Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl[C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:32]=3)[CH:25]=2)[CH:21]=[CH:22][CH:23]=1.CCOCC>COCCOCCOC>[O:37]([C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[O:30][C:26]1[CH:25]=[C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:14][C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[CH:19]=2)[CH:29]=[CH:28][CH:27]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: Clc1cccc(-c2cccc(Oc3cccc(Oc4ccccc4)c3)c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: COCCOCCOC
Product: c1ccc(Oc2ccc(Oc3cccc(-c4cccc(Oc5cccc(Oc6ccccc6)c5)c4)c3)cc2)cc1
Temperature: 150 °C
Reaction time: 0.75 h

Procedure:
A 250 ml. reaction flask equipped with stirrer, dropping funnel, thermometer, and Dean-Stark trap surmounted by a Friedrichs condenser, was charged with 200 g. (1.07 moles) of p-phenoxyphenol, and 34.9 g. (0.567 mole) of potassium hydroxide was added in increments at 90°C. To the resulting melt was added 50 ml. of toluene and the theoretical amount of water azeotroped from the reaction mixture followed by removal of toluene up to 230°C. On cooling to 150°C., the reaction mixture was diluted with 150 ml. of diglyme and 5.0 g. of cuprous chloride and 1.0 g. of copper powder was added. Over a 45 min. period, 20 g. (0.054 mole) of 3-chloro-3'-(m-phenoxyphenoxy)-biphenyl in diglyme was added, and the diglyme was removed by distillation. The stirred reaction mixture was heated at 235°C. for 19 hours. On cooling, an equal volume of ether was added and this mixture centrifuged to remove salts. The ethereal solution was washed with 25 % potassium hydroxide solution to remove excess phenol, water until neutral, and then dried over anhydrous magnesium sulfate. After filtration and concentration to remove ether, the oil obtained was distilled to obtain 17.5 g. of the desired product, bp 297°-302° C./0.05 mm.; nD25 1.6500.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C:27](=[O:28])[NH:26][N:25]=[CH:24]4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.C[C:30]1[CH:35]=[CH:34][C:33](S(OCCC#CCC)(=O)=O)=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>>[CH2:34]([N:26]1[C:27](=[O:28])[N:23]([C:20]2[CH:21]=[CH:22][C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][CH:7]=4)[CH2:16][CH2:15]3)=[CH:18][CH:19]=2)[CH:24]=[N:25]1)[CH2:35][C:30]#[C:31][CH2:32][CH3:33]
Reactant: COCOc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Reactant: CCC#CCCOS(=O)(=O)c1ccc(C)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC#CCCn1ncn(-c2ccc(N3CCN(c4ccc(OCOC)cc4)CC3)cc2)c1=O
Yield: 60 %

