Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Cl:11][CH2:12][C:13](Cl)=[O:14]>>[Cl:11][CH2:12][C:13]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])=[O:14]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1C(=O)O
Product: O=C(CCl)Nc1ccccc1C(=O)O

Procedure:
Anthranilic acid shown by formula (10) is reacted with chloroacetyl chloride to obtain N(chloroacetyl)anthranilic acid shown by formula (15). This reaction is suitably carried out by heating under reflux in a solvent such as benzene.
Reaction SMILES: [Cl:1][C:2]1([Cl:9])[N:6]=[C:5](Cl)[C:4]([Cl:8])=[N:3]1.[Cu][C:11]#[N:12]>C1(C)C(C)=CC=CC=1>[C:11]([C:5]1[C:4]([Cl:8])=[N:3][C:2]([Cl:1])([Cl:9])[N:6]=1)#[N:12]
Reactant: ClC1=NC(Cl)(Cl)N=C1Cl
Reactant: N#C[Cu]
Solvent: Cc1ccccc1C
Product: N#CC1=NC(Cl)(Cl)N=C1Cl
Yield: 40.2 %

Procedure:
A mixture of 20.5 g (0.1 mol) of 2,2,4,5-tetrachloro-2H-imidazole, 41 g (0.5 mol) of anhydrous copper-(I) cyanide and 230 ml of anhydrous xylene was heated for about 30 hours at 110° - 120° C. After cooling, the reaction mixture was filtered and the brown residue was repeatedly washed with ether. The combined solutions were shaken with active charcoal and the resulting coloured solution was concentrated in vacuo. The concentrated solution was taken up in n-hexane and the product crystallised out. It was filtered off and recrystallised from n-hexane, giving 7.9 g (40% of theory) of 4-cyano-2,2,5-trichloroimidazole (melting point 114° - 115° C).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[S:7][C:6]([CH2:8][NH:9][C:10]([NH:12][C:13]([S-:15])=[NH:14])=O)=[CH:5][CH:4]=1.[CH:18](OCC)(OCC)OCC.[CH2:28]([OH:30])C>>[CH3:18][S:15][C:13]1[N:12]=[CH:10][N:9]([CH2:8][C:6]2[S:7][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)[C:28](=[O:30])[N:14]=1
Reactant: CCOC(OCC)OCC
Reactant: N=C([S-])NC(=O)NCc1ccc(C(F)(F)F)s1
Reactant: CCO
Product: CSc1ncn(Cc2ccc(C(F)(F)F)s2)c(=O)n1
Temperature: 25 °C
Yield: 61 %

Procedure:
N-[({[5-(trifluoromethyl)thiophen-2-yl]methyl}amino)carbonyl]-carbamimidothioate (2.68 g, 9.03 mmol) synthesized in Reference Synthesis Example 290, triethyl orthoformate (10 mL) was added and the resultant mixture was stirred at 150° C. for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature and ethanol (20 mL) was added, followed by cooling the resultant mixture to 0° C. The precipitated solid was collected by filtration and the solid was washed with ethanol to obtain the title compound (1.69 g, yield 61%).
Reaction SMILES: [OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=O)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[C:17]([NH:25][NH2:26])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO.O.Cl>[OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=[N:26][NH:25][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6]
Reactant: NNC(=O)c1ccccc1
Reactant: CC(=O)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(=NNC(=O)c1ccccc1)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
1-[4-((1R,2S,3R)-1,2,3,4-Tetrahydroxy-butyl)-1H-imidazol-2-yl]-ethanone (150 mg, 0.65 mmol) was suspended in methanol (3 ml) and water (1 ml). Benzoic acid hydrazide (102 mg, 0.75 mmol, 1.2 eq.) and hydrochloric acid (one drop, 12 N) were added, and the suspension was stirred at 50° C. for 18 hours. LCMS analysis indicated the formation of the product and the absence of starting material. The homogeneous reaction mixture was cooled to room temperature and concentrated in vacuo. C-18 Reverse-Phase SPE (10 g Alltech Hi-load C18, gradient from water to 20% methanol/water) to yield the product, a mixture of approximately 1:1 E:Z isomers, as a colorless solid: 193 mg (85%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:13](Cl)(Cl)=[O:14].[Cl:17][C:18]1[CH:23]=[C:22]2[NH:24][C:25](=[O:44])[C:26]3([CH:30]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:29][NH:28][CH:27]3[C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=3[F:43])[C:21]2=[CH:20][CH:19]=1.C(N(CC)CC)C>O1CCCC1.C1(C)C=CC=CC=1>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[CH:4][C:3]([CH2:2][O:1][C:13]([N:28]2[CH2:29][CH:30]([CH2:31][C:32]([CH3:34])([CH3:35])[CH3:33])[C:26]3([C:21]4[C:22](=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=4)[NH:24][C:25]3=[O:44])[CH:27]2[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=2[F:43])=[O:14])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(=O)c1ccc(CO)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(COC(=O)N2CC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a solution of methyl 4-(hydroxymethyl)benzoate (20 mg, 0.12 mmol) in tetrahydrofuran (3 mL) was added a toluene solution (Aldrich, 20%) of phosgene (0.25 mL, 0.48 mmol) dropwise via a syringe. The reaction mixture was stirred at room temperature for 1 h, then the solvents were removed. The residue was dissolved into tetrahydrofuran (3 mL), and rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one prepared in Example 6 (56 mg, 0.13 mmol) and triethylamine (0.04 mL, 0.29 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 18 h. The solvents were removed, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (35% EtOAc in hexanes) to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid 4-methoxycarbonyl-benzyl ester as a white solid (Yield 55 mg, 68%).
Reaction SMILES: [ClH:1].Cl[C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.N1C=CC=CC=1>O>[Cl:1][C:5]1[CH:4]=[CH:3][CH:8]=[C:7]2[C:6]=1[NH:9][C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=1
Reactant: O=C1CCCCC1
Reactant: Cl
Reactant: NNc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Clc1cccc2c3c([nH]c12)CCCC3
Temperature: 25 °C

