Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][N:10]=[C:11]2[C:15](=O)[O:14][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:12]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[NH4+:23].[OH-].Cl.O>CC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:12][C:11]([C:15]([NH2:23])=[O:14])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: [NH4+]
Reactant: Cc1ccc(NN=C2N=C(c3ccccc3)OC2=O)cc1C
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(-n2nc(C(N)=O)nc2-c2ccccc2)cc1C
Yield: 76.9 %

Procedure:
Three grams (0.01 mole) of 4-(3,4-dimethylphenylhydrazono)-2-phenyl-oxazoline-5-one (R1 =3--CH3, R2 =4--CH3 and R3 =H in the formula II) was suspended in 16 ml of acetone. To the resulting suspension, 1.57 ml of 29% solution of NH4OH (0.013 mole) was added dropwise at room temperature. After refluxing for 25 minutes, heating was stopped and 1.57 ml of concentrated hydrochloric acid was added dropwise. The resulting mixture was again refluxed for 5 minutes. 42 ml of water was then added to the reaction mixture, and obtained crystal was filtered out, washed with acetone containing water and dried. The thus treated crystal was recrystallized from a mixture of 8.8 ml of ethanol and 3 ml of water to obtain 2.25 g of almost colorless crystal, m.p. 169°-170° C., with a yield of 76.9%.
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([N+:21]([O-])=O)[C:16]([CH3:20])=[CH:17][C:18]=2[Br:19])=[C:6]([CH2:26][CH2:27][CH3:28])[C:5]=1[OH:29])(=[O:3])[CH3:2]>[Ni].O1CCCC1>[C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([C:16]([CH3:20])=[CH:17][C:18]=2[Br:19])[NH2:21])=[C:6]([CH2:26][CH2:27][CH3:28])[C:5]=1[OH:29])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2cc([N+](=O)[O-])c(C)cc2Br)ccc(C(C)=O)c1O
Agent: [Ni]
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2cc(N)c(C)cc2Br)ccc(C(C)=O)c1O

Procedure:
3.0 g of Raney nickel are added to a solution of 15.9 g (34.1 mmol) of 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-bromo-6-methylnitrobenzene in 160 ml of tetrahydrofuran and the whole is hydrogenated at room temperature. The catalyst is filtered off and washed with tetrahydrofuran. The filtrate is concentrated to dryness by evaporation under reduced pressure. 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-bromo-6-methylaniline having a melting point of 108°-109° is obtained (ether/petroleum ether).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:26][CH2:27][CH3:28])[N:5]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[C:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[CH:14][CH:13]=2)[C:6](=[O:8])[CH:7]=1.[H][H]>O1CCOCC1.[Pd]>[CH3:1][C:2]1[N:3]=[C:4]([CH2:26][CH2:27][CH3:28])[N:5]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:25])=[CH:16][CH:17]=2)[C:6](=[O:8])[CH:7]=1
Reactant: CCCc1nc(C)cc(=O)n1CCOc1ccc(C=C2SC(=O)NC2=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CCCc1nc(C)cc(=O)n1CCOc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 92 %

Procedure:
A solution of 5-[4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methylene]thiazolidine-2,4-dione (5.0 g, 12.46 mmol) obtained from example 1 in 1,4-dioxane (75 ml) was reduced with hydrogen in the presence of 10% palladium on charcoal (12.0 g) at 60 psi pressure for 40 h. The mixture was filtered through a bed of celite. The filtrate was evaporated to dryness under reduced pressure, purified by column chromatography (2:1 EtOAc/petroleum ether as eluent) followed by crystallisation (CH2Cl2) to afford the title compound (4.6 g, 92%), mp 144°-146° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[S:11][C:10]3=[N:12][CH:13]=[C:14](I)[N:9]3[N:8]=2)=[CH:4][CH:3]=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.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.ClCCl>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[S:11][C:10]3=[N:12][CH:13]=[C:14]([C:22]4[CH:23]=[CH:24][C:19]([OH:18])=[CH:20][CH:21]=4)[N:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Oc2nn3c(I)cnc3s2)cc1
Reactant: OB(O)c1ccc(O)cc1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(-c2cnc3sc(Oc4ccc(F)cc4)nn23)cc1
Temperature: 140 °C
Yield: 26.9 %

