Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].O>CN(C=O)C>[CH3:1][CH:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:20][CH2:21][N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])=[CH:10][CH:11]=1)[CH2:3][CH3:4]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CCC(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)Oc1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-(1-methylpropoxy)phenol (44.3 mmol) in 25 ml of DMF is added, under N2, potassium carbonate (51.0 mmol) followed by dropwise addition of N-(bromoethyl)phthalimide (51.0 mmol) in 30 ml of DMF. The mixture is stirred at RT overnight. Water is then added and the aqueous phase is extracted with ether. The combined organic layers are washed with 5% sodium hydroxide, with water and with brine, dried and the solent removed to give N-{2-[4-(1-methylpropoxy)phenoxy]ethyl}phthalimide. Following the procedures of Example 7, the above phthalimide (5.7 mmol) is reacted with hydrazine hydrate (5.7 mmol) to give 2-[4-(1-methylpropoxy)phenoxy]ethylamine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:23]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([Cl:23])[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccc2ccccc2c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)NCC(Cl)c1ccc2ccccc2c1

Procedure:
16 g of 2-t-butoxycarbonylamino-1-(2-naphthyl)ethanol [prepared as described in step (a) above] were chlorinated with phosphorus pentachloride in the same manner as in Example 36(b) to give 9.1 g of the crystalline title compound, melting at 97°-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:27])[N:22]=[C:23]([CH2:25][CH3:26])[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1.Cl.N[C@@H:32](CCN1CC(OC2C=CC(Cl)=C(C)C=2)C1)CO>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:8][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:27])[N:22]=[C:23]([CH2:25][CH3:26])[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:10]2)=[CH:28][C:29]=1[CH3:32]
Reactant: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)n(C)n1
Reactant: Cc1cc(OC2CN(CC[C@H](N)CO)C2)ccc1Cl
Agent: Cl
Product: CCc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)c(C)c3)C2)n(C)n1

