Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)=[CH:17][C:16]=1[C:28](=[O:30])[CH3:29].[OH-].[K+].Cl>CCO>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)=[CH:17][C:16]=1[C:28](=[O:30])/[CH:29]=[CH:1]/[C:3]1[CH:13]=[CH:12][C:6](/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CC(=O)c1cc(N2CCN(C)CC2)ccc1Cl
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCN(c2ccc(Cl)c(C(=O)/C=C/c3ccc(/C=C/C(=O)O)cc3)c2)CC1
Temperature: 0 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
A mixture of 4-formylcinnamic acid (250 mg, 1.42 mmol), 1-[2-chloro-5-(4-methyl-piperazin-1-yl)-phenyl]-ethanone (obtained as described in Preparation 13, 358 mg, 1.42 mmol) and 1.7 M KOH (1.67 ml) in EtOH (10 ml) was stirred at 0° C. for 6 h and then acidified with 10% HCl until reaching a pH value of 6. The resulting yellow precipitate was filtered and rinsed with EtOH and Et2O to give 519 mg of (E)-3-(4-{(E)-3-[2-chloro-5-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid. The reaction product was used in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=2)[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[N-:33]=[N+:34]=[N-:35].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH:33]1[C:29]([C:25]2[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=2)[CH2:22][N:8]([CH2:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:32][CH:31]=2)[CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[N:30][N:35]=[N:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(CCc2ccc(Cl)cc2)Cc2cccc(C#N)c2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(N(CCc2ccc(Cl)cc2)Cc2cccc(-c3nnn[nH]3)c2)CC1
Temperature: 25 °C
Yield: 60 %

Procedure:
tert-Butyl 4-((4-chlorophenethyl)(3-cyanobenzyl)amino)piperidine-1-carboxylate obtained in Step 1 was dissolved in toluene (5 mL/mmol) and sodium azide (3 equiv) and triethylamine hydrochloride (0.1 equiv) were added to this solution. The heterogeneous mixture was refluxed for 3 days after which time the starting material could no longer be detected. After cooling down to ambient temperature the solids were filtered off and the solvent was stripped off in vacuo. The crude product was purified by silica gel chromatography (yield 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:4]=1.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:29][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:5]([CH:4]=1)[O:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: COc1ccc(C=O)c(OCCCN2CCOCC2)c1
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(C=NCCc2ccccc2)c(OCCCN2CCOCC2)c1
Yield: 81.4 %

Procedure:
4-Methoxy-2-[3-(4-morpholinyl)propoxy]benzaldehyde (29.7 g) and 13.0 g of phenethylamine are reacted in 110 ml of toluene following the procedure described in Example 1B, yielding 33.1 g of the title compound, boiling point 240°-245° C. at 0.1-0.2 mm of Hg.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21]CC3C=CC=CC=3)[CH:14]=2)[C:8]2[C:4]=1[N:5]=[C:6]([C:29]([O:32]CC1C=CC=CC=1)([CH3:31])[CH3:30])[N:7]=2>C1COCC1.CO.[Pd]>[ClH:1].[NH2:2][C:3]1[N:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=2)[C:8]2[C:4]=1[N:5]=[C:6]([C:29]([OH:32])([CH3:30])[CH3:31])[N:7]=2
Reactant: COc1ccc(Cn2cnc(N)c3nc(C(C)(C)OCc4ccccc4)nc2-3)cc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cn2cnc(N)c3nc(C(C)(C)O)nc2-3)cc1O
Yield: 77.4 %

Procedure:
A solution of the above 6-amino-3-(3-benzyloxy-4-methoxy-benzyl)-8-(1-benzyloxy-1-methyl-ethyl)-3H-purine hydrochloride (3.22 g) in THF:methanol (1:1) (60 ml) was hydrogenated at room temperature and pressure for 2.5 hours with 10% Pd-C (0.64 g). The catalyst was filtered off and the solution evaporated to dryness in vacuo. The residue was crystallized from acetone to give 6-amino-3-(3-hydroxy-4-methoxy-benzyl)-8-(1-hydroxy-1-methyl-ethyl)-3H-purine hydrochloride, (1.67 g, 77.3%) mp 155-160° C.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:11])([CH3:10])[C:4]1[O:5][CH:6]=[CH:7][C:8]=1[CH3:9].[I-:12].[Na+]>CC(=O)CC>[I:12][CH2:2][Si:3]([CH3:11])([CH3:10])[C:4]1[O:5][CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccoc1[Si](C)(C)CCl
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: Cc1ccoc1[Si](C)(C)CI