Procedure:
This compound was synthesized as a yellowish amorphous solid from 13 (56.0 mg, 0.147 mmol), 3o (48.2 mg, 0.191 mmol), K2CO3 (40.6 mg, 0.294 mmol), and 18-Crown-6 (38.9 mg, 0.147 mmol) in 60% yield by following general procedure 1.3: 1H NMR (400 MHz, CDCl3, δH) 7.61 (s, 1H), 7.45-7.34 (m, 2H), 7.10-6.87 (m, 6H), 5.12 (s, 2H), 3.97 (t, J=7.3 Hz, 2H), 3.47 (s, 3H), 3.35 (dd, J=6.3, 3.6 Hz, 4H), 3.23 (dd, J=6.3, 3.6 Hz, 4H), 2.63 (tt, J=7.3, 2.3 Hz, 2H), 2.14 (qt, J=7.5, 2.3 Hz, 2H), 1.09 (t, J=7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3, δC) 152.25, 151.76, 150.85, 146.67, 134.50, 125.93, 123.81, 118.52, 117.50, 116.85, 95.28, 83.95, 75.42, 56.10, 50.72, 49.39, 45.03, 19.25, 14.34, 12.62. MALDI-MS: 462.2 (M+H+), 484.2 (M+Na+).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:27].[O:37]=[C:38]1[CH2:42][CH2:41][CH2:40][N:39]1[CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:46]3[CH2:45][CH2:44][CH:43]([N:39]4[CH2:40][CH2:41][CH2:42][C:38]4=[O:37])[CH2:48][CH2:47]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:27]
Reactant: O=C1c2c(-c3ccc(F)cc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCCN1C1CCNCC1
Product: O=C1c2c(-c3ccc(F)cc3)cc(N3CCC(N4CCCC4=O)CC3)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 39.3 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (53.3 mg) was reacted with 4-(2-oxopyrrolidine-1-yl)piperidine (20.2 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-9-[4-(2-oxopyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (26.1 mg, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1)=[O:5].[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[SH:27].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:27][C:19]2[S:18][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=2)=[CH:8][CH:7]=1)=[O:5]
Reactant: Sc1nc2ccccc2s1
Reactant: O=C(c1ccc(F)cc1)c1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(c1ccc(Sc2nc3ccccc3s2)cc1)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
269.1 g (1.000 mol) of 2,5-dichloro-4′-fluorobenzophenon, 175.6 g (1.050 mol) of 2-benzothiazolethiol, 152.0 g (1.100 mol) of potassium carbonate, and 1.500 ml of N,N′-dimethylacetamide were added into a 3 L three-necked flask equipped with a stirrer, thermometer, cooling pipe, and nitrogen inlet tube, and dehydrated. The reaction solution was heated by use of an oil bath and was allowed to react at 110 degrees C. in a nitrogen atmosphere for 2 hours. After the disappearance of material was confirmed by a thin layer chromatography, the mixture was cooled to ambient temperature. Then, the reaction solution was gradually poured into 3 L of water to cause coagulation. The resulting product by filtration was dissolved into 4 L of toluene. The organic layer was washed by brine to be neutral. After the organic layer was dried by magnesium sulfate, the solvent was removed by an evaporator. The rough yield was 350.3 g. By using 1.5 L of toluene heated at 80 degrees C., the dried product was recrystallized for isolation to obtain 325.4 g of the refining material in 78.2% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].[CH2:21]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br)[CH2:22][CH2:23][C:24]#[CH:25].P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][O:26][CH2:21][CH2:22][CH2:23][C:24]#[CH:25])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Reactant: C#CCCCOCCCCCCBr
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCCCOCCCCCCN1C[C@@H](c2ccc3c(c2)COC(C)(C)O3)OC1=O
Reaction time: 0.17 h
Yield: 84 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (Example 1vi) (500 mg) in DMF (15 ml) under nitrogen at 0° was treated with sodium hydride (60% dispersion in mineral oil, 96 mg) and the mixture stirred at 20° for 10 min. A solution of 6-bromohexyl 4-pentyn-1-yl ether (WO 02/066422) (545 mg) in DMF (1 ml) was added and the mixture stirred at 20° for 18 h. Phosphate buffer solution (pH 6.5) and water were added and the mixture was extracted with EtOAc. The extract was washed with water and dried (Na2SO4). Solvent evaporation in vacuo gave a residue, which was purified by flash chromatography on silica gel. Elution with EtOAc-PE (2:3) gave the title compound (700 mg). LCMS RT=3.48 min.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[NH:6][C:5]2=[O:17])[CH2:3][CH2:2]1.[H-].[Na+].[N+:20](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>O1CCOCC1.CN(C)C=O>[NH2:20][N:6]1[C:7](=[O:16])[C:8]2[C:13](=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]1=[O:17]
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: O=c1[nH]c(=O)n(C2CC2)c2cc(F)c(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Nn1c(=O)c2cc(F)c(F)cc2n(C2CC2)c1=O
Temperature: 60 °C
Yield: 63.8 %

Procedure:
To a solution of 1-cyclopropyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example 23a, 2.0 g, 8.92 mmol) in dioxane (7.5 mL) and dimethylformamide (7.5 mL) is added NaH (60% dispersion in oil, 428 mg, 10.7 mmol). The solution is heated to 60° C. for 10 minutes and cooled to room temperature. To the cooled solution is added O-(2,4-dinitrophenyl)hydroxylamine (1.77 g, 8.92 mmol), and the solution is heated to 80° C. for 30 minutes. The resulting red solution is cooled to room temperature, poured over crushed ice, and extracted with EtOAc. The combined organic layers are dried over MgSO4, filtered, and the solvent removed under reduced pressure. The resulting solid is triturated with Et2O and air dried to afford 1.44 g of the title compound. MS CI: m/z 254 (MH+).
Reaction SMILES: Br.O=[C:3]1[CH:12]([CH2:13][C:14]([O:16]C)=O)[CH2:11][CH2:10][C:9]2[CH:8]=[N:7][CH:6]=[CH:5][C:4]1=2.[Cl:18][C:19]1[CH:20]=[C:21]([NH:25][NH2:26])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([N:25]2[C:14](=[O:16])[CH2:13][CH:12]3[C:3]([C:4]4[CH:5]=[CH:6][N:7]=[CH:8][C:9]=4[CH2:10][CH2:11]3)=[N:26]2)[CH:22]=[CH:23][CH:24]=1
Reactant: NNc1cccc(Cl)c1
Reactant: COC(=O)CC1CCc2cnccc2C1=O
Agent: Br
Product: O=C1CC2CCc3cnccc3C2=NN1c1cccc(Cl)c1