Procedure:
This compound is prepared analogously to 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea in Example 88 except using (S)-2-amino-4-[3-(4-chloro-3-methyl-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:37])[C@@H:15]4[C@@H:32]([C@H:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]4[C:17]=3[C:18]([O:20]CC3C=CC([N+]([O-])=O)=CC=3)=[O:19])[S:10][C:9]=12)=[O:2].[CH3:38]I>CN(C=O)C.C1COCC1.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[Pd]>[CH:1]([NH:3][CH2:4][C:5]1[N:6]([CH3:38])[CH:7]=[N+:8]2[CH:12]=[C:11]([C:13]3[C@H:14]([CH3:37])[C@@H:15]4[C@@H:32]([C@H:33]([OH:35])[CH3:34])[C:31](=[O:36])[N:16]4[C:17]=3[C:18]([O-:20])=[O:19])[S:10][C:9]=12)=[O:2]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(CNC=O)c4s3)[C@H](C)[C@H]12
Reactant: CI
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3c[n+]4cn(C)c(CNC=O)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 134 mg of 4-nitrobenzyl (1S,5R,6S)-2-(7-formylaminomethyl imidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 2 ml of DMF was added 1.6 ml of methyl iodide, and the mixture was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure. The residue thus obtained was dissolved in 5 ml of THF and 5 ml of 0.1 M sodium phosphate buffer (pH 6.8), and 150 mg of 10% Pd-C. The reactor was purged with hydrogen, the reaction mixture was stirred at room temperature for 1 hour. The catalyst was collected by filtration, and washed with a mixed solution of 2 ml of 0.1 M sodium phosphate buffer (pH 6.8) and 2 ml of THF. The filtrate was washed with 10 ml of ethyl acetate, and the aqueous layer obtained was purified by column chromatography on COSMOSEAL 40C18-PREP (water:methanol=20:1). The fraction containing the aimed product was concentrated under reduced pressure, and then lyophilized to give 58 mg of the title compound.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]#[N:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH3:22][CH2:23][O:24][C:25]([CH2:27]Br)=[O:26]>CCOCC>[CH2:23]([O:24][C:25](=[O:26])[CH2:27][C:13]1([C:15]#[N:16])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[S:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: N#CC1c2ccccc2Sc2ccccc21
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCOC(=O)CC1(C#N)c2ccccc2Sc2ccccc21
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
9H-thioxanthene-9-carbonitrile [33] (1.20 g, 5.37 mmol) was dissolved in anhydrous Et2O and cooled in an icebath. n-Butyl lithium (2.14 mL, 5.37 mmol, 2.5M soln. in hexanes) was added dropwise over 10 min. with continuous stirring. Stirring was continued for 30 min. at the same temperature and then brought to room temperature. The reaction mixture was heated at reflux (1 hr), cooled in an icebath and ethyl bromo acetate (0.83 mL, 7.52 mmol) was added dropwise via syringe. The resulting mixture was heated at reflux (4 h) cooled and filtered. The residue was washed with ether (25 mL). Water (25 mL) was added to the filterate and the organic layer was separated. The aqueous layer was once again extracted with ether (25 mL). The combined ether extracts were washed with water and brine, dried (MgSO4) and evaporated under reduced pressure to give an oil which was purified by mplc using pet. ether: EtOAc (9:1) as eluent to give 0.97 g (59%) of the product as a colorless oil. 1H NMR (CDCl3)d: 1.08-1.12 (t, J=6 Hz, CH3), 3.08 (s, 2H, CH2), 3.95-4.03 (q, 2H, CH2), 7.31-8.00 (m, 8H, Ar—H). 13C NMR (CDCl3)d: 38.49, 47.63, 60.76, 118.91, 127.00, 127.24, 127.80, 128.15, 130.73, 130.98, 167.66.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]([C:24]1[CH:29]=[C:28]([S:30][CH2:31][CH2:32][CH2:33]O)[CH:27]=[C:26]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:25]=1[OH:39])([CH3:23])[CH3:22].C(Br)(Br)(Br)[Br:41]>CCOCC>[Br:41][CH2:33][CH2:32][CH2:31][S:30][C:28]1[CH:29]=[C:24]([C:21]([CH3:23])([CH3:22])[CH3:20])[C:25]([OH:39])=[C:26]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:27]=1
Reactant: CC(C)(C)c1cc(SCCCO)cc(C(C)(C)C)c1O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(C)(C)c1cc(SCCCBr)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triphenylphosphine (17.54 g, 66.89 mmol) was added to a stirred solution of 2 (9.9 g, 33.44 mmol) and carbon tetrabromide (22.18 g, 66.89 mmol) in dry ether. After stirring at room temperature for 18 hours, the reaction mixture was concentrated and the crude product was chromatographed (silica gel; hexane/ethyl acetate 98/2) to give 3 in quantitative yield. The structural assignment was supported by the 1H-NMR spectra in CDCl3.
Reaction SMILES: CN(C=[N:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]([N:18]=[CH:19]N(C)C)=[S:17])[CH:10]=1)(=[O:8])=[O:7])C.[CH2:23](Br)[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25].Cl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:24]([C:23]1[S:17][C:16]([NH:15][C:11]2[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=2)=[N:18][CH:19]=1)(=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)C=NC(=S)Nc1cccc(S(=O)(=O)N=CN(C)C)c1
Reactant: O=C(CBr)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1cccc(Nc2ncc(C(=O)c3ccccc3)s2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.8 %

Procedure:
A mixture of 44 mg (0.13 mmol) N-Dimethylaminomethylene-3-(3-dimethylaminomethylene-thioureido)-benzenesulfonamide and 26 mg (0.13 mmol) phenacyl bromide in 0.8 ml DMF was stirred for 16 h at room temperature. 0.12 ml HCl (37%) was added and the mixture was stirred for 69 h at 100° C. After addition of 0.12 ml N,N-Diisopropylethylamine the mixture was subjected to preparative HPLC separation on reversed phase eluting with an acetonitrile/water gradient. Evaporation of the product fractions yielded 6 mg (13%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10]2[C:11]([NH2:28])=[N:12][CH:13]=[C:14]([C:16]3[N:20]([CH3:21])[N:19]=[C:18]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[N:17]=3)[N:15]=2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:29][CH2:30][C@@H:31]([CH3:35])[C:32](O)=[O:33]>>[NH2:28][C:11]1[N:12]=[CH:13][C:14]([C:16]2[N:20]([CH3:21])[N:19]=[C:18]([CH:22]3[CH2:23][CH2:24][N:25]([C:30](=[O:29])[C@H:31]([CH3:35])[CH2:32][OH:33])[CH2:26][CH2:27]3)[N:17]=2)=[N:15][C:10]=1[C:8]1[O:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]=1
Reactant: C[C@H](CO)C(=O)O
Reactant: Cn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Product: C[C@H](CO)C(=O)N1CCC(c2nc(-c3cnc(N)c(-c4nnc(C(C)(C)C)o4)n3)n(C)n2)CC1
Yield: 47.4 %

