Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[N:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:10]=[C:11]2[C:16]=1[C:15](=[O:17])[N:14]([CH3:18])[C:13](=O)[NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:35]>>[CH2:1]([C:8]1[N:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:10]=[C:11]2[C:16]=1[C:15](=[O:17])[N:14]([CH3:18])[C:13]([Cl:35])=[N:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)[nH]c2nn(Cc3ccc(-c4ccccc4)cc3)c(Cc3ccccc3)c2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1c(Cl)nc2nn(Cc3ccc(-c4ccccc4)cc3)c(Cc3ccccc3)c2c1=O
Yield: 100 %

Procedure:
3-benzyl-2-(biphenyl-4-ylmethyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (10 mg, 0.024 mmol) is refluxed in POCl3 (10 mL) for 4 days, and then the mixture is evaporated to dryness. The residue is purified by silica gel flash chromatography to give 10.4 mg product as white solids (Yield: 100%). MS (FAB) m/z 441.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH2:15][C:16]1[CH:35]=[CH:34][C:19]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:22]=2)=[CH:18][C:17]=1[F:36]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:15][C:16]2[CH:35]=[CH:34][C:19]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[CH:22]=3)=[CH:18][C:17]=2[F:36])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
At room temperature, 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (1.06 g, 4.77 mmol, 1.05 eq) was dissolved in dichloromethane (10 mL). A solution of tert-butyl 4-(4-amino-3-fluorophenoxy)picolinate (1.38 g, 4.54 mmol, 1 eq) in dichloromethane (50 mL) was added dropwise slowly. The resulted mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure, and the resulted solid was purified by column chromatography (dichloromethane: methanol=30:1) to give the title compound (1.9 g, purity 94%, yield 80%) as a reddish-brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Temperature: 79.5 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 2.12 g (13.2 mmol) of 3-bromo-1-chloropropane (purity: 98 wt. %), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt. %), and 10 mL of methyl ethyl ketone. The resulting mixture was refluxed under stirring at 77-82° C. in an argon gas atmosphere for 2 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 1.36 g (reaction yield: 95.4%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:8][NH:9][C:10](=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1)=[O:18])[CH3:7])[CH:2]([CH3:4])[CH3:3]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([O:5][CH:6]([O:8][NH:9][C:10](=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]=[O:27])=[CH:24][CH:25]=1)=[O:18])[CH3:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COC(C)ONC(=O)CCCCCCC(=O)Nc1ccc(CO)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)COC(C)ONC(=O)CCCCCCC(=O)Nc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 801 %

Procedure:
Octanedioic acid (4-hydroxymethyl-phenyl)-amide(1-isobutoxyethoxy)-amide (100 mg, 0.025 mmol, 1.0 eq) was dissolved in DCM (5 mL). To the reaction mixture, was added MnO2 (286 mg, 0.33 mmol, 13.0 eq) and was stirred at room temperature for 1.5 h. The reaction mixture was filtered over Celite and washed through with DCM, followed by evaporation of solvent to give a yellow oil (78.6 mg, 79% yield) LCMS purity 53%, m/z 415 [M++Na]+. The product was used in the subsequent steps without further purification.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=1)C.Cl.CO>CO>[CH3:14][N:12]([CH2:11][C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[O:3])=[CH:10][CH:9]=1)[CH3:13]
Reactant: CCOC(OCC)c1ccc(CN(C)C)cc1
Agent: Cl
Solvent: CO
Product: CN(C)Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.2 %