Procedure:
2-(4-Fluoro-phenoxy)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole (0.15 g, 0.42 mmol) was suspended in 1,4-dioxane (1.5 mL) at room temperature and argon was bubbled into the mixture while tetrakis(triphenylphosphine)palladium(0) (48 mg, 0.042 mmol), 4-hydroxyphenylboronic acid (66 mg, 0.48 mmol), cesium carbonate (271 mg, 0.83 mmol) and water (1.5 mL) were added. The mixture was deoxygenated for 10 minutes and heated under microwave irradiation at 140° C. for 20 minutes. On cooling, the mixture was diluted with dichloromethane (7 mL), adsorbed in silica and purified by column chromatography (Biotage™/Flash, silica, methanol:dichloromethane 0.2:9.8 to 1.5:7.5). The product obtained was treated with dichloromethane (5 mL) and filtered to give 4-[2-(4-fluoro-phenoxy)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-phenol as a white solid (37 mg, 27% yield).
Reaction SMILES: [C:1]([CH:5]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:10]2[N:6]1[CH2:7][CH2:8][CH2:9]2)([O:3]C)=O.N(C[C@@H]1CCCN1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[Mg+2].[Cl-].C1([Mg]Br)C=CC=CC=1.[Cl-].[NH4+]>C1COCC1.CCOCC>[C:1]([CH:5]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:10]2[N:6]1[CH2:7][CH2:8][CH2:9]2)(=[O:3])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)C1N(c2ccccc2)CC2CCCN21
Reactant: c1ccc(NC[C@@H]2CCCN2)cc1
Agent: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(c1ccccc1)C1N(c2ccccc2)CC2CCCN21
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
2-Carbomethoxy-3-phenyl-1,3-diazabicyclo[3,3,0]octane prepared from 181 mg of (S)-2-(anilinomethyl)pyrrolidine was dissolved in 5.5 ml of THF, then admixed with 108 mg of anhydrous magnesium chloride, and heated and refluxed for 10 minutes. To the mixture cooled to -70° C., was added dropwise 1.38 equivalents of phenylmagnesium bromide dissolved in ether. After having been stirred at -70° C. for 15 minutes, the reaction mixture was admixed with saturated aqueous ammonium chloride solution and ether, and brought to room temperature. The mixture was extracted with ether and the ether layer was washed with 1N aqueous sodium hydroxide solution and then with saturated aqueous sodium chloride solution. After drying, the ether layer was freed from the solvent by distillation under reduced pressure. The oily residue was purified by alumina column chromatography to obtain 230 mg (77%) of 2-benzoyl-3-phenyl-1,3-diazabicyclo[3,3,0]octane. NMR peaks: δ(ppm)=1.6-2.2 (4H, multiplet), 2.4-3.9 (5H, multiplet), 5.4 (1H, singlet), 6.1-7.9 (10H, multiplet).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11](=O)[C:12]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[C:13]=1[CH3:26]>C1COCC1>[F:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[C:13]=2[CH3:26])=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: Cc1c(-c2cccc(F)c2)ccc(F)c1C(=O)Nc1c(F)ccc(O)c1F
Solvent: C1CCOC1
Product: Cc1c(-c2cccc(F)c2)ccc(F)c1CNc1c(F)ccc(O)c1F
Temperature: 60 °C
Yield: 60.1 %

Procedure:
To a solution of N-(2,6-difluoro-3-hydroxy-phenyl)-6-fluoro-3-(3-fluorophenyl)-2-methyl-benzamide (400 mg, 1.06 mmol, 1.0 eq) in THF (5 mL) under N2 was added a solution of BH3 (1M in THF, 5.3 mL, 5.3 mmol, 5.0 eq). The reaction mixture was heated at 60° C. overnight, then quenched by addition of methanol and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: EtOAc, 50:1 to 20:1) to give title compound as colorless oil (230 mg, 59%).
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:8]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26](=[C:29](Br)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH2:25][C:26](=[C:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:3]2[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:8]=2)[CH2:27][CH2:28]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: C[Sn](C)(C)c1cncc(CCC(=O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccccc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=C(c2ccccc2)c2cncc(CCC(=O)O)c2)CC1
Temperature: 90 °C
Yield: 73.3 %