Procedure:
Using a similar procedure as Example 4, 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-methyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine was reacted with (R)-3-hydroxy-2-methylpropanoic acid to afford the title compound (87 mg, 47.4%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][CH:17]=2)[NH:14][CH2:13][CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1.[C:18]([N:26]=C=O)(=[O:25])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][CH:17]=2)[N:14]([C:18]([NH2:26])=[O:25])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1
Reactant: Brc1cncc(-c2cnc3c(c2)CCCN3)c1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)N1CCCc2cc(-c3cncc(Br)c3)cnc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
6-(5-Bromo-pyridin-3-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (190 mg, 0.67 mmol) and benzoyl isocyanate (220 mg, 1.3 mmol) are mixed in 3.0 mL of DCM and the mixture is stirred at 50° C. for 2 hrs and room temperature for 16 hrs. Then the solvent is removed and the residue is suspended in 3.0 mL of EtOH. K2CO3 (160 mg, 1.1 mmol) is added and the mixture is heated at 70° C. for 30 min. Then the solvent is removed and the residue is partitioned between water (20 mL) and EtOAc (50 mL). The aqueous layer is separated and extracted with DCM (2×50 mL). The organic layers are combined and concentrated to give the crude product. To the crude product is added EtOAc (10 mL) and the solid formed is filtered, washed again with EtOAc (2×10 mL) and dried to give 158 mg of 6-(5-bromo-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide.
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5]Cl.[K].[C:8]1(=[O:18])[NH:12][C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>CN(C)C=O>[Cl:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:12]1[C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]2[C:8]1=[O:18]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClC/C=C/CCl
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C/C=C/CCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
To a solution of 10 g of 1,4-dichloro(trans) 2-butene in 100 ml of N,N-dimethylformamide was added 16.5 g of phthalimide potassium with ice cooling. The mixture was stirred at room temperature for 8 hours, the mixture was subjected to extraction with water-ethyl acetate, and the organic layer was distilled to remove the solvent. The residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), giving 9.6 g of N-[4-chloro(trans) 2-butenyl]phthalimide (yield 51% ).
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25][N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[N:26]1([CH2:25][C:22]2[CH:21]=[CH:20][C:19]([C:17]3[NH:16][C:12]4[N:13]=[CH:14][N:15]=[C:10]([NH:9][C:6]5[CH:5]=[CH:4][C:3](=[O:2])[NH:8][CH:7]=5)[C:11]=4[CH:18]=3)=[CH:24][CH:23]=2)[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: COc1ccc(Nc2ncnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=c1ccc(Nc2ncnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)c[nH]1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To 84 mg (0.20 mmol) of (6-methoxy-pyridin-3-yl)-[6-(4-morpholin-4-ylmethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine and 10 ml chloroform in an ampoule under N2-atmosphere, 0.1 ml (0.73 mmol) Me3Sil is added. After stirring for 6 h at 70° C., diluted NaHCO3 solution and EtOAc is added to the suspension at RT. Stirring, filtration and washing with water yields the title compound; TLC (THF/methanol/conc. ammonia 90:10:1) Rf=0.23; MS-ES+: (M+H)+=403; HPLC (conditions see Examples 67-78) tR=4.7 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH2:14][S:13][CH:12]3[N:9]([C:10](=[O:23])[CH:11]3[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]=2[C:24]([O:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:5][N:6]=1.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C>O1CCCC1>[C:40]([NH:1][C:2]1[S:3][C:4]([C:7]2[CH2:14][S:13][CH:12]3[N:9]([C:10](=[O:23])[CH:11]3[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]=2[C:24]([O:26][CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:25])=[CH:5][N:6]=1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(N)s3)CSC12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(NC(=O)c4ccccc4)s3)CSC12