Procedure:
p-Chlorophenylhydrazine hydrochloride (1.79 g., 0.010 mole) is added to a solution of 1.0 ml. (0.010 mole ) cyclohexanone and 3.0 ml. pyridine. The resulting mixture is heated under nitrogen at reflux for 4 hours, cooled to room temperature and water added to precipitate the product. After crystallization from ethanol-water 1.34 g. of the title compound was obtained, M.P. 144.0°-145.5° C. A second crop of crystals 0.18 g. is obtained from the mother liquor. Total yield, 74%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C@@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[C:27]([C:35]([OH:37])=[O:36])[CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)#[N:2].[Si](C=[N+]=[N-])(C)(C)[CH3:39]>CO.C1(C)C=CC=CC=1.CCO>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C@@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:26]=[C:27]([C:35]([O:37][CH3:39])=[O:36])[CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)[CH2:23][CH2:24]2)[CH2:15][CH2:14]1)#[N:2]
Reactant: Cn1cc([C@H]2CC[C@@H](N3CCN(c4cc(C(=O)O)cc5cccnc45)CC3)CC2)c2cc(C#N)ccc21
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CO
Product: COC(=O)c1cc(N2CCN([C@H]3CC[C@@H](c4cn(C)c5ccc(C#N)cc54)CC3)CC2)c2ncccc2c1
Temperature: 23 °C
Reaction time: 12 h

Procedure:
To 50 mg (0.1 mmol) of 8-[4-[(Cis)-4-(5-cyano-1-methyl-1H-indole-3-yl)cyclohexyl]-1-piperazinyl]-6-quinolinecarboxylic acid in 1 mL of MeOH and 3 mL of C6H5CH3 at 23° C. was added 0.9 mL (0.39 mmol) of a 10% solution of (CH3)3SiCHN2 in hexanes. After stirring at 23° C. for 12 hours, the volatiles were removed by rotary evaporation. The crude product was chromatographed on silica gel eluting with 20:1 CH2Cl2:MeOH. The product fractions were pooled, stripped, and treated with 5 mg (0.05 mmol) of (CO2H)2 in absolute EtOH to give 20 mg (0.04 mmol, a 40% yield) of the oxalate salt of the title compound as a tan crystalline solid. mp: 153-155° C.; MS (ES) m/z: 599 (MH)+.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[CH:29][C:30]([OH:39])=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27]3[CH:28]=[CH:29][C:30]([OH:39])=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:32]=3)[CH2:25][CH2:26]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)ccc1O
Product: CC(C)C(=O)Nc1cc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)ccc1O