Procedure:
Prepared according to the method described in Example 1 from methyl 5,6,7,8-tetrahydro-5-oxoisoquinoline-6-acetate hydrobromide and 3-chlorophenylhydrazine.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:11])[C:5]([C:9]#[N:10])=[C:6](Cl)[N:7]=1.[SH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[NH:3][C:4](=[O:11])[C:5]([C:9]#[N:10])=[C:6]([S:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[N:7]=1
Reactant: SCCc1ccccn1
Reactant: N#Cc1c(Cl)nc(N)[nH]c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(SCCc2ccccn2)nc(N)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
To a stirred suspension of 500 mg (2.93 mmol) 2-amino-4-chloro-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile in 10 ml DME were added 0.61 g (4.40 mmol) 2-mercapto-ethylpyridine and 1.10 ml (7.33 mmol) DBU and the mixture stirred at room temperature for 1 hour. The reaction mixture was then partitioned between water and ethyl acetate and the organic phase was dried over sodium sulfate and concentrated in vacuo. Chromatography (dichloromethane then methanol/dichloromethane 5/95) followed by trituration in ether/methanol afforded 310 mg (39%) 2-amino-6-oxo-4-(2-pyridin-2-yl-ethylsulfanyl)-1,6-dihydro-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 274 (M+H+, 100).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:40]=O)=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)[CH:21]=1.[Br:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[Br:42][C:43]1[CH:49]=[CH:48][C:46]([NH:47][CH2:40][C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][C:20]=2[C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[O:29])=[N:26][CH:27]=2)=[CH:45][CH:44]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(Br)cc2)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Solid NaBH(OAc)3 (1.4 g, 6.8 mmol) was added to a DCM solution (10 mL) of tert-butyl 3-(5-(5-chloro-2-formylphenyl)picolinamido)propanoate (1.3 g, 3.4 mmol) and 4-bromoaniline (882 mg, 5.1 mmol), and the resulting mixture was stirred at room temperature. After 40 h the resulting mixture diluted with DCM and saturated aqueous Na2CO3 and stirred vigorously. After 5 min, the layers were separated and the aqueous phase was extracted with DCM. The combined organics were washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [O:1]1[C@H:3]2[C:4]3[C:5]([O:17][C:18]([CH3:20])([CH3:19])[C@:2]12O)=[CH:6][C:7]1[C:8]([CH3:16])=[CH:9][C:10]([CH2:14][OH:15])=[N:11][C:12]=1[CH:13]=3.[C:22]1([CH2:28][CH2:29][NH2:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)CC>[OH:15][CH2:14][C:10]1[CH:9]=[C:8]([CH3:16])[C:7]2[CH:6]=[C:5]3[O:17][C:18]([CH3:19])([CH3:20])[C@H:2]([OH:1])[C@@H:3]([NH:30][CH2:29][CH2:28][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:4]3=[CH:13][C:12]=2[N:11]=1
Reactant: Cc1cc(CO)nc2cc3c(cc12)OC(C)(C)[C@]1(O)O[C@@H]31
Reactant: NCCc1ccccc1
Solvent: CCCO
Product: Cc1cc(CO)nc2cc3c(cc12)OC(C)(C)[C@H](O)[C@H]3NCCc1ccccc1
Yield: 125.8 %

Procedure:
To a liquid mixture of 7.98 g (29.4 mmol) of the obtained (3R,4S)-3,4-epoxy-7-hydroxymethyl-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinolin-3-ol and 16.07 g of 1-propanol, 4.30 g (35.5 mmol, 1.2 equivalent) of 2-phenylethylamine was added and the resultant mixture was heated and refluxed for 5 hours. The solvent was distilled off to produce 14.52 g of (3R,4S)-7-hydroxymethyl-2,2,9-trimethyl-4-(phenethylamino)-3,4-dihydro-2H-pyrano[2,3-g]quinolin-3-ol as a brown oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.Br[CH2:14][CH2:15][CH2:16][CH3:17]>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=2)[CH:3]=1
Reactant: CCCCBr
Reactant: Oc1ccc2cc(Br)ccc2c1
Product: CCCCOc1ccc2cc(Br)ccc2c1