Procedure:
On treating 3-(2-amino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (4.5 g) with benzoyl chloride (1.11 cc) in dry tetrahydrofuran (55 cc) in the presence of triethylamine (1.23 cc), using the working method of Example 1 (B), 3-(2-benzamido-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene (1.8 g) is obtained in the form of cream-coloured crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[N:15]1([C:21]#[N:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:18]3[CH2:19][CH2:20][N:15]([C:21]#[N:22])[CH2:16][CH2:17]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: N#CN1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 92.2 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (3.48 g, 15.65 mmol), piperazine-1-carbonitrile (2 g, 17.99 mmol) and DIPEA (3.54 mL, 20.34 mmol) in DMF (20 mL) was heated at 70° C. for 1 hour. The solution was evaporated and partitioned between DCM and 1M aqueous K2CO3. The organic phase was washed with brine, dried over MgSO4, evaporated and triturated with ether. The precipitate was collected by filtration, washed with ether and dried under vacuum to afford 4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazine-1-carbonitrile (4.29 g, 92%) as a cream crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:3]=1N.S(=O)(=O)(O)[OH:11].S(O)(O)(=O)=O.BrC1C=CC(Br)=CC=1N>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:3]=1[OH:11]
Reactant: Nc1cc(Br)ccc1Br
Reactant: O=S(=O)(O)O
Solvent: Cc1ccccc1C
Product: Oc1cc(Br)ccc1Br

Procedure:
61.6 Grams of 2,5-dibromoaniline and 250 g of 75% aqueous sulfuric acid solution were charged into a ceramic ball mill having one liter capacity. A suspension of fine particles of 2,5-dibromoaniline sulfate was prepared by a method similar to that described in Example 5. The suspension was transferred into a beaker having one liter capacity. The ceramic ball mill used was washed with 120 g of 75% aqueous sulfuric acid solution and the washings were transferred into the beaker. Diazotization of 2,5-dibromoaniline sulfate in the form of suspension of fine particles was carried out by a method similar to that described in Example 5 except that 18.2 g of sodium nitrite powder was added. Hydrolysis of 2,5-dibromobenzenediazonium sulfate was carried out by a method similar to that described in Example 5. A xylene layer was isolated from the hydrolyzed product and a crude product of 2,5-dibromophenol was obtained after the xylene was removed by distillation. The crude product of 2,5-dibromophenol was steam distilled by introducing superheated steam. After the distillate was cooled, crystallized 2,5-dibromophenol thus formed was obtained by filtration and dried. 47.3 Grams of 2,5-dibromophenol having melting point of 71°-74° C was obtained. The yield was found to be 85.0%.
Reaction SMILES: [Sn](Cl)[Cl:2].[Cl:4][C:5]1[C:6]([N+:20]([O-])=O)=[CH:7][C:8]2[C:9]3[N:10]([C:16](=[O:19])[NH:17][N:18]=3)[C:11](=[O:15])[NH:12][C:13]=2[CH:14]=1>Cl>[ClH:2].[NH2:20][C:6]1[C:5]([Cl:4])=[CH:14][C:13]2[NH:12][C:11](=[O:15])[N:10]3[C:16](=[O:19])[NH:17][N:18]=[C:9]3[C:8]=2[CH:7]=1
Reactant: O=c1[nH]nc2c3cc([N+](=O)[O-])c(Cl)cc3[nH]c(=O)n12
Reactant: Cl[Sn]Cl
Agent: Cl
Product: Nc1cc2c(cc1Cl)[nH]c(=O)n1c(=O)[nH]nc21
Yield: 67 %

Procedure:
672 mg (2.98 mmol) of tin dichloride were dissolved in 3.4 ml of conc. hydrochloric acid at 80° C. 200 mg (0.71 mmol) of 8-chloro-9-nitro-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione were added portionwise thereto. After heating at reflux for 2 hrs. the precipitate was filtered off, washed with water and dried in a vacuum. 137 mg (67%) of 9-amino-8-chloro-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione hydrochloride were obtained as white crystals;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1.Cl.[OH:21][C:22]1[C:31]([N:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[C:15]([C:17]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:31]([N:32]([CH3:34])[CH3:33])[C:22]=4[OH:21])[CH2:27]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1
Reactant: O=C(O)c1nc(-c2cccnc2)nc2ccccc12
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Agent: Cl
Product: CN(C)c1ccc2c(c1O)CCN(C(=O)c1nc(-c3cccnc3)nc3ccccc13)C2
Yield: 7 %