Procedure:
To a solution of 1-(4-(diethoxymethyl)phenyl)-N,N,-dimethylmethanamine (1.0 g, 4 mmol) in methanol (5 mL), a hydrochloric acid-methanol solution (10 mL) was added dropwise at 0° C. The reaction solution was stirred at room temperature overnight. Then methanol was removed in vacuo to give 4-((dimethylamino)methyl)benzaldehyde (0.68 g, yield 99%) as a light yellow oil. 1H-NMR (400 MHz, CDCl3): δ 2.26 (s, 6H), 3.50 (s, 2H), 7.49 (d, J=6.4 Hz, 2H), 7.84 (d, J=6.4 Hz 2H), 10 (s, 1H). LC-MS (ESI) m/z: 164 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[S:25](=[O:40])(=[O:39])[NH:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH2:37][CH3:38])[N:32]=[CH:31]2)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[S:25](=[O:39])(=[O:40])[N:26]([C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1)[CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH2:37][CH3:38])[N:32]=[CH:31]2)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3CC)c2)c(Cl)c1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3CC)c2)c2ncc(C(F)(F)F)cc2Cl)c(Cl)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and ethyl 3-chloro-4-(N-((1-ethyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-4 of Example 14).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([CH:7]=O)[CH:4]=[C:3]([CH:9]=O)[CH:2]=1.NCCC[N:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:22][CH2:23][CH2:24][NH2:25].[BH4-].[Na+].[OH-].[Na+]>CO>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([CH2:7][NH:21][CH2:26][CH2:27][CH2:28][NH:25][CH2:24][CH2:23][CH2:22][NH:21][CH2:26][CH:27]([CH3:29])[CH3:28])[CH:4]=[C:3]([CH2:9][NH:25][CH2:24][CH2:23][CH2:22][NH:25][CH2:24][CH2:23][CH2:22][NH:21][CH2:26][CH:27]([CH3:28])[CH3:29])[CH:2]=1
Reactant: CC(C)CN(CCCN)CCCN
Reactant: O=Cc1cc(C=O)cc(-c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CNCCCNCCCNCc1cc(CNCCCNCCCNCC(C)C)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
[1,1′-Biphenyl]-3,5-dicarbaldehyde (3.03 g, 14.4 mmol) and MeOH (60 mL) were added to a round-bottom flask. To the solution was added N′-(3-aminopropyl)-N3-isobutylpropane-1,3-diamine (5.40 g, 28.8 mmol), and the reaction mixture was stirred at rt for 24 h. Sodium borohydride (0.55 g, 14.4 mmol) was added, and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure to afford a white solid. Aqueous NaOH (10%, 50 mL) was added, and the reaction mixture stirred for 30 min. The solution was extracted with CHCl3 (3×75 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a clear oil which was used without further purification.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(C=CC=2)N)C=CN=1.[Cl:23][C:24]1[C:29]([C:30]2[N:31]=[C:32]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[S:33][C:34]=2[C:35]2[CH:40]=[CH:39][N:38]=[C:37]([Cl:41])[N:36]=2)=[CH:28][CH:27]=[CH:26][C:25]=1[NH:48]C(=O)OCC=C>>[Cl:23][C:24]1[C:29]([C:30]2[N:31]=[C:32]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[S:33][C:34]=2[C:35]2[CH:40]=[CH:39][N:38]=[C:37]([Cl:41])[N:36]=2)=[CH:28][CH:27]=[CH:26][C:25]=1[NH2:48]
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl
Agent: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Product: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl

