]3[C:16]4[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=4[C:10]4[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]3=4)[CH:5]=[CH:6][CH:7]=2)[CH:25]=[N:24]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
Reactant: OB(O)c1cn[nH]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: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3cn[nH]c3)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1H-pyrazole-4-boronic acid (62 mg, 0.56 mmol) and K2CO3 (116 mg, 0.84 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.014 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure and residue and dissolved in EtOAc (30 mL). The organic layer was washed with water (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 5-(3-(1H-pyrazol-4-yl)phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 8.03 (s, 2H), 7.7 (d, 1H), 7.58 (m, 2H), 7.3 (s, 1H), 7.22 (d, 1H), 7.1 (d, 1H), 7.0 (d, 1H), 4.8 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.57 (m, 1H), 3.2 (m, 1H), 3.17 (s, 3H), 3.0 (m, 1H), 2.42 (s, 3H).
Reaction SMILES: O=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]([OH:21])=O)[CH2:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.[NH2:23][NH2:24]>C(O)C>[C:5]1([C:4]2[CH:3]=[C:2]3[C:12]4[C:13]([CH2:18][C:19](=[O:21])[N:24]3[N:23]=2)=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NN
Reactant: O=C(O)Cc1ccccc1C(=O)CC(=O)c1ccccc1
Solvent: CCO
Solvent: O
Product: O=C1Cc2ccccc2-c2cc(-c3ccccc3)nn21
Yield: 81.5 %

Procedure:
To ethanol (10 ml), there were added 2-(1,3-dioxo-3-phenylpropyl) phenylacetic acid (1.42 g) and hydrazine hydrate (0.25 g), followed by heating under reflux for 2 hours. Thereafter, the reaction mixture was cooled to give 2-phenyl-5,6-dihydropyrazolo-[5,1-a]isoquinolin-5-one (1.06 g). Mp. 181°-183° C.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([S:20][CH3:21])[N:17]=[C:18]([Cl:19])[C:9]=2[C:8]1=[O:22].[H-].[Na+].[CH3:34]I>CN(C)C=O.C(OCC)(=O)C>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:23]=[C:5]([CH:4]=[C:3]([C:2]([F:30])([F:1])[F:31])[CH:25]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][N:11]([CH3:34])[C:10]2[N:15]=[C:16]([S:20][CH3:21])[N:17]=[C:18]([Cl:19])[C:9]=2[C:8]1=[O:22]
Reactant: CSc1nc(Cl)c2c(n1)NCCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c2c(n1)N(C)CCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 7; 1.50 g) was dissolved in N,N-dimethylformamide (6 mL). To this solution, sodium hydride (185 mg, 60% oil suspension) was added and the mixture was stirred at room temperature for 1 hour. Methyl iodide (0.4 mL) was then added and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, was sequentially washed with water and a saturated aqueous solution of sodium chloride, and was then dried over anhydrous sodium sulfate. Following removal of the solvent, the residue was purified on a silica gel column-chromatography (ethyl acetate:hexane=1:1) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-10-methyl-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine (1.36 g, 88%).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[C:17]([CH3:20])([CH3:19])[CH3:18].[C:21]1([CH2:27][CH2:28]O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:21]1([CH2:27][CH2:28][O:15][C:14](=[O:16])[CH2:13][CH2:12][C:5]2[CH:4]=[C:3]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:2]([OH:1])=[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:6]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCCc1ccccc1
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(CCC(=O)OCCc2ccccc2)cc(C(C)(C)C)c1O