Procedure:
Reflux chloromethyl(dimethyl)(3-methyl-2-furyl)silane (114.5 mmol) in butanone (200 mL) containing sodium iodide (116 mmol) for 4 h, according to the procedure described in Example 1, step b to provide the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[OH-].[K+].[CH:14]([OH:17])([CH3:16])[CH3:15]>O>[CH:14]([O:17][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([CH3:16])[CH3:15]
Reactant: CC(C)O
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)OCc1cccc([N+](=O)[O-])c1

Procedure:
A 500-milliliter flask equipped with a reflux condenser and a magnetic stirring bar was charged with 17.1 grams (0.1 mole) of 3-nitrobenzyl chloride in 250 milliliters of isopropanol. To this stirred solution was added 6.43 grams (0.1 mole) of potassium hydroxide in 25 milliliters of water. The reaction mixture was heated to reflux and maintained at reflux for 23 hours. The reaction mixture was then cooled, filtered, and the filtrate was concentrated on a rotary evaporator at 55° C. The residue was slurried with 300 milliliters of methylene chloride and transferred to a separatory funnel wherein it was washed consecutively with 100 milliliter portions of 1 Normal hydrochloric acid, water, 1 Normal sodium hydroxide, and water, respectively. The organic phase was separated, dried over magnesium sulfate, and concentrated on a rotary evaporator at 55° C., leaving a dark brown liquid. The dark brown liquid was charged to a distillation flask and distilled at a pressure of 2.4 millimeters of mercury. A main fraction (8.2 grams) was collected, said fraction having a boiling point of 123°-125° C. at 2.4 mm Hg pressure. This main fraction was identified by NMR spectroscopy as 1-(isopropoxymethyl)-3-nitrobenzene.
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>CO>[CH2:16]([NH:17][CH2:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC1CO1
Reactant: NCCCCCCN
Solvent: CO
Product: CCCCCCC(O)CNCCCCCCNCC(O)CCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-octene oxide (42 g.) and hexamethylenediamine (19.05 g.) and recrystallization of the resulting product from methanol gave N,N'-(1,6-hexylene)-bis[2-hydroxyoctylamine] (I: R = (CH3 (CH2)5, R' = H, X = (CH2)6, Z = H) (17.2 g., m.p. 124.0°-127.4° C.).
Reaction SMILES: [Cl:1][C:2]1[C:10]([I:11])=[C:9]([Cl:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[C:10]([I:11])=[C:9]([Cl:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)c(Cl)c(I)c1Cl
Product: O=C(Cl)c1cc(F)c(Cl)c(I)c1Cl

Procedure:
10.0 g of 2,4-dichloro-5-fluoro-3-iodo-benzoic acid and 9.5 ml of thionyl chloride are boiled until gas is no longer produced. The remaining thionyl chloride is then stripped off in vacuo. 10.2 g of crude acyl chloride, which can be employed without further purification, remain.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([N:11]=[C:12]2[S:16][CH2:15][C:14]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:13]2)[N:3]=1.[CH2:21](Br)[CH:22]([CH3:24])[CH3:23].[H-].[Na+].CO>CN(C=O)C>[CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([N:11]=[C:12]2[S:16][CH2:15][C:14]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[N:13]2[CH2:21][CH:22]([CH3:24])[CH3:23])[N:3]=1
Reactant: Cc1cc(N=C2NC3(CCCC3)CS2)nc(C)c1C#N
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(N=C2SCC3(CCCC3)N2CC(C)C)nc(C)c1C#N
Temperature: 50 °C
Yield: 17 %