Procedure:
Following a procedure analogous to the procedure described in Intermediate 13 using 2-propen-1-yl {2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}carbamate (2.50 g, 5.08 mmol) the title compound of Step D was obtained as a yellow solid (2.08 g, 4.99 mmol, 98% yield). MS (ESI): 407.97 [M+H]+.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH3:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[S:13]([N:23]1[CH2:27]C[C@@H:25](O)[CH2:24]1)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[S:13]([N:23]1[CH2:24][CH2:25][C@H:11]([O:10][S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:12])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[CH2:27]1)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccc(S(=O)(=O)N2CC[C@@H](O)C2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)O[C@H]2CCN(S(=O)(=O)c3ccc(C)cc3)C2)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Methyl para-toluenesulphonate (54 g) was added in portions to solution of 1-tosyl-3-(R)-(-)-hydroxypyrrolidine (49 g--see Preparation 2) and triphenylphosphine (76 g) in anhydrous tetrahydrofuran (700 ml) at 0° C. The mixture was cooled to -20° C. and diethyl azodicarboxylate (58 g--"DEAD") was added, dropwise, over 30 minutes. During this time, the temperature of the mixture was not allowed to rise above -10° C. When the addition was complete the mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was concentrated in vacuo to give a solid which was purified by column chromatography on silica eluting with hexane containing dichloromethane (50%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was crystallised from 1-propanol to give the title compound as a colourless solid, yield 56 g, m.p. 110° C., [α]25D -5.2° (c 1.0, CH2Cl2).
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[N:5]2)[CH2:3][CH2:2]1>C(O)C>[CH:1]1([N:4]2[CH:8]=[CH:7][C:6]([NH2:9])=[N:5]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccn(C2CC2)n1
Solvent: CCO
Product: Nc1ccn(C2CC2)n1
Reaction time: 3 h
Yield: 93.2 %

Procedure:
A 250-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 137 mg dry weight) and a solution of 123a (600 mg, 3.92 mmol) in ethanol (70 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 3 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (1.00 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×25 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a 93% yield of 123b (450 mg) as a purple oil: 1H NMR (300 MHz, CDCl3) d 7.17 (d, 1H, J=2.4 Hz), 5.55 (d, 1H, J=2.4 Hz), 3.43 (m, 1H), 2.92 (br s, 2H), 1.01 (m, 2H), 0.93 (m, 2H); MS (ESI+) m/z 124.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:29])[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:47][CH2:48][N:49]2[CH:53]=[CH:52][N:51]=[N:50]2)(=O)=O)=CC=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C(NCC)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(Cl)(Cl)Cl.C(N(CC)CC)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:47][CH2:48][N:49]4[CH:53]=[CH:52][N:51]=[N:50]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:29])[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26]
Reactant: CCN(CC)C(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)OCCn2ccnn2)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)Nc1ccc(Oc2ncnc3cc(OCCn4ccnn4)c(OC)cc23)cc1Cl
Temperature: 80 °C
Reaction time: 18 h
Yield: 29 %

Procedure:
A starting compound (N′-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N,N-diethylurea, 83 mg), potassium carbonate (138 mg), and 2-(1H-1,2,3-triazol-1-yl)ethyl 4-methyl-1-benzenesulfonate (59 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 80° C. for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give an intermediate. Triphosgene (90 mg) was added to a solution of the intermediate and triethylamine (0.027 ml) in chloroform (1 ml) at 0° C., and the mixture was stirred for 30 min. The reaction mixture was cooled to 0° C., and diethylamine (0.044 ml) was then added dropwise to the cooled reaction mixture. The temperature of the mixture was raised to room temperature over a period of 2 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, followed by extraction with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC to give 30 mg (yield 29%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[S:19]1[CH:23]=[CH:22][C:21]2[CH:24]=[C:25]([C:28](Cl)=[O:29])[CH:26]=[CH:27][C:20]1=2>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:28]([C:25]4[CH:26]=[CH:27][C:20]5[S:19][CH:23]=[CH:22][C:21]=5[CH:24]=4)=[O:29])[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: O=C(Cl)c1ccc2sccc2c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1ccc2sccc2c1
Yield: 30 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and benzo[b]thiophene-5-carbonyl chloride to afford the title compound (25 mg, 30%). 1H-NMR (δ, ppm, DMSO-d6): 6.50 (d, 1H, HPy,5, J=6.0 Hz), 6.91 (d, 1H, Harom, J=7.0 Hz), 7.43 (t, 1H, Harom, J=8.0 Hz), 7.60 (d, 1H, Harom, J=5.0 Hz), 7.67 (t, 1H, Harom, J=2.5 Hz), 7.81 (d, 1H, HPy,6, J=6.0 Hz), 7.89 (d, 1H, Harom, J=6.0 Hz), 7.91 (d, 1H, Harom, J=8.0 Hz), 8.15 (d, 1H, Harom, J=8.5 Hz), 8.49 (d, 1H, Harom, J=1.5 Hz), 10.44 (s, 1H, NHamide), 11.20 (s, 1H, NHPy3), 11.39 (s, 1H, NHPy2). HRMS (EI): m/z [M+H] calcd for C21H15N4O3: 403.0865; found: 403.0867.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([OH:10])[CH:3]=1.CC(C)([O-])C.[K+].[CH3:17][O:18][CH2:19]Cl.O>CN(C)C(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([O:10][CH2:17][O:18][CH3:19])[CH:3]=1
Reactant: COCCl
Reactant: OCc1ccc(Cl)cc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COCOc1cc(Cl)ccc1CO
Reaction time: 0.17 h
Yield: 92 %