Procedure:
3-(4-hydroxy-3,5-di-tert.-butylphenyl)-propionic acid-2-phenylethyl ester was prepared from 278 g (1 mol) of 3-(4-hydroxy-3,5-di-tert.-butylphenyl)-propionic acid and 122 g (1 mol) of 2-phenylethanol by azeotropic esterification in toluene with 0.5 g of 4-toluenesulfonic acid. The product was analyzed and the results of this analysis were as follows:
Reaction SMILES: [CH2:1]([N:8]1[C:16](Br)=[N:15][C:14]2[C:9]1=[N:10][C:11]([NH:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[N:12][C:13]=2[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:25].[Na+]>Cl>[CH2:1]([N:8]1[C:16]([OH:25])=[N:15][C:14]2[C:9]1=[N:10][C:11]([NH:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[N:12][C:13]=2[NH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: COC(=O)CNc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Agent: Cl
Agent: [Na+]
Product: COC(=O)CNc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Thus obtained 9-benzyl-8-bromo-2-methoxycarbonylmethylaminoadenine was added to concentrated hydrochloric acid (10 ml), and the mixture was stirred for 8 hours at 100° C. The mixture was neutralized in an ice bath with 5% sodium hydroxide solution (pH 7) and the solvent was removed. To the residue were added methanol (30 ml) and sulfuric acid (1 ml), and the mixture was refluxed for 4 hours. After being neutralized (pH 6) in an ice bath with saturated sodium hydrogencarbonate solution, the solution was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by column chromatography and the obtained compound was washed with methanol to give the captioned compound (0.02 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:25])[C:13]([CH3:24])([S:15]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[CH3:14])[O:8][N:7]=1)([CH3:5])[CH:3]=O.[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C1COCC1>[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:33][CH2:5][C:2]([C:6]2[CH:10]=[C:9]([NH:11][C:12](=[O:25])[C:13]([CH3:24])([S:15]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)(=[O:16])=[O:17])[CH3:14])[O:8][N:7]=2)([CH3:1])[CH3:3])=[CH:30][CH:29]=1
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)(C=O)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CNCC(C)(C)c2cc(NC(=O)C(C)(C)S(=O)(=O)C3CCOCC3)on2)cc1
Reaction time: 18 h
Yield: 83 %

Procedure:
To a solution of N-[3-(1,1-dimethyl-2-oxo-ethyl)-isoxazol-5-yl]-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (130 mg, 0.35 mmol) in THF (2 mL) is added 4-methoxybenzylamine (0.055 mL, 0.42 mmol) and 2.7 mmol/g of MP-triacetoxyborohydride (323 mg, 0.87 mmol). The reaction mixture is placed on a shaker for 18 h. After this time, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. Purification by flash chromatography on silica gel using methanol/DCM provides the title compound. Yield: 83%; LC-MS retention time: 1.23 mins. ESI+ion mode. Zorbax SB-C18 column (3.5 μm, 4.6×30 mm). Gradient: 5% B to 80% B (0 min to 1.7 mins), 80% B to 95% B (1.7 mins to 2 mins), 95% B to 95% B (2 mins to 2.1 mins). Flow rate: 2.5 mL/min. A=(Water+0.1% Formic Acid) B=(Acetonitrile+0.1% Formic Acid). Diode Array Detector; m/z 494 [M+H].
Reaction SMILES: [CH2:1]([O:4][C:5](Cl)=[O:6])[CH:2]=[CH2:3].[NH2:8][CH2:9][C:10]([OH:12])=[O:11]>O.[OH-].[Na+]>[CH2:1]([O:4][C:5]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)Cl
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCOC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At 0°, 12 ml of chloroformic acid allyl ester are added dropwise to a solution of 7.51 g of glycine in 20 ml of water and 44 ml of 5N NaOH solution. The suspension is then stirred for 16 hours at room temperature. After removing the insoluble material by filtration, the filtrate is diluted with 100 ml of water and washed twice with CH2Cl2. The aqueous phase is adjusted to pH 2 with 4N HCl and extracted twice with CH2Cl2. The combined organic extracts are washed once with brine, dried over MgSO4 and concentrated by evaporation to form the white crystals of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:31])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=2)=[O:31])=[CH:13][CH:14]=1
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
The compound (1.38 g) obtained in Example 77-1 was dissolved in methanol (10 ml) and then added with a 4 mol/l hydrogen chloride/dioxane solution (15 ml), followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure and added with anion-exchange resin (Amberlite IRA-410) in methanol to adjust the solution to pH 8. After the resin had been removed through filtration, the solvent was distilled off, thereby obtaining the subject compound (0.79 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][NH:13][CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH:15]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)=[CH2:16].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:15][C:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc2ccccc2n1
Reactant: Clc1ccc2[nH]c3c(c2c1)CNCC3
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Clc1ccc2[nH]c3c(c2c1)CN(CCc1ccc2ccccc2n1)CC3

Procedure:
The title compound was prepared following the procedure of Example 2 with the exception that 8-chloro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole was used instead of 8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and 2-vinylquinoline was used instead of 2-vinylpyridine. The product was converted to the dihydrochloride salt; mp 187°-190° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:7]=1.[NH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][OH:31]>CO.CCOC(C)=O>[OH:32][C@H:29]([CH2:30][OH:31])[CH2:28][NH:27][C:22]([C:21]1[CH:20]=[N:19][N:16]2[CH:17]=[CH:18][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@@H:8]3[C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:25][CH3:26])=[N:14][C:15]=12)=[O:24]
Reactant: NC[C@H](O)CO
Reactant: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NC[C@H](O)CO)c2n1
Yield: 53 %