Procedure:
To a solution of 2-(2,4-dimethyl-3-cyano-6-pyridylimino)-3-thia-1-azaspiro[4.4]nonane (Method C1e; 0.192 g, 0.669 mmol) and isobutyl bromide (0.5 mL) in anh. DMF (0.5 mL) was added NaH (95%; 0.62 g, 6.69 mmol) portionwise. The resulting mixture was heated at 50° C. for 3 h, then treated with MeOH (approximately 0.5 mL) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, gradient from 20% EtOAc/hex to 100% CH2Cl2) to give 2-(2,4-dimethyl-3-cyano-6-pyridylimino)-1-isobutyl-3-thia-1-azaspiro[4.4]nonane (0.04 g, 17%): CI-MS m/z 343 ((M+H)+).
Reaction SMILES: C([N:8]1[CH2:14][CH:13]2[CH2:15][CH:10]([CH2:11][N:12]2[C:16]2[C:17]3[CH2:27][CH2:26][CH2:25][C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[C:18]=3[N:19]=[C:20]([NH2:22])[N:21]=2)[CH2:9]1)C1C=CC=CC=1>CCO.C(Cl)Cl.[OH-].[OH-].[Pd+2]>[CH:10]12[CH2:15][CH:13]([N:12]([C:16]3[C:17]4[CH2:27][CH2:26][CH2:25][C:24]5[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=5[C:18]=4[N:19]=[C:20]([NH2:22])[N:21]=3)[CH2:11]1)[CH2:14][NH:8][CH2:9]2
Reactant: Nc1nc2c(c(N3CC4CC3CN(Cc3ccccc3)C4)n1)CCCc1ccccc1-2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: Nc1nc2c(c(N3CC4CNCC3C4)n1)CCCc1ccccc1-2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product from Example 81A (69 mg) in EtOH (1.5 mL) was treated with 20% Pd(OH)2/C (35 mg), stirred under an atmosphere of H2 for 16 hours at room temperature, then at 60° C. for 3 hours, after which the reaction was cooled, diluted with 5:1 CH2Cl2:EtOH, stirred for 20 minutes, filtered, concentrated and purified by chromatography (eluting with 2, 3.5, 5 and 10% (9:1 MeOH:saturated aqueous NH4OH) in CH2Cl2) to provide the title compound. 1H NMR (CDCl3) δ 1.83 (d, J=11.19 Hz, 1H), 1.97-2.08 (m, 1H), 2.09-2.20 (m, 2H), 2.24-2.42 (m, 2H), 2.52 (dt, J=14.50, 5.47 Hz, 1H), 2.61-2.75 (m, 3H), 2.84-2.92 (m, 1H), 2.93-3.01 (m, 1H), 3.31-3.38 (m, 1H), 3.63 (d, J=10.17 Hz, 1H), 3.93 (dd, J=9.83, 5.43 Hz, 1H), 4.43 (dd, J=5.26, 3.56 Hz, 1H), 4.65 (s, 2H), 7.18-7.23 (m, 1H), 7.29-7.39 (m, 2H), 7.72-7.79 (m, 1H); MS (M+H)+ m/z 322.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[C:13](=[O:22])[C:14]4[CH:15]=[N:16][N:17]=[CH:18][C:19]=4[C:20](=[O:21])[C:11]=3[N:10]=[N:9]2)=CC=1>C(O)(C(F)(F)F)=O>[NH:8]1[C:12]2[C:13](=[O:22])[C:14]3[CH:15]=[N:16][N:17]=[CH:18][C:19]=3[C:20](=[O:21])[C:11]=2[N:10]=[N:9]1
Reactant: COc1ccc(Cn2nnc3c2C(=O)c2cnncc2C3=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2cnncc2C(=O)c2[nH]nnc21
Yield: 57.8 %

Procedure:
415 mg (1.29 mmol) of 1-(4-methoxybenzyl)-1H-[1,2,3]triazolo[4,5-g]phthalazin-4,9-dione was dissolved in 30 ml of TFA and refluxed for 2 days. TFA was removed under reduced pressure and 100 ml of 1M NaOH was added to residue, followed by washing with ethyl acetate. The resulting aqueous layer was acidified to pH 1 with HCl, and extracted with ethyl acetate. 150 mg of light brown powder was obtained by drying and concentrating the organic layer (yield 58%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([CH2:11][NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:10])[C:6]([F:9])([F:8])[F:7])[CH3:2].C(N)C.[F:31]C1C=CC(N2C3C=CC=C(NCC4(C(F)(F)F)CO4)C=3C=N2)=CC=1>>[CH2:1]([NH:3][CH2:4][C:5]([CH2:11][NH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[C:22]1[CH:27]=[CH:26][C:25]([F:31])=[CH:24][CH:23]=1)([OH:10])[C:6]([F:9])([F:8])[F:7])[CH3:2]
Reactant: Fc1ccc(-n2ncc3c(NCC4(C(F)(F)F)CO4)cccc32)cc1
Reactant: CCNCC(O)(CNc1cccc2c1cnn2-c1ccccc1)C(F)(F)F
Agent: CCN
Product: CCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F