Procedure:
A mixture of 3-trimethylstannyl-5-carboxyethylpyridine (0.298 g, 0.949 mmol) and 4-(1-bromo-1-phenyl-methylene)-piperidine-1-carboxylic acid tert-butyl ester (0.334 mL, 0.949 mmol) in dry THF (5 mL) was degassed with a stream of Ar bubbles for 10 min. To this solution was added bis(triphenylphosphine)palladium dichloride (0.033 g, 0.047 mmol) and then the reaction vessel was sealed and the mixture was heated at 90° C. (oil bath temperature) for 16 h. The cooled mixture was then evaporated to dryness and the residue chromatographed (SiO2/hexane-EtOAc, 7:3) to give the title compound (0.294 g, 73%) as a clear yellow oil:
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CI.[C:17](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([F:14])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[CH3:1]
Reactant: Cc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(F)cc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 65 h
Yield: 25.9 %

Procedure:
8.56 g (42.99 mmol) of 2-methyl-5-fluoro-3-nitrobenzoic acid is added in 76 ml of N,N-dimethylformamide and mixed with 9.15 g (64.48 mmol) of methyl iodide and 8.91 g (64.48 mmol) of potassium carbonate. After 65 hours of stirring at room temperature, the reaction mixture is added to ice water and extracted several times with ethyl acetate. The combined organic extracts are washed with water and brine. After drying (sodium sulfate), desiccant is suctioned out, and the solvent is spun off. Repeated chromatography on silica gel (mobile solvent ethyl acetate/hexane) yields the desired compound, specifically in a yield of 25.9% (2.37 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[N:9][NH:8][C:7]=2[CH:11]=1)#[N:2].[OH-].[Na+].[Cl:14][CH:15]([CH3:19])[CH2:16][CH2:17]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:14][CH:15]([CH3:19])[CH2:16][CH2:17][N:8]1[C:7]2[CH:11]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[N:10]=[N:9]1
Reactant: N#Cc1ccc2nn[nH]c2c1
Reactant: CC(Cl)CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CC(Cl)CCn1nnc2ccc(C#N)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 38.8 %

Procedure:
6-cyano-1H-benzotriazole (15.9 g, 0.10 mol) is dissolved into 100 ml of 30% wt. sodium hydroxide, 3-chlorobromobutane (32.6 g, 0.10 mol), tetrabutyl ammonium bromide (0.8 g) are added, and mixed for 5 min. The reaction solution is gradually heated to 60° C., stirred for reaction for 2 hours. Post treatment was performed based on common method one for synthesis. The solution was separated and purified by HPLC to produce 9.1 g of 1-(3-chlorobutyl)-6-cyano-1H-benzotriazole, with a yield of 32.6%.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.FC(F)(F)C(O)=O>O1CCCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[OH:12])=[CH:4][CH:3]=1
Reactant: O=C1CCCc2ccc(Br)cc21
Reactant: COc1ccc([Mg]Br)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCCc3ccc(Br)cc32)cc1

Procedure:
A solution of 0.55 g (1.65 mmol ) of 7-bromo-1-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalen-1-ol, obtained analogously to Example 1a) from 7-bromo-3,4-dihydro-2H-naphthalen-1-one and 4-methoxyphenyl-magnesium bromide, and 0.2 ml of trifluoroacetic acid in 20 ml of tetra-hydrofuran is warmed at 50° C. for 12 hours and subsequently evaporated to dryness. 10 ml of saturated sodium hydrogencarbonate are added to the residue, and the aqueous mixture is extracted twice with 10 ml of ethyl acetate each time. After the combined organic phases have been dried over sodium sulfate and the solvent has been stripped off, the crude product is purified by column chromatography on silica gel (petroleum ether ethyl acetate 9:1), giving 0.54 g of 7-bromo-1-(4-methoxyphenyl)-3,4-dihydronaphthalene; LC/MS: 338 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)=[C:10]2Br)[CH2:6]1)=[O:4].[CH3:34][Sn](C)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@H:7]([N:9]2[C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]=3[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)=[C:10]2[CH3:34])[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1C[C@H](n2c(Br)c(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Reactant: C[Sn](C)(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](n2c(C)c(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
In a sealed tube, 4.68 g (9.02 mmol) trans-3-[4-amino-5-(3-benzyloxy-phenyl)-6-bromo-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylic acid methylester of Example 103, 2.08 g (1.8 mmol) tetrakistriphenylphosphin palladium and 5.3 ml (38.05 mmol) tin tetramethyl (Fluka, Buchs, Switzerland) are heated under Argon in 20 ml dry N,N-dimethylformamide for 30 h at 100-105° C. bath temperature. The reaction mixture is filtered on hyflo (Hyflo Super Cel®; Fluka, Buchs, Switzerland), and the residue washed thouroughly with N,N-dimethylformamide. The dark filtrate is evaporated at 60° C. to dryness, the residual mass dissolved in hot ethyl acetate and chromatographed on silicagel (hexane-ethyl acetate 25:75). The title compound is obtained as yellow crystals. Analytical HPLC: tR=3.54 min (shorty); ES-MS: m/eo=443; NMR (DMSO-d6): 8.08/s (1H), 7.25-7.5/several m's (6H), 6.99/“d” (1H); 6.90/s (1H); 6.85/“d” (1H); 5.09/s (2H); 5.06/m (1H); 3.64/s (3H); 3.2-3.5/2×m (3H); 2.59/m (2H); 2.18/s (3H).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[N:25]1[C:34]2[C:29](=[C:30]([NH:35]N)[CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:35]([C:30]4[CH:31]=[CH:32][CH:33]=[C:34]5[C:29]=4[CH:28]=[CH:27][CH:26]=[N:25]5)[N:20]=[CH:19][CH:18]=3)=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Reactant: NNc1cccc2ncccc12
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1cccc2ncccc12