Procedure:
4.00 g of 4-chloro-2-hydroxybenzyl alcohol [prepared as described in step (a) above] were dissolved in 80 ml of N,N-dimethylacetamide, and then 2.83 g of potassium t-butoxide were added to the resulting solution, whilst ice-cooling, and the mixture was stirred for 10 minutes. 2.09 ml of methoxymethyl chloride were then added to the reaction mixture, whilst ice-cooling, and the mixture was then stirred at room temperature for 1 hour. At the end of this time, 60 ml of water and 300 ml of ethyl acetate were added, and the ethyl acetate layer was separated and washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. It was then concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 4.69 g (yield 92%) of the title compound as an oily substance.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([O:25][C:21]3[CH:20]=[C:19]([CH3:18])[CH:24]=[CH:23][CH:22]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: Cc1cccc(O)c1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: Cc1cccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-methyl-phenol to give (1H-pyrazol-3-yl)-(1-m-tolyloxy-isoquinolin-3-yl)-amine. LC-MS m/e 317(MH+).
Reaction SMILES: [N:1]1[C:11]2[O:10][C:9]3[CH:12]=[CH:13][C:14]([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(=O)([O-])O.[Na+].[CH2:27](O)[CH3:28]>>[N:1]1[C:11]2[O:10][C:9]3[CH:12]=[CH:13][C:14]([CH:16]([CH3:20])[C:17]([O:19][CH2:27][CH3:28])=[O:18])=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(=O)O)c1ccc2c(c1)CCc1cccnc1O2
Reactant: CCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C(C)c1ccc2c(c1)CCc1cccnc1O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of 30 mg of 2-(5,6-dihydro benzo[b]pyrido[3,2-f]-oxepin-8-yl)-propionic acid in 0.5 ml of ethanol and 2 ml of ethanol saturated with hydrogen chloride gas was stirred at room temperature for 1 hour. The mixture was alkalified with saturated sodium hydrogencarbonate and extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain oily substance, which was chromatographed over silica gel, eluted with chloroform/benzene(1/4-1/3), and there was obtained 30 mg of ethyl 2-(5,6-dihydro benzo[b]pyrido-[3,2-f]oxepin-8-yl)-propionate as colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:24]2[S:25][CH:26]=[C:27]([CH:29]=[O:30])[N:28]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH3:23])[CH3:13].[Cl-].[NH4+]>O1CCCC1>[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:24]2[S:25][CH:26]=[C:27]([CH:29]([OH:30])[C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=3)[N:28]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH3:23])[CH3:13]
Reactant: COc1ccc(Br)cc1OC
Reactant: CCOc1ccc(-c2nc(C=O)cs2)cc1OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1ccc(-c2nc(C(O)c3ccc(OC)c(OC)c3)cs2)cc1OCC
Yield: 48.9 %