Procedure:
2-Bromo-6-butoxynaphthalene was prepared according to the method of Example 1, part a, except using 6-bromo-2-naphthol instead of 4-hydroxyacetophenone and using 1-bromobutane instead of benzylbromide.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[Br:12][CH2:13][CH2:14][CH2:15]Br.C([O-])([O-])=O.[K+].[K+]>CCO>[Br:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: BrCCCBr
Reactant: O=c1[nH]c2ccc(O)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1[nH]c2ccc(OCCCBr)cc2[nH]1
Reaction time: 8 h
Yield: 2.7 %

Procedure:
A solution of intermediate 38 (5 g, 33.3 mmol), 1,3-dibromopropane (4 mL, 33.3 mmol) and anhydrous K2CO3 (4.6 g, 33.3 mmol) in EtOH (25 mL) was heated to reflux and stirred overnight. The solvent was removed under vacuum. The residue was diluted with water and extracted with EtOAc. The combined EtOAc layers were washed with water, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=100:1) to give 5-(3-bromopropoxy)-1H-benzo[d]imidazol-2(3H)-one (intermediate 39) (240 mg, 12%) as a yellow solid.
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]1([CH:14]=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.C(O)(=O)C>CCOCC>[OH:15][CH:14]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[C:1]#[N:2]
Reactant: [C-]#N
Reactant: O=Cc1cccc2ccccc12
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: N#CC(O)c1cccc2ccccc12
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of potassium cyanide in ether (100 mL) at 0° C. was added dropwise a mixture of 1-naphthalenecarboxaldehyde (1.56 g, 10 mmol) and acetic acid (1.41 g, 23.5 mmol) in ether (10 mL). The resulting mixture was warmed to 25° C. for 20 h, the precipitate was filtered and the filtrate was concentrated affording the title compound as a clear oil (1.67 g, 9.14 mmol, 91%): LCMS (ES) m/z 184 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.[C:14]([C:16]1[CH:17]=[C:18]([C:30]2[CH:31]=[C:32]([CH:37]=[CH:38][N:39]=2)[C:33]([O:35][CH3:36])=[O:34])[CH:19]=[CH:20][C:21]=1OS(C(F)(F)F)(=O)=O)#[N:15].[CH:40]([Si:43]([CH:55]([CH3:57])[CH3:56])([CH:52]([CH3:54])[CH3:53])[N:44]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45]1)([CH3:42])[CH3:41]>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.O>[C:14]([C:16]1[CH:17]=[C:18]([C:30]2[CH:31]=[C:32]([CH:37]=[CH:38][N:39]=2)[C:33]([O:35][CH3:36])=[O:34])[CH:19]=[CH:20][C:21]=1[C:46]1[CH:47]=[CH:48][N:44]([Si:43]([CH:52]([CH3:54])[CH3:53])([CH:55]([CH3:57])[CH3:56])[CH:40]([CH3:41])[CH3:42])[CH:45]=1)#[N:15]
Reactant: COC(=O)c1ccnc(-c2ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c2)c1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccnc(-c2ccc(-c3ccn([Si](C(C)C)(C(C)C)C(C)C)c3)c(C#N)c2)c1
Temperature: 130 °C
Yield: 5.2 %

Procedure:
58 mg of tetrakis(triphenylphosphine)palladium and 208 mg of potassium carbonate were added to a toluene (10 ml) solution of 386 mg of methyl 2-(3-cyano-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)isonicotinate and 534 mg of 1-(triisopropylsilyl)pyrrole-3-boronic acid, then this was irradiated with microwaves and heated at 130° C. in a nitrogen atmosphere for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 to 70:30) to obtain 24 mg of methyl 2-{3-cyano-4-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]phenyl}isonicotinate. (2) 24 mg of this compound was dissolved in 1 ml of THF, and 63 μL of 1 M tetrabutylammonium fluoride/THF solution was added thereto, followed by stirring at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10 to 70:30) to obtain 6 mg of methyl 2-[3-cyano-4-(1H-pyrrol-3-yl)phenyl]isonicotinate. (3) 6 mg of this compound was dissolved in a mixture of 0.5 ml of methanol and 0.5 ml of THF, and 22 μl of aqueous 1 M sodium hydroxide solution was added, followed by heating at 60° C. for 2 hours. The reaction liquid was cooled, and the solvent was removed under reduced pressure. Water was added to the residue, followed by neutralization with 1 M hydrochloric acid. The precipitated crystal was collected by filtration and washed with a mixture of ethanol and water to obtain 1.5 mg of 2-[3-cyano-4-(1H-pyrrol-3-yl)phenyl]isonicotinic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)=[C:12]([CH3:19])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].F[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14]3[N:15]=[CH:16][N:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[CH:18]=3)=[C:12]([CH3:19])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1onc(-c2ccc(F)c(F)c2)c1-c1c[nH]cn1
Reactant: Fc1ccc(C(F)(F)F)cc1
Product: Cc1onc(-c2ccc(F)c(F)c2)c1-c1cn(-c2ccc(C(F)(F)F)cc2)cn1
Yield: 10 %

