Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH2:11])=[O:5])[CH3:2].[CH3:12][C:13]1[C:21]2[N:20]=[C:19]([CH:22]=O)[NH:18][C:17]=2[CH:16]=[CH:15][C:14]=1[CH3:24].CC(O)=O.[BH3-]C#N.[Na+].[OH-].[Na+]>CO>[CH3:12][C:13]1[C:21]2[N:20]=[C:19]([CH2:22][NH:11][C:10]3[CH:9]=[CH:8][NH:7][C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])[NH:18][C:17]=2[CH:16]=[CH:15][C:14]=1[CH3:24]
Reactant: Cc1ccc2[nH]c(C=O)nc2c1C
Reactant: CCOC(=O)c1[nH]ccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)c1[nH]ccc1NCc1nc2c(C)c(C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.5 %

Procedure:
3-Amino-1H-pyrrole-2-carboxylic acid ethyl ester (0.077 g, 0.5 mmol), 4,5-dimethyl-1H-benzimidazole-2-carbaldehyde (0.130 g, 0.75 mmol) and HOAc (0.045 g, 0.75 mmol) were stirred in methanol (4 mL) followed by addition of NaCNBH3. The resulting mixture was stirred at r.t. for 16 h. The reaction mixture was neutralized with 2M NaOH and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and extracted with water. The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by flash column chromatography (heptane/ethyl acetate gradient; 0 to 100% ethyl acetate), obtaining a white solid, 0.043 g (27%) of the title compound, as a tautomeric mixture (1:1).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27](F)=[C:28]([N+:31]([O-:33])=[O:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:16]=[CH:17][C:18]=1[F:19].Cl>CN(C)C=O.O>[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)=[C:28]([N+:31]([O-:33])=[O:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1F
Reactant: OCC1CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
29.36 g of cyclopropylmethanol are dissolved in 310 ml of N,N-dimethylformamide and cooled to about 10° C. in an ice bath. Then 41.58 g potassium tert-butoxide is added in batches, while the temperature should stay below 15° C. The reaction mixture is then stirred for another 30 minutes at 10° C., then 31.19 g of 4-[(3-chloro-4-fluorophenyl)amino]-7-fluoro-6-nitroquinazoline is added in batches, while again the temperature should not exceed 15° C. The dark red reaction mixture is stirred for another hour at 15° C. For working up, the mixture is poured onto 2.5 1 of water and neutralized with 2N hydrochloric acid. The yellowish precipitate formed is suction filtered, washed with water, and dried at 50° C. in a drying cupboard. Yield: 36.02 g (100% of theory); melting point: 204° C.; mass spectrum (ESI+): m/z=389, 391 [M+H]+.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1CS/[C:13](=[N:15]\[C:16](=[O:22])[CH2:17][C:18](OC)=[O:19])/[CH3:14].[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1>C1COCC1>[OH:22][C:16]1[N:15]=[C:13]([CH3:14])[N:33]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([C:25]([O:24][CH3:23])=[O:34])=[CH:27][CH:28]=2)[C:18](=[O:19])[CH:17]=1
Reactant: COC(=O)CC(=O)/N=C(/C)SCc1ccc2ccccc2c1
Reactant: COC(=O)c1ccc(CN)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cn2c(C)nc(O)cc2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.1 %