Procedure:
Example 150 was prepared from diphenylacetyl chloride and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-hydroxyphenyl}-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.30–7.11 (m, 10H), 7.10–6.9 (m, 2H), 6.74 (d, 1H, J=8.3 Hz), 6.63 (dd, 1H, J=8.3, 2.0 Hz), 4.93 (s, 1H), 3.51 (t, 1H, J=5.4 Hz), 3.36 (quintet, 1H, J=6.5 Hz), 3.24–3.18 (m, 2H), 3.07–3.00 (m, 2H), 2.54–2.45 (m, 3H), 2.37–2.28 (m, 1H), 2.19–2.09 (m, 2H), 1.79–1.54 (m, 4H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 514.3 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].[H-].[Na+].C([Li])CCC.[C:13]([C:17]1[C:18]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)=[C:19](/[CH:34]=[CH:35]/[CH:36]=[O:37])[CH:20]([CH:31]([CH3:33])[CH3:32])[N:21]([CH2:26][O:27][SiH:28]([CH3:30])[CH3:29])[C:22]=1[CH:23]([CH3:25])[CH3:24])([CH3:16])([CH3:15])[CH3:14].[O:45]1CC[CH2:47][CH2:46]1>CCCCCC.O.C(O)(=O)C>[C:13]([C:17]1[C:18]([C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)=[C:19](/[CH:34]=[CH:35]/[CH:36]([OH:37])[CH2:47][C:46](=[O:45])[CH2:2][C:1]([O:4][CH3:5])=[O:3])[CH:20]([CH:31]([CH3:33])[CH3:32])[N:21]([CH2:26][O:27][SiH:28]([CH3:29])[CH3:30])[C:22]=1[CH:23]([CH3:25])[CH3:24])([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)C1=C(C(C)(C)C)C(c2ccc(F)cc2)=C(/C=C/C=O)C(C(C)C)N1CO[SiH](C)C
Reactant: COC(C)=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COC(=O)CC(=O)CC(O)/C=C/C1=C(c2ccc(F)cc2)C(C(C)(C)C)=C(C(C)C)N(CO[SiH](C)C)C1C(C)C
Reaction time: 0.25 h

Procedure:
1.02 g (8.8 mmol) of methyl acetate in 5 ml of dry tetrahydrofuran are added dropwise under nitrogen to a suspension of 330 mg (11 mmol) of 80% strength sodium hydride in 30 ml of dry tetrahydrofuran at -5° C. After 15 min, 5.5 ml (8.8 mmol) of 15% strength butyllithium in n-hexane are added dropwise at the same temperature and the mixture is stirred for 15 minutes. Subsequently, 2 g (4.4 mmol) of the compound from Example 8 dissolved in 20 ml of dry tetrahydrofuran are added dropwise and the mixture is stirred for 30 minutes at -5° C., 3 ml of 50% strength acetic acid are cautiously added to the reaction solution, and the mixture is diluted using 100 ml of water and extracted three times using 100 ml of ether each time. The combined organic phases are washed twice with saturated sodium hydrogen carbonate solution and once with saturated sodium chloride solution, dried over magnesium sulphate and concentrated in vacuo. The residue is chromatographed on a column (100 g of silica gel 70-230 mesh, φ3 cm, using ethyl acetate/petroleum ether 3:7).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:22](O)[CH3:23].Cl[CH:26]([Cl:28])[CH3:27]>ClC1C=CC(CN)=CC=1>[Cl:28][C:26]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)[CH:10]=2)=[CH:4][CH:27]=1
Reactant: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Reactant: CCO
Reactant: CC(Cl)Cl
Agent: NCc1ccc(Cl)cc1
Product: O[C@H](CNCc1ccc(Cl)cc1)COc1cccc(-c2noc3cc(F)ccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane, 4-chlorobenzylamine, and ethanol, essentially as described above in Example 57. Purity by LC/MS=95%, [M+H]+=427.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl.Cl[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]Cl>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Cc1ccccc1C
Product: Fc1ccc(N2CCNCC2)cc1Cl

Procedure:
A xylene (20 ml.) solution of 3-chloro-4-fluoroaniline (5.0 g., 34.3 mmol) and bis-(2-chloroethyl)amine hydrochloride (6.13 g., 34.3 mmol) is heated to reflux for 64 hrs. The mixture is extracted with warm water and the aqueous phase then extracted with methylene chloride. The aqueous phase is made basic with 50% sodium hydroxide and extracted with methylene chloride which is dried over potassium carbonate and concentrated under reduced pressure. Residual material is distilled and the fraction having a b.p. of about 100° C. at 0.25 mmHg collected. Conversion of the amine to the hydrochloride salt and crystallization from ethanol affords N-(3-chloro-4-fluorophenyl)piperazine.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12](SC)=[NH:13])[CH2:2][CH2:3][CH2:4][CH3:5].[CH:16]([NH:18][NH2:19])=O>C(O)C>[CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]1[NH:19][N:18]=[CH:16][N:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNc1nc[nH]c1C(=N)SC
Reactant: NNC=O
Solvent: CCO
Product: CCCCCNc1nc[nH]c1-c1ncn[nH]1