Procedure:
60 ml of a tetrahydrofuran solution of a Grignard reagent prepared from 2.4 g of 1-bromo-3,4-dimethoxybenzene was stirred with ice-cooling. Thereto was added 20 ml of a tetrahydrofuran solution of 3 g of 2-(3,4-diethoxyphenyl)-4-formylthiazole. The mixture was stirred at the same temperature for 1 hour and at room temperature for 3 hours. 10 ml of a saturated aqueous ammonium chloride solution was added. The solvent was removed by distillation. The residue was extracted with 100 ml of chloroform. The extract was washed with 20 ml of water and 20 ml of a saturated aqueous sodium chloride solution, and dried. The solvent was removed by distillation. The residue was purified by silica gel column chromatography (elutant: dichloromethane/acetone=99/1 by v/v) and recrystallized from diethyl ether to obtain 2.2 g of 2-(3,4-diethoxyphenyl)-4-[1-hydroxy-1-(3,4-dimethoxyphenyl)methyl]thiazole
Reaction SMILES: O1CCCC1.[H-].[Na+].[Cl:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1.[F:16][CH2:17][CH2:18][OH:19]>O>[F:16][CH2:17][CH2:18][O:19][C:12]1[N:11]=[N:10][C:9]([Cl:8])=[CH:14][CH:13]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: OCCF
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FCCOc1ccc(Cl)nn1
Reaction time: 0.02 h
Yield: 83.1 %

Procedure:
To anhydrous tetrahydrofuran (5 mL) containing sodium hydride (NaH 60%, 121 mg, 3.02 mmol) was slowly added anhydrous tetrahydrofuran (2 mL) having 3,6-dichloropyridazine (107, 300 mg, 2.01 mmol) dissolved therein at 0° C., and added dropwise 2-fluoroethanol (194 mg, 3.02 mmol). The reaction mixture was stirred for one minutes and water was carefully added. Organic compounds were extracted with ethyl acetate, and the recovered organic solution was washed with an aqueous solution of saturated sodium chloride and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 3-(2-fluoroethoxy)-6-chloropyridazine (108b, 295 mg, 83%) as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24](OB(O)O)[CH:25]=[CH:26][CH:27]=1)=[O:21]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:26]2[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=2)[C:20]([O:19][CH3:18])=[O:21])[CH2:13]1
Reactant: c1ccc2sc(OCC3CCCNC3)nc2c1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Product: COC(=O)c1cccc(N2CCCC(COc3nc4ccccc4s3)C2)c1
Yield: 19.7 %

Procedure:
Using 3-[(benzothiazol-2-yl)oxymethyl]piperidine (58.0 mg, 0.234 mmol) and 3-(methoxycarbonyl)phenylboric acid (84.2 mg, 0.468 mmol), the same procedure was followed as in Example 2 to give 17.6 mg (20%) of the desired compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH3:11])=[C:5]([C:7](OC)=[O:8])[N:6]=1.[Li+].[BH4-].CO>C1COCC1>[Br:1][C:2]1[S:3][C:4]([CH3:11])=[C:5]([CH2:7][OH:8])[N:6]=1
Reactant: COC(=O)c1nc(Br)sc1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1sc(Br)nc1CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.1 %

Procedure:
To a stirred solution of methyl 2-bromo-5-methyl-1,3-thiazole-4-carboxylate (2.89 g, 12.26 mmol, 1 eq.) in 120 ml dry THF cooled to 5° C., was added LiBH4 (2M in THF, 12.26 ml, 24.53 mmol, 2 eq.) followed by MeOH (0.994 ml, 24.53 mmol, 2 eq.). The reaction was allowed to warm to r.t. and was stirred for further 18 hrs. The reaction was quenched by addition of sat. aqueous NH4Cl and diluted with DCM. The aqueous layer was extracted with DCM, and the organic layers combined, dried over MgSO4 and concentrated. The residue was chromatographed on silica gel to (2-bromo-5-methyl-1,3-thiazol-4-yl)methanol (2.07 g, 77% yield) as a white solid.