Procedure:
To a solution of methyl 3-({(1Z)-1-[(2-naphthylmethyl)thio]ethylidene}amino)-3-oxopropanoate (1.9 g, 0.006 mol, from step 1) in THF (25.0 mL), at 0° C., is added methyl-4-aminomethylbenzoate (1.1 g, 0.0067 mol). The reaction mixture is stirred at room temperature for 1 hour, and then concentrated to dryness. The resulting residue is dissolved in dioxane (20.0 mL), DBU (0.1 mL) is added, and the resulting reaction mixture is heated at 70° C. for 1 h under an argon atmosphere. After removing the solvent under reduced pressure, the residue is purified by reverse-phase HPLC using 10–90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=275) are combined and freeze-dried to afford the title compound (0.33 g) as a white powder: 1H NMR (CD3OD/400 MHz) δ 7.99 (d 2H, J=8.4 Hz), 7.29 (d, 2H, J=8.4 Hz), 5.42 (s, 1H), 5.36 (s, 2H), 3.88 (s, 3H), and 2.42 (s, 3H); ES-HRMS m/z 275.1021 (M+H calcd for C14H15N2O4 requires 275.1026).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=2)[NH:12][CH:11]=1)(=O)=O.[O:23]=[C:24]1[CH:29]=[CH:28][C:27]2[CH:30]=[C:31]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[CH:32]=[CH:33][C:26]=2[O:25]1>C(#N)C>[O:23]=[C:24]1[CH:29]=[CH:28][C:27]2[CH:30]=[C:31]([N:34]3[CH2:35][CH2:36][N:37]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]4[C:18]5[C:13](=[CH:14][CH:15]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=5)[NH:12][CH:11]=4)[CH2:38][CH2:39]3)[CH:32]=[CH:33][C:26]=2[O:25]1
Reactant: O=c1ccc2cc(N3CCNCC3)ccc2o1
Reactant: COC(=O)c1ccc2[nH]cc(CCCCOS(C)(=O)=O)c2c1
Solvent: CC#N
Product: COC(=O)c1ccc2[nH]cc(CCCCN3CCN(c4ccc5oc(=O)ccc5c4)CC3)c2c1

Procedure:
A mixture of 0.0098 mol of 4-(5-methoxycarbonylindol-3-yl)butyl methanesulfonate (preparation as described in Example 3) and 0.0097 mol of 4-(2-oxo-2H-1-benzopyran-6-yl)piperazine is heated in acetonitrile for about 96 hours on a steam bath. The reaction mixture is worked up in the customary manner and purified. Methyl 3-{4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinyl]-butyl}indole-5-carboxylate is thus obtained.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]1[C:18](=[O:19])[CH2:17][N:16]=[C:15]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)[CH:14]=[C:9]12)(=[O:3])[CH3:2].I[C:27]1C=CC=C2C=1CCN1C(=O)CN=C(C3C=CN(C)N=3)C=C12.C([Sn](CCCC)(CCCC)C(OCC)=C)CCC.Cl>O1CCOCC1.C1COCC1.CCOC(C)=O.CCOCC.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>[CH3:27][O:3][CH:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]1[C:18](=[O:19])[CH2:17][N:16]=[C:15]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)[CH:14]=[C:9]12)[CH3:2]
Reactant: Cn1ccc(C2=NCC(=O)N3CCc4c(I)cccc4C3=C2)n1
Reactant: CC(=O)c1cccc2c1CCN1C(=O)CN=C(c3ccn(C)n3)C=C21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(C)c1cccc2c1CCN1C(=O)CN=C(c3ccn(C)n3)C=C21
Temperature: 140 °C
Reaction time: 1.5 h