Procedure:
Prepared similarly to Intermediate 15 from ethylamine (2M in tetrahydrofuran) and 1-(4-fluorophenyl)-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-indazol-4-amine.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([N:20]=O)=[C:12]([OH:22])[CH:11]=2)=[CH:6][CH:5]=1)[CH3:2].[CH3:25][C:26]1([CH3:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH3:36])[C:27]1=[CH2:28]>CO>[CH3:36][N:29]1[C:27]2([O:22][C:12]3[CH:11]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([N:3]([CH2:23][CH3:24])[CH2:1][CH3:2])=[CH:5][CH:6]=4)[C:19]4[C:14]([C:13]=3[N:20]=[CH:28]2)=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:26]([CH3:25])([CH3:37])[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2
Reactant: CCN(CC)c1ccc(-c2cc(O)c(N=O)c3ccccc23)cc1
Reactant: C=C1N(C)c2ccccc2C1(C)C
Solvent: CO
Product: CCN(CC)c1ccc(-c2cc3c(c4ccccc24)N=CC2(O3)N(C)c3ccccc3C2(C)C)cc1
Yield: 36.6 %

Procedure:
A solution of 4-(p-diethylaminophenyl)-1-nitroso-2 -hydroxynaphthalene (0.85 g; 0.0027 mol) and 1,3-dihydro-1,3,3-trimethyl-2-methyleneindoline (0.5 g; 0.0029 mol) in methanol (60 ml) under nitrogen, was heated under reflux for 24 hours. The solution was then evaporated and chromatographed over silica (1 part diethyl ether to 10 parts pet. ether) to afford 1,3-dihydro-1,3,3-trimethyl-6'-(p-diethylaminophenyl)spiro[2H-indole-2,3'-[3H]naphth[2,1-b][1,4]oxazine] (0.47 g; 36%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][CH:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=3)[CH2:9][C:8]([CH2:24][CH3:25])([CH3:23])[C:7]=2[N:6]=1)=[O:4].[H-].[Na+].I[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=3)[CH2:9][C:8]([CH2:24][CH3:25])([CH3:23])[C:7]=2[N:6]=1)=[O:4]
Reactant: CC(C)CCI
Reactant: CCC1(C)CC(c2ccc(F)c(Cl)c2)Nc2ccc(C(=O)OC)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(C)CC(c2ccc(F)c(Cl)c2)N(CCC(C)C)c2ccc(C(=O)OC)nc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a 0° C. solution of 6-(3-chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid methyl ester (200 mg, 0.5 mmol) in N,N-dimethylformamide (5 mL) was added a 60% dispersion of sodium hydride in mineral oil (44 mg, 1.1 mmol) portionwise. The mixture was stirred at 0° C. for 30 min and then 1-iodo-3-methyl-butane (327 mg, 1.6 mmol) was added to above mixture dropwise at 0° C. The mixture was stirred at 0° C. for 3 hours and then extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The yellowish residue was purified by ISCO combi-flash chromatography (gradient elution, 0-5% ethyl acetate/hexane) to afford 6-(3-chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5-(3-methyl-butyl)-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid methyl ester (160 mg, 67.5%) as a yellow oil. MS (ESI+) [(M+H)+] 433.1.
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].[C:21](#[N:24])[CH:22]=[CH2:23].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[C:1]([C:3]1[C:7](/[CH:23]=[CH:22]/[C:21]#[N:24])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#C/C=C/c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Temperature: 70 °C
Reaction time: 24 h

Procedure:
A mixture of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.864 g), acrylonitrile (0.264 g), triethylamine (0.4 ml), palladium acetate (0.04 g) and dimethylformamide (10 ml) were stirred under an atmosphere of nitogen at 70° C. for 24 hours. The reaction mixture was evaporated and the residue partitioned between water and dichloromethane. The organic layer was separated, washed with water, brine, then dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (40 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white solid m.p. 144-145° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[NH2:23][C:24]1[S:25][CH:26]=[N:27][N:28]=1>C(Cl)CCl.C(OCC)(=O)C>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:21])(=[O:20])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[S:25][CH:26]=[N:27][N:28]=1)=[O:2])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1nncs1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CN1C(C(=O)Nc2nncs2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 41 %

Procedure:
4-Hydroxy-2-methyl-N-(1,3,4-thiadiazolyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 2-amino-1,3,4-thiadiazole. Yield: 41% of theory; m.p.217°-219° C (decomp.; from ethylene chloride/ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9]3[C:15](=[O:16])[N:14]([CH3:17])[C:13]4[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=4[O:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[N:22]1([CH2:28][CH2:29]Cl)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH2:29][CH2:28][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:9]3[C:15](=[O:16])[N:14]([CH3:17])[C:13]4[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=4[O:11][C:10]=3[C:5]2=[CH:4][CH:3]=1
Reactant: CN1C(=O)c2[nH]c3cc(Cl)ccc3c2Oc2ccccc21
Reactant: ClCCN1CCCCC1
Product: CN1C(=O)c2c(c3ccc(Cl)cc3n2CCN2CCCCC2)Oc2ccccc21