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and quinolin-5-yl-hydrazine according to the method described for example 91. MS: M=432.2 (M+H)+
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1C=CC(C([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[NH:23][CH:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]#[N:32])[CH2:26][CH2:25]2)=O)=C1.O.[OH-].[Na+]>O1CCCC1>[NH2:32][CH2:31][CH2:30][N:27]1[CH2:26][CH2:25][CH:24]([NH:23][C:15]2[NH:14][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=2)[CH2:29][CH2:28]1
Reactant: N#CCN1CCC(Nc2nc3ccccc3n2C(=O)c2ccoc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCCN1CCC(Nc2nc3ccccc3[nH]2)CC1
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To 180 parts of tetrahydrofuran were added carefully 2.4 parts of lithium aluminium hydride under nitrogen atmosphere. Then there was added dropwise a solution of 7 parts of 4-[[1-(3-furanylcarbonyl)-1H-benzimidazol-2-yl]amino]-1-piperidineacetonitrile in tetrahydrofuran: temp. rose to 50° C. Upon completion, stirring was continued overnight at reflux temperature. The reaction mixture was cooled in an ice-bath and decomposed by the successive additions of 3 parts of water, 9 parts of a sodium hydroxide solution 15% and 9 parts of water. The whole was filtered over Hyflo and the filtrate was evaporated. The residue was purified by filtration over silica gel using a mixture of trichloromethane and methanol (80:20 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 3.6 parts (69.5%) of N-[1-(2-aminoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 99.8° C. (intermediate 129).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][CH2:24][NH2:25])=[CH:15]1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:15]4[NH:14][C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16]=4[CH2:23][CH2:24][NH:25]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=CC1(c2ccc(Cl)cc2)CCC1
Reactant: NCCc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(C2(C3NCCc4c3[nH]c3ccccc43)CCC2)cc1
Temperature: 25 °C

Procedure:
1-(4-Chlorophenyl)cyclobutanecarbaldehyde (30 mg, 0.154 mmol) and 2-(1H-indol-3-yl)ethanamine (27.7 mg, 0.17 mmol) were dissolved in dichloromethane (3 mL). Trifluoroacetic acid (88 mg, 0.771 mmol) were added at 0° C. and the reaction mixture was stirred at room temperature over night. The 5% NaHCO3 solution was added. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed successively with 5% NaHCO3 solution and saturated sodium chloride solution, dried (MgSO4) and concentrated in vacuo. Yield: 36 mg (oil, 0.107 mmol, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:12])=[CH:5][N:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2.[N+:13]([C:16]1[CH:17]=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>>[CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([S:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)(=[O:23])=[O:24])[N:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: COc1c(C)cn2ccccc12
Product: COc1c(C)c(S(=O)(=O)c2cccc([N+](=O)[O-])c2)n2ccccc12
Yield: 98 %

Procedure:
This compound is prepared according to the protocol described for the example above, by sulphonylation of 1 g (6.2 mmol) of 1-methoxy-2-methylindolizine with 3-nitrobenzenesulphonyl chloride. 540 mg of a yellow oil are obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[Cl:14][C:15]1[C:20](O)=[C:19]([Cl:22])[C:18]([Cl:23])=[C:17]([Cl:24])[C:16]=1[Cl:25]>ClCCl.C(OCC)C>[Cl:14][C:15]1[C:20]([O:5][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[C:19]([Cl:22])[C:18]([Cl:23])=[C:17]([Cl:24])[C:16]=1[Cl:25]
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: N#CCC(=O)O
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: N#CCC(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 25 °C