Procedure:
9-acetyl-2-(1-methyl-1H-pyrazol-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one. 47-1. A mixture of 9-iodo-2-(1-methyl-1H-pyrazol-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (Example 31) (2.0 g, 4.78 mmol), tributyl(1-ethoxyvinyl)stannane (2.02 mL, 5.98 mmol) and Pd(PPh3)4 (276 mg, 0.24 mmol) in 1,4-dioxane (15 mL) was heated to 140° C. for 90 min. The mixture was then filtered and concentrated in vacuo and the residue obtained was purified by flash chromatography (SiO2, DCM to DCM/MeOH 95:5). The brown oil obtained was taken up in THF (100 mL) and treated with a 0.1 N aq. solution of HCl (48 mL, 4.78 mmol). The mixture was stirred at RT for 90 min. The mixture was then diluted with AcOEt and washed with a saturated aq. solution of NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was purified by flash chromatography (SiO2, DCM to DCM/MeOH 95:5) to give a brown oil that was suspended in Et2O. The suspension was filtered and the filter cake was dried in vacuo to give the title compound (912 mg) as a yellow solid. UPLC-MS: MS 335.0 (M+H+); UPLC rt 0.62 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 2.62 (s, 3 H); 3.24 (t, J=6.06 Hz, 2 H); 3.81 (t, J=6.45 Hz, 2 H); 3.92 (s, 3 H); 4.49 (br. s., 2 H); 6.81 (br. s., 1 H); 7.17 (s, 1 H); 7.34-7.45 (m, 2 H); 7.77 (d, J=7.82 Hz, 1 H); 7.84 (d, J=7.82 Hz, 1 H).
Reaction SMILES: C(OC([N:8]1[CH2:32][CH2:31][C:11]2([CH2:14][N:13]([C@H:15]3[C:23]4[C:18](=[CH:19][C:20]([C:24]5[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26][N:25]=5)=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:33]>CO.O1CCOCC1>[ClH:33].[ClH:33].[CH3:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]([C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[CH:15]([N:13]2[CH2:14][C:11]4([CH2:31][CH2:32][NH:8][CH2:9][CH2:10]4)[CH2:12]2)[CH2:16][CH2:17]3)[CH:29]=1
Reactant: Cc1cc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCN(C(=O)OC(C)(C)C)CC3)C2)ncn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(-c2ccc3c(c2)CCC3N2CC3(CCNCC3)C2)ncn1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
2-[(R)-5-(6-Methyl-pyrimidin-4-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (3-1f, 72.6 g, 167 mmol) was suspended in methanol (363 mL) and 4M HCl in 1,4-dioxane (251 mL) was added. After stirring for 2 hours, the slurry was concentrated to dryness. The crude material was re-suspended in MeOH (500 mL) and concentrated (3×). The resulting solids were further dried under vacuum at 45° C. to afford 2-[5-(6-methyl-pyrimidin-4-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-dihydrochloride (3-1g, 74.1 g, 99.9%). MS (ES+) 335.2 (M+H)+. 1H NMR (CD3OD) δ 2.16-2.23 (m, 5H), 2.59 (br s, 1H), 2.78-2.80 (m, 3H), 3.12 (br s, 1H), 3.19-3.24 (m, 4H), 3.37-3.49 (m, 1H), 4.14-4.23 (m, 3H), 4.49 (br s, 1H), 5.11 (br s, 1H), 7.84 (d, 1H), 8.30-8.34 (m, 2H), 8.46 (s, 1H), 9.36 (s, 1H).
Reaction SMILES: CC(C)COC(=O)[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.[C:16]([O:19][C@H:20]([CH2:26]Cl)[CH2:21][NH:22][C:23](=[O:25])[CH3:24])(=[O:18])C.CO.[Cl-].[NH4+]>CCCCCCC.C1(C)C=CC=CC=1.O.CN(C)C=O>[F:13][C:9]1[CH:8]=[C:7]([N:6]2[CH2:26][C@H:20]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:19][C:16]2=[O:18])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)COC(=O)Nc1cccc(F)c1
Reactant: CC(=O)NC[C@@H](CCl)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: CCCCCCC
Product: CC(=O)NC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Temperature: 1.5 °C
Reaction time: 21 h
Yield: 63 %