Procedure:
Reaction of 2-(3-pyridinyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 87 (7% yield) as yellow oil. 1H NMR (300 MHz, CD3OD) δ 2.77 and 2.80 (2s, 6H), 2.84 and 3.07 (2t, 2H), 3.60 and 4.20 (2t, 2H), 4.50 and 5.06 (2s, 2H), 6.39 and 6.88 (2d, 1H), 7.01 and 7.22 (2d, 1H), 7.62-7.82 (m, 2H), 7.96-8.25 (m, 3H), 8.71 (m, 1H), 8.92-9.02 (2d, 1H), 9.65 and 9.73 (2s, 1H); MS (ESI) m/z 426 ([M+H]+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH:11]=[CH:10]2.[CH3:24][NH:25][CH2:26][CH2:27][OH:28]>>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([N:12]2[C:13]3[C:9](=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:25]([CH3:24])[CH2:26][CH2:27][OH:28])=[C:15]([F:16])[CH:14]=3)[CH:10]=[CH:11]2)=[CH:18][CH:19]=1
Reactant: Fc1cc2c(ccn2-c2ccc(Cl)cc2)cc1OCCCCBr
Reactant: CNCCO
Product: CN(CCO)CCCCOc1cc2ccn(-c3ccc(Cl)cc3)c2cc1F

Procedure:
In analogy to example 23.7, 5-(4-Bromo-butoxy)-1-(4-chloro-phenyl)-6-fluoro-1H-indole and 2-(methylamino)ethanol were converted to yield 2-({4-[1-(4-Chloro-phenyl)-6-fluoro-1H-indol-5-yloxy]-butyl}-methyl-amino)-ethanol as a colorless oil, MS: 391 (MH+,1Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[C:4]=1Br.[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>C1COCC1.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>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[C:4]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1ccc(-c2ccc3c(Br)c(OC)ccc3c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3c(-c4ccccc4)c(OC)ccc3c2)cc1
Temperature: 25 °C
Yield: 53 %

Procedure:
To a mixture of 2-methoxy-6-(4-methoxyphenyl)-1-bromonaphthalene (0.80 g, 2.33 mmol) and tetrakis(triphenylphosphine)palladium (0.13 g, 0.12 mmol) in THF (10 mL) was added phenylmagnesiumbromide (2.2 mL of 3 N in ether). The reaction mixture was stirred at reflux overnight, cooled to room temperature, poured into 1 N HCl (100 mL), and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with sodium bicarbonate solution, dried over magnesium sulfate, filtered, evaportation of the solvent, and purification by silica column chromatography (10% ethyl acetate-hexanes) yielded 0.42 g (53%) of a gray solid: mp 157-160° C.; 1H NMR (CDCl3): δ 3.85 (3H, s), 3.87 (3H, s), 7.01 (2H, d, J=8.64 Hz), 7.38-7.46 (4H, m), 7.49-7.57 (4H, m), 7.64 (2H, d, J=8.64 Hz), 7.92 (1H, d, J=9.05 Hz), 7.97 (1H, s); MS (ESI) m/z 341 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10](CC2C=CC(OC)=CC=2)[C:9]2[CH:22]=[CH:23][S:24][C:8]=2[C:7]=1O)=[O:5])[CH3:2].C(Cl)(=O)C([Cl:29])=O>>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:22]=[CH:23][S:24][C:8]=2[C:7]=1[Cl:29])=[O:5])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1c(O)c2sccc2n(Cc2ccc(OC)cc2)c1=O
Product: CCOC(=O)c1c(Cl)c2sccc2[nH]c1=O

Procedure:
The preferred intermediate in the preparation of compounds of structure (I), 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester depicted by formula (4) below, was also prepared by an alternative route as shown in Scheme 34. In this method, methyl-3-amino-thiophene-2-carboxylate was reacted with 4-methoxy benzylchloride to yield methyl 3-(4-methoxybenzylamino)thiophene-2-carboxylate, depicted by formula (65). This intermediate was reacted with ethylmalonyl chloride followed by a cyclization reaction to yield 7-hydroxy-4-(4-methoxybenzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester, depicted by formula (67). Chlorination of 7-hydroxy-4-(4-methoxybenzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester, depicted by formula (67) by reacting with oxalyl chloride followed by deprotection yielded the intermediate 7-chloro-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester, depicted by formula (4), as shown in Scheme 34.