Procedure:
In the same way as described in example 19, 3-chloro-7-methyl-7H-indolo[3,2-b][1,5]benzoxazepin-6(5H)-one was alkylated with piperidinoethyl chloride. The crude solid base was recrystallized from acetonitrile, mp. 160°-162°.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH2:12][CH2:13][N:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)[CH2:15][CH:16]=1
Reactant: C1=C(c2nc3ccccc3s2)CCNC1
Reactant: N#Cc1ccc(CBr)cc1
Agent: Cl
Product: N#Cc1ccc(CN2CC=C(c3nc4ccccc4s3)CC2)cc1
Yield: 60.3 %

Procedure:
4-(Benzothiazol-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (300 mg, 1.2 mmol) was reacted with α-bromo-p-tolunitrile (280 mg, 1.44 mmol) as exemplified in Example 1. The crude product was purified by flash chromatography eluting with 25% ethyl acetate in petroleum spirit to give a solid. Recrystallisation of this solid from ethyl acetate yielded the title compound as a yellow solid (240 mg, 60%) mp. 165°-166° C. (Found: C, 72.00; H, 4.92; N, 12.61. C20H17N3S requires C, 72.48; H, 5.17; N, 12.68%). δH (CDCl3), 2.76 (2H, m, NCH2CH2), 2.83 (2H, m, NCH2CH2), 3.24 (2H, m, NCH2CH2), 3.72 (2H, s, NCH2Ar), 6.68 (1H, m, NCH2CH), 7.41 (4H, m, ArH), 7.51 (1H, d, J 8.4Hz, ArH), 7.64 (1H, d, J 8.4Hz, ArH), 7.83 (1H, d, J 7.0Hz, ArH), 8.00 (1H, d, J 8.3Hz, ArH). m/z (ES+) 332 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].S(OC)(O[CH3:26])(=O)=O.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:19])[N:7]([C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])[CH3:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: COS(=O)(=O)OC
Reactant: COc1ccc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution at 0° C. of N-(5-methoxy-2-nitrophenyl)carbamic acid t-butyl ester (5.5 g) in dimethylformamide (35 ml) was added sodium hydride (0.9 g, 60% dispersion in mineral oil) and the mixture was stirred at 0° C. for 1 hour. A solution of dimethyl sulfate (2.2 ml) in dimethylformamide (5.5 ml) was slowly added dropwise at 0° C. and the mixture was stirred at the same temperature for 0.5 hours. At the end of this time, to the reaction mixture was slowly added water (55 ml) and the mixture was extracted with toluene (66 ml). The extract was washed with water and concentrated in vacuo to give the desired compound (5.8 g, yield 100%).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]1[C:28]3[C:23](=[CH:24][C:25]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:26][CH:27]=3)[CH:22]=[C:21](Br)[C:20]=1[O:38][CH3:39])=[C:14]([O:40][CH3:41])[C:13](Br)=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:43]1([Mg]Br)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CCOCC>[CH2:1]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]1[C:28]3[C:23](=[CH:24][C:25]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:27][CH2:26][CH2:25][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:26][CH:27]=3)[CH:22]=[C:21]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:20]=1[O:38][CH3:39])=[C:14]([O:40][CH3:41])[C:13]([C:10]1[CH:9]=[CH:18][CH:17]=[CH:16][CH:11]=1)=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: Br[Mg]c1ccccc1
Reactant: CCCCCCCCc1ccc2c(-c3c(OC)c(Br)cc4cc(CCCCCCCC)ccc34)c(OC)c(Br)cc2c1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCc1ccc2c(-c3c(OC)c(-c4ccccc4)cc4cc(CCCCCCCCCCCCCCCCCC)ccc34)c(OC)c(-c3ccccc3)cc2c1
Reaction time: 0.25 h
Yield: 50.6 %

Procedure:
A suspension of 80 mg of Ni[PPh3 ]2Cl2 and 20 ml of ether were added to 1.9 g of Compound 3, and stirred for 15 minutes in a nitrogen atmosphere. 10 mmol of phenylmagnesium bromide were added and refluxed for 4 hours. After cooling down, the solution was quenched with 20 ml of 1N hydrochloric acid and extracted with chloroform. The organic layer was evaporated under reduced pressure, and purified with column chromatography (silica gel, hexane/benzene) to get 670 mg of pure 6,6'-dioctadecyl-3,3'-diphenyl-2,2'-dimethoxy-1,1'-binaphthyl. (yield 36%) (Compound 4).