Procedure:
8.5 g (0.1 mole) of cyano acetic acid are dissolved in 350 ml. of ethylether and cooled to 0° C. 20.1 g. (0.1 mole) of phosphorus pentachloride are added. The cooling is stopped and the temperature is slowly raised to room temperature. When the HCl evolution ceases the solvent is distilled off in vacuo. The residue containing the formed cyanoacetic acid chloride and phosphoroxychloride is taken up in 50 ml. of dichloromethane and 26 g. (0.1 mole) of pentachlorophenol and 11 ml. (0.1 mole) of N,N'-dimethylaniline are added dropwise in 300 ml. of dichloromethane.
Reaction SMILES: O[CH:2]1[C:11]2[N:10]=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[C:6]=2[CH2:5][CH2:4][CH2:3]1.[NH2:14]C1C2N=CC=CC=2CCC1>>[NH2:14][CH:2]1[C:11]2[N:10]=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: NC1CCCc2cccnc21
Reactant: COc1ccnc2c1CCCC2O
Product: COc1ccnc2c1CCCC2N
Yield: 68 %

Procedure:
8-amino-4-methoxy-5,6,7,8-tetrahydroquinoline was prepared in 68% yield from 8-hydroxy-4-methoxy-5,6,7,8-tetrahydroquinoline (preparation and characterization described by: Uchida, M.; Morita, S.; Chihiro, M.; Kanbe, T.; Yamasaki, K.; Yabuuchi, Y.; Nakagawa, K. Chem. Pharm. Bull. 1989, 37, 1517-1523) using the same procedure employed to prepare 8-amino-5,6,7,8-tetrahydroquinoline (see Bridger et al. PCT International Application PCT/CA00/00321). 1H NMR (CDCl3) □1.59-2.15 (m, 6H), 2.60-2.65 (m, 2H), 3.84. (s, 3H), 3.95 (dd, 1H, J=6.0, 9.0 Hz), 6.61 (d, 1H, J=6.0 Hz). 8.32 (d, 1H, J=6.0 Hz); 13C NMR (CDCl3) □19.53, 22.89, 31.94, 51.57, 55.62, 104.04, 120.94, 148.52, 160.42, 163.71; ES-MS m/z 179 (M+H).
Reaction SMILES: Br[CH2:2][N:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[N-:20]=[N+:21]=[N-:22].[Na+].CC(C)=O>[I-].[K+].O>[N:20]([CH2:2][N:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N+:21]=[N-:22]
Reactant: CCOC(=O)CC1c2ccccc2C(=O)NN1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)CC1c2ccccc2C(=O)NN1CN=[N+]=[N-]
Yield: 96.1 %

Procedure:
A mixture of ethyl 2-bromomethyl-4-oxo-3H-phthalazine-1-yl-acetate (2.0 g), sodium azide (0.4 g), acetone (20 ml), water (2 ml) and a catalytic amount of potassium iodide (10 mg) was stirred at room temperature for 4 hours. The mixture was concentrated under vacuum to remove the solvents and obtain the title product as a white solid (1.7 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O)#[N:17].C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:15][C:12]1[S:13][CH:14]=[C:10]([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:16]#[N:17])=[N:3][CH:4]=2)[N:11]=1
Reactant: N#Cc1ccccc1B(O)O
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(C#Cc2ccc(-c3ccccc3C#N)nc2)cs1
Temperature: 150 °C

Procedure:
2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (1.0 mmol, 234 mg), 2-cyanophenylboronic acid (1.2 mmol, 176 mg), dichlorobis(triphenylphosphine)palladium(II) (0.05 mmol, 35 mg), and potassium carbonate (3.5 mmol, 500 mg) were added to deoxygenated DME:water (1:1, 5 mL) at room temperature. The reaction was heated for 5 min at 150° C. via microwave irradiation, then partitioned in a separatory funnel with EtOAc (100 mL) and water (30 mL). The organic layer was washed with one additional portion of water (20 mL) and the combined aqueous layers back extracted with EtOAc (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2, eluting with a 0% to 60% EtOAc gradient in hexanes, to afford the title compound as a white solid, which was dissolved in ether and precipitated as the hydrochloride salt with 1M HCl in ether. MS (ESI) 301.4 (M+H+).