Procedure:
Prepared by the method of Example 1, using (R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation G) and (S)-3-aminopropane-1,2-diol (2.0 equiv). The crude material was purified by SiO2 column chromatography, eluting with EtOAc then 10% MeOH-EtOAc to afford the title compound as a white solid (53% yield). MS (apci) m/z=430.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=3[Cl:20])=[N:8][C:5]2=[N:6][CH:7]=1.O.O.Cl[Sn]Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[C:15]([CH:14]=[CH:13][C:12]=3[Cl:20])[NH2:17])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(-c2nc3ncc(Br)cc3[nH]2)c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(Cl)c(-c2nc3ncc(Br)cc3[nH]2)c1
Yield: 73 %

Procedure:
To a suspension of 6-bromo-2-(2-chloro-5-nitrophenyl)-1H-imidazo[4,5-b]pyridine I-2a (18 g, 50.91 mmol, 1.00 equiv) in ethanol (200 mL) was added SnCl2.2H2O (17.3 g, 76.55 mmol, 1.50 equiv) and heated to reflux overnight. The resulting mixture was concentrated under vacuum and the residue was diluted with 200 mL of H2O. The pH value of the mixture was adjusted to 8 with sodium carbonate (sat.). A filtration was performed and the solids were applied on a silica gel column and eluted with ethyl acetate/PE (1/1) to give 12 g (73%) of 3-[6-bromo-1H-imidazo[4,5-b]pyridin-2-yl]-4-chloroaniline (I-2b) as a yellow solid. 1H-NMR (DMSO, 400 MHz): 13.00-13.53 (m, 1H), 8.46 (s, 1H), 8.30 (brs, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.05 (brs, 1H), 6.76 (dd, J=8.4, 2.8 Hz, 1H), 5.57 (brs, 2H). MS M/Z=325 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=O)[CH2:18][C:19](OCC)=[O:20]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:19](=[O:20])[CH2:18][C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[F:10])=[N:9]1
Reactant: NNc1ccccc1F
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Solvent: CC(=O)O
Product: O=C1CC(c2ccccc2F)=NN1c1ccccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Fluorophenyl hydrazine (1.26 g, 9.99 mmol) and ethyl 3-(2-fluorophenyl)-3-oxopropanoate (2.10 g, 9.99 mmol, 1 equiv) were combined in acetic acid (20 mL) and placed into an oil bath preheated at 120° C. for 3 hours. The mixture was cooled of ambient temperature and concentrated in vacuo. The residue was concentrated from toluene (3×50 mL), providing the titled compound.
Reaction SMILES: [C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[CH2:23]1COCC1>>[C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[CH2:23])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: C1CCOC1
Solvent: O
Product: C=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reaction time: 2 h
Yield: 89 %

Procedure:
Thereafter, 20 g (0.066 mol) of 4-(diphenylamino)benzaldehyde (1) dissolved in 40 ml of THF was charged into the dropping funnel, and was gradually added dropwise to the mixture. After the addition, a reaction was caused at room temperature for 2 hours. Then, 70 ml of water was added thereto. The product was extracted with ethyl acetate, and the extract was washed with water until neutralized. The organic phase was dried, concentrated and then purified by column chromatography. Pale yellow crystals of 4-(diphenylamino)styrene (3) (16 g, yield: 89%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)=[CH:4][CH:3]=1.[NH2:20][NH2:21]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[NH:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(CC(=O)c1ccc(F)cc1)c1ccc(F)cc1
Solvent: C1CCOC1
Product: Fc1ccc(-c2cc(-c3ccc(F)cc3)[nH]n2)cc1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
3.9 g 1,3-Bis-(4-fluoro-phenyl)-1,3-propandione was dissolved in 45 mL of a solution of 1 N hydrazine in THF and stirred for 2 h at 75° C. The solvent was removed to give 3.6 g of the desired compound. Rt: 1.03 min (method D), (M+H)+: 257
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]([CH3:10])[C:8](=[O:11])[N:7]([CH3:12])[C:6](=[O:13])[C:5]=1[CH:14]=O)[CH3:2].Cl.[CH2:17]([O:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][N:25]=[CH:14][C:5]1[C:6](=[O:13])[N:7]([CH3:12])[C:8](=[O:11])[N:9]([CH3:10])[C:4]=1[O:3][CH2:1][CH3:2])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NOCc1ccccc1
Reactant: CCOc1c(C=O)c(=O)n(C)c(=O)n1C
Agent: Cl
Product: CCOc1c(C=NOCc2ccccc2)c(=O)n(C)c(=O)n1C