Procedure:
As described for Example 53, 3-(3,4-difluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (78 mg, 0.3 mmol) using 4-fluorobenzotrifluoride instead of 4-fluoroacetophenone was converted to the title compound (12 mg, 10%) which was obtained as a colourless gum. MS: m/e=406.3 [M+H]+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1.[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1.O>C(OCC)C>[CH3:16][N:17]1[CH2:22][CH2:21][C:20]([C:7]2[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[S:10][CH:11]=2)([OH:23])[CH2:19][CH2:18]1
Reactant: Brc1csc2ccccc12
Reactant: CN1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CN1CCC(O)(c2csc3ccccc23)CC1
Reaction time: 0.5 h

Procedure:
13.5 g (0.21 mole) of n-butyllithium in 145 ml of absolute diethyl ether is precooled to -70° to -80°. To this solution there is then added dropwise within 30 minutes, at a temperature of -70°, a solution of 42.6 g of 3-bromobenzo[b]thiophene in 250 ml of absolute diethyl ether. The solution is thereupon stirred for a further 30 minutes at -70°. An addition is then made dropwise, in the course of 30 minutes, of a solution of 23.5 g of 1-methyl-4-piperidone in 100 ml of absolute diethyl ether; the reaction temperature is held by external cooling at -70°, and the reaction solution is subsequently stirred for a further 10 hours at -70°. The reaction solution is thereupon heated to -5°, and 300 ml of water is added dropwise. The organic phase is separated, and the aqueous phase is extracted twice with 400 ml of ethyl acetate. The organic phases are combined, dried with sodium sulphate, filtered off with suction and concentrated by evaporation. The residue is dissolved in 500 ml of 2N hydrochloric acid, and the acid solution is washed with ether. The aqueous solution is then adjusted be addition by 10% sodium hydroxide solution to have a pH-value of 12, and extracted with one litre of chloroform. The chloroform solution is dried with sodium sulphate, filtered off with suction and concentrated by evaporation to obtain crude 1-methyl-4-(benzo[b]thien-3-yl)-4-piperidinol. The free base melts at 150°-151° after recrystallisation from acetone.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=O.P(Cl)(Cl)(Cl)=O.[N+:14]([C:17]1[N:21]([CH3:22])[C:20]([C:23]2[N:27]3[N:28]=[C:29]([NH2:32])[CH:30]=[CH:31][C:26]3=[N:25][N:24]=2)=[N:19][CH:18]=1)([O-:16])=[O:15]>O1CCOCC1>[N+:14]([C:17]1[N:21]([CH3:22])[C:20]([C:23]2[N:27]3[N:28]=[C:29]([N:32]=[CH:1][N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)[CH:30]=[CH:31][C:26]3=[N:25][N:24]=2)=[N:19][CH:18]=1)([O-:16])=[O:15]
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N)nn12
Reactant: O=CN1CCCCC1
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N=CN3CCCCC3)nn12
Reaction time: 1.5 h

Procedure:
2.85 ml. N-formyl-piperidine in 10 ml. dioxan were stirred with 2.4 ml. phosphorus oxychloride, which was introduced portionwise at 35° - 40° C., for 30 minutes at this temperature, then 1.5 g. crude 3-(5-nitro-1-methyl-2-imidazolyl)-6-amino-s-triazolo[4,3-b]pyridazine was added and the reaction mixture was stirred for 1.5 hours at 35° - 40° C. The solution obtained was now poured into 75 ml. ice water, filtered with suction and the clear filtrate was rendered alkaline (about pH 10) with concentrated aqueous ammonia, cooled, left to stand for some time and the resultant crystals (1.28 g.) filtered off with suction and recrystallized from 25 ml. isopropanol, with the addition of charcoal, 0.82 g. of the desired 3-(5-nitro-1-methyl-2 -imidazolyl)-6-(1-piperidinyl-methyleneamino)-s-triazolo[4,3-b]pyridazine thereby being obtained in the form of yellowish-white crystals which melt at 187° - 189° C.