Procedure:
A mixture of methyl 4-(pentylamino)-1H-imidazole-5-carbimidothioate (0.53 g, 2.4 mmol) and formic hydrazide (0.21 g, 3.5 mmol) in ethanol (10 mL) was refluxed overnight. The reaction mixture was concentrated under reduced pressure to yield the desired product as a slightly green viscose oil. LCMS calculated for C10H17N6 (M+H): 221.2. found: 221.1.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=O)[CH2:20][CH2:19]1>>[CH2:2]([O:9][C:10]1[CH:15]=[C:14]2[C:13](=[CH:12][CH:11]=1)[NH:16][C:21]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[O:18][CH2:19][C:20]2=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCOc2ccccc21
Reactant: NNc1ccc(OCc2ccccc2)cc1
Agent: Cl
Product: c1ccc(COc2ccc3[nH]c4c(c3c2)COc2ccccc2-4)cc1

Procedure:
Following the procedure described in Example 4, using (4-benzyloxy-phenyl)-hydrazine hydrochloride salt and Chroman-4-one (2.93 g, 16.84 mmol) as the starting material, the title compound was prepared as a brown solid.
Reaction SMILES: [C:1]([CH2:3][C:4]#[N:5])#[N:2].Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]>O1CCCC1>[C:1]([CH:3]([C:4]#[N:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])#[N:2]
Reactant: N#CCC#N
Reactant: COC(=O)CCCCCCCCCCBr
Solvent: C1CCOC1
Product: COC(=O)CCCCCCCCCCC(C#N)C#N

Procedure:
100 ml of anhydrous tetrahydrofuran are introduced into a three-neck flask with stirrer, reflux condenser and dropping funnel, and 11.22 g (0.10 mol) of potassium tert.butylate are suspended with stirring. 6.61 g (0.10 mol) of 1,1-dicyanomethane dissolved in 20 ml of anhydrous tetrahydrofuran are added dropwise to this, while cooling in ice so that the temperature does not rise above 10° C. Subsequently, 28.0 g (0.10 mol) of methyl 11-bromoundecanoate are added, and the mixture is refluxed for 15 h. After cooling, the precipitated potassium bromide is filtered off, the filtrate is evaporated to dryness in a rotary evaporator, the residue is taken up in 100 ml of diethyl ether, and the solution is washed three times with 50 ml of water each time. The ethereal phase is dried over sodium sulfate and evaporated to dryness in a rotary evaporator, and the resulting crude product is distilled in a short-path distillation apparatus (boiling point 150 to 160° C./0.6 mbar).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12]I)[C:7]=2[CH:14]=1.[N:15]1([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]=2[N:29]=[CH:28][CH:27]=[CH:26]3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH2:12][N:18]3[CH2:19][CH2:20][N:15]([C:21]4[CH:22]=[CH:23][CH:24]=[C:25]5[C:30]=4[N:29]=[CH:28][CH:27]=[CH:26]5)[CH2:16][CH2:17]3)[C:7]=2[CH:14]=1
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Reactant: COc1ccc2occ(CCI)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1ccc2occ(CCN3CCN(c4cccc5cccnc45)CC3)c2c1

Procedure:
A mixture of 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg. 1 mmol) (obtained by the above mentioned process) and 8-piperazino quinoline(213 mg, 1 mmol) was heated at 120° C. in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end, reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO4 and concentrated to dryness. The dark colored solid was purified by silica-gel column chromatography by eluting it initially with 70% ethyl acetae:hexane and then with 5% methanol:ethyl acetate. 8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline was isolated as brown solid. mp 78° C.; Yield: 120 mg (31%); (M+H): 388; 1HNMR (400 MHz, CDCl3): δ 8.90˜8.88 (dd, J1=1.7 Hz, J2=1.7 Hz,, 1H); 8.13˜8.10 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.51˜6.88 (m, 8H); 3.68 (s, 3H); 3.68˜2.82 (m, 12H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2.Br[C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2.[B:37]1([B:46]2[O:50][C:49]([CH3:52])([CH3:51])[C:48]([CH3:54])([CH3:53])[O:47]2)[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]1.C([O-])(=O)C.[K+]>CN(C=O)C.CCOC(C)=O>[CH3:44][C:39]1([CH3:45])[C:40]([CH3:43])([CH3:42])[O:41][B:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]3)[O:38]1.[CH3:52][C:49]1([CH3:51])[C:48]([CH3:53])([CH3:54])[O:47][B:46]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)[O:50]1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(Br)c2C1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)ccc2C1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1
Product: CC(C)(C)OC(=O)N1CCc2cccc(B3OC(C)(C)C(C)(C)O3)c2C1
Temperature: 85 °C