Procedure:
The process described in Method A was followed. 6-Ethoxy-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (0.074 mg, 0.35 mmol) (Example 16, Step 1) and O-benzyl-hydroxyl-amine hydrochloride (0.073 mg, 0.46 mmol) were used to obtain the title compound.
Reaction SMILES: [N:1]1([CH:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:22]1([S:32](Cl)(=[O:34])=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>ClCCl>[C:22]1([S:32]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]2[CH:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:8])(=[O:34])=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CC(C1CCCCN1)N1CCCCC1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C1CCCCN1S(=O)(=O)c1cccc2ccccc12)N1CCCCC1
Reaction time: 24 h
Yield: 58.2 %

Procedure:
To a stirred solution of 2-[1-(piperidinyl)ethyl]piperidine (196 mg, 1 mmol) and triethylamine (0.14 ml, 1 mmol) in dichloromethane (10 ml) cooled by an ice bath, was added dropwise a solution of 1 -naphthalene sulfonyl chloride (226 mg, 1 mmol) in dichloromethane. Stirring continued, allowing the solution to reach room temperature for 24 hours. The solution was washed thoroughly (10% NaOH), and brine, dried (Na2SO4) and concentrated in vacuo to afford a pale yellow oil (225 mg, 58%) M+=387.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8]([OH:11])[C:7]([F:12])=[CH:6][C:3]=1[CH:4]=[O:5].Cl[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>>[F:10][C:9]1[C:2]([F:1])=[C:3]([CH:4]=[O:5])[CH:6]=[C:7]([F:12])[C:8]=1[O:11][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][N:15]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=Cc1cc(F)c(O)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1ccc(Oc2c(F)cc(C=O)c(F)c2F)nc1
Yield: 57.8 %

Procedure:
Using a method similar to Example 710, Part 2, using 2,3,5-trifluoro-4-hydroxy-benzaldehyde (1.00 g, 5.64 mmol), 6-chloronicotinonitrile (782 mg, 5.64 mmol) and K2CO3 (1.17 g, 8.47 mmol) gives 6-(2,3,6-trifluoro-4-formyl-phenoxy)-nicotinonitrile (907 mg) contaminated with 6-chloronicotinonitrile starting material. Dissolve this mixture in MeOH (15 ml) and treat with isoamylamine (194 mg, 2.23 mmol). After stirring for two hours, add NaBH4 (105 mg, 2.79 mmol) and stir for an additional hour. Purification as described in Example 710, Step 4, gives 6-{2,3,6-trifluoro-4-[(3-methyl-butylamino)-methyl]-phenoxy}-nicotinonitrile (383 mg) as a colorless oil.
Reaction SMILES: Br[CH2:2][CH:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[O:4][CH3:5].[NH3:18]>C(O)C>[NH2:18][CH2:2][CH:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[O:4][CH3:5]
Reactant: COC(CBr)c1ccc(-c2ccccc2)cc1
Reactant: N
Solvent: CCO
Product: COC(CN)c1ccc(-c2ccccc2)cc1
Temperature: 100 °C
Yield: 61 %

Procedure:
4-Vinyl-biphenyl, 1.70 g (9.4 mmol), was dissolved in methanol (10 mL) and dichloromethane (15 mL). Bromine, 0.48 mL (9.4 mmol), dissolved in methanol (10 mL) was added over 30 minutes and TLC analysis showed complete reaction. The mixture was diluted with dichloromethane and added to an aqueous solution of sodium hydrogen sulphite and the mixture was shaken. The dichloromethane phase was washed with aqueous sodium hydrogen carbonate and water and evaporated to give 2.81 g product. The product was purified by silica gel chromatography silica gel (200 mL) with heptane/ethyl acetate (95+5) to give 1.00 g (39 %) of pure 4-(2-bromo-1-methoxy-ethyl)-biphenyl. 4-(2-Bromo-1-methoxyethyl)-biphenyl, 1.00 g (3.64 mmol), was dissolved in ethanol (20 mL) and added to a large excess of concentrated ammonia (20 mL). The mixture was heated to 100° C. in a sealed vessel for 16 hours and evaporated. Chromatography on silica gel (180 mL) with dichloromethane followed by dichloromethane/methanol/concentrated ammonia (90+10+1) gave 0.47 g (61%) of the sub-titled compound.