Procedure:
A solution of tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate and tert-butyl 8-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (19.5 mmol), bis(pinacolato)diboron (21.4 mmol) and potassium acetate (61 mmol) in DMF (100 mL) was degassed. To this solution was added PdCl2dppf (1:1 complex with DCM, 0.8 mmol). The reaction mixture was heated at 85° C. for 4 hr and then allowed to cool to room temperature and diluted with EtOAc. The solution was washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate and tert-butyl 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. LCMS: (FA) ES+ 360 (for each).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=2)[C:30](O)=[O:31])[CH2:23][CH2:22]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][N:35]=[C:27]([N:24]4[CH2:23][CH2:22][O:21][CH2:26][CH2:25]4)[CH:28]=3)=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccnc(N2CCOCC2)c1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccnc(N2CCOCC2)c1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-2-morpholin-4-yl-iso-nicotinamide was prepared starting from intermediate D and 2-morpholinoisonicotinic acid. MS calcd. for C26H24ClN4O3 [(M+H)+] 475.2, obsd. 475.0.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1([C:13](=O)[CH2:14][C:15]2[CH:16]=[C:17]([N:21]3[CH:25]=[C:24]([C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[NH:28][N:27]=4)[N:23]=[N:22]3)[CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.O.CCOC(C)=O>C1COCC1>[N:7]1([CH2:13][CH2:14][C:15]2[CH:16]=[C:17]([N:21]3[CH:25]=[C:24]([C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[NH:28][N:27]=4)[N:23]=[N:22]3)[CH:18]=[CH:19][CH:20]=2)[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1
Reactant: O=C(Cc1cccc(-n2cc(-c3n[nH]c4ccccc34)nn2)c1)N1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: c1cc(CCN2CCOCC2)cc(-n2cc(-c3n[nH]c4ccccc34)nn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
LAH (1M in THF, 107 μl; 0.26 mmol; 2.0 eq.) was added dropwise to a cooled (0° C.) solution of 3-{1-[3-(2-morpholin-4-yl-2-oxoethyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole (50 mg, 0.13 mmol, 1 eq.) in dry THF (1 mL). The reaction mixture was allowed to warm to RT and stirred overnight. Water was added and the reaction mixture was extrated three times with EtOAc. Combined organic phases were dried over magnesium sulfate, filtered and concentratd. The crude was purified by preparative HPLC to give the title compound as a beige powder. 1H NMR (300 MHz, DMSO-d6) δ 13.37 (brs, 1H), 9.31 (s, 1H), 8.37 (dt, J=8.2 Hz, 1.0 Hz, 1H), 7.96 (t, J=1.5 Hz, 1H), 7.90-7.87 (m, 1H), 7.61 (dt, J=1.0, 8.4 Hz, 1H), 7.53 (t, J=7.9 Hz, 1H), 7.47-7.41 (m, 1H), 7.40-7.38 (m, 1H), 7.28-7.23 (m, 1H), 3.59 (t, J=4.6 Hz, 4H), 2.91-2.86 (m, 2H), 2.64-2.59 (m, 2H), 2.47 (t, J=4.6 Hz, 4H). HPLC (Condition A): Rt 2.47 min (purity 95.5%). MS (ESI+): 375.2, MS (ESI−): 373.3.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=O)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:19][CH3:20])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[S:30])(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(S(=O)(=O)N2CCCC2=O)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCN(CC)c1ccc(S(=O)(=O)N2CCCC2=S)cc1
Yield: 50.5 %

Procedure:
A mixture comprising 9 g of 1-[4-(diethylamino)benzenesulphonyl]-2-pyrrolidinone, prepared as in Example 2 of the European Patent published under No. 0,033,578, and 6.15 g of Lawesson reagent (or 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulphide) in 180 cm3 of toluene is heated to reflux for 1 hour. The mixture is allowed to return to room temperature and is evaporated to dryness, the residue is taken up in 200 cm3 of chloroform and the resulting mixture is dried, filtered on celite and evaporated to dryness. 3.6 g of crude product (m.p. 170°-180° C.) are recovered, which product is chromatographed on silica (eluant: ethyl acetate/n-hexane, 2:1) and the residue is then crystallized in ethanol. 2.4 g of expected product are obtained. M.p. 183°-184° C.