Procedure:
To a mixture of 3-fluorophenylcarbamic acid 2-methylpropyl ester (300.0 g, 1.42 mol), (S)-N-[2-(acetyloxy)-3-chloropropyl]acetamide (556.1 g, 2.87 mol, 2.02 eq), methanol (90.03 g, 2.81 mol, 1.98 eq) and N,N-dimethylformamide (500 ml) is added a slurry of lithium t-amylate (401.3 g, 4.27 mol, 3.00 eq) in heptane (1 liter) while maintaining −4 to 7° C., followed by heptane (100 ml). The mixture is then stirred at 19 to 20° C. for 21 h. The reaction mixture is then added to a mixture of ammonium chloride (228 g, 4.26 mol, 3.00 eq), water (2.0 liter) and toluene (1.0 liter) while maintaining 8 to 10° C. The reaction mixture is rinsed in with a mixture of water (100 ml), saturated ammonium chloride (50 ml) and toluene (100 ml). The precipitate is collected by vacuum filtration and washed with heptane (1 liter) and water (1 liter) and dried in a nitrogen stream to give 252.4 g of crude product. This is triturated in acetonitrile (1 kg) at 90° C. and the slurry concentrated under reduced pressure to 800 ml total volume. Toluene (1900 ml) is added while concentrating to maintain 800 ml total volume. Water (1 liter) and heptane (1 liter) are added and the precipitate collected by vacuum filtration, washed with water (750 ml) and heptane (250 ml) and dried in a nitrogen stream to give the title compound (225.7 g, 63.0%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[C:23]1[C:24]2[CH:31]=[CH:30][S:29][C:25]=2[N:26]=[CH:27][N:28]=1>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:23]2[C:24]3[CH:31]=[CH:30][S:29][C:25]=3[N:26]=[CH:27][N:28]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Clc1ncnc2sccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ncnc3sccc23)cc1
Temperature: 130 °C
Reaction time: 30 h
Yield: 51.7 %

Procedure:
After adding 600 mg of 4-nitrophenol, 1.2 g of potassium carbonate and 2 ml of dimethylformamide to 302 mg of the 4-chlorothieno[2,3-d]pyrimidine described in Seans Acad. Sci., Ser, C (1967) 264(2)207, and stirring the mixture for 30 hours at 130° C., the mixture was returned to room temperature, water was added, liquid separation and extraction were performed with an ethyl acetate-tetrahydrofuran mixed solvent, and the solid obtained by concentration to dryness was washed with ether to obtain 250 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]=1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5])[CH3:2].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:28])[CH:34]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:7]=1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccccc1
Reactant: OB(O)c1cccc(Cl)c1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3cccc(Cl)c3)ccc2n1-c1ccccc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-phenylindole-3-carboxylic acid ethyl ester (140 mg, 0.38 mmol, see step (b) Example 3) and 3-chlorophenylboronic acid (119 mg, 0.76 mmol). Yield 53 mg (29%).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[NH:18])=[CH:16][C:10]=3[N:9]=2)=[CH:6][C:5]([S:20](=[O:33])(=[O:32])[NH:21][C:22](=[O:31])[CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[CH:4][C:3]=1[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N+:40]([O-])=O)[CH:35]=1>FC(F)(F)C(O)=O.O=[Pt]=O>[NH2:40][C:36]1[CH:35]=[C:34]([C:3]2[CH:4]=[C:5]([S:20](=[O:33])(=[O:32])[NH:21][C:22](=[O:31])[CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)[CH:6]=[C:7]([C:8]3[NH:12][C:11]4[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[NH:18])=[CH:16][C:10]=4[N:9]=3)[C:2]=2[OH:1])[CH:39]=[CH:38][CH:37]=1
Reactant: N=C(N)c1ccc2[nH]c(-c3cc(S(=O)(=O)NC(=O)CCc4cccnc4)cc(-c4cccc([N+](=O)[O-])c4)c3O)nc2c1
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)c1ccc2[nH]c(-c3cc(S(=O)(=O)NC(=O)CCC4CCCNC4)cc(-c4cccc(N)c4)c3O)nc2c1
Yield: 35.6 %

Procedure:
2-[2-Hydroxy-3′-nitro-5-(3-pyridin-3-yl-propionylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (0.031 g, 0.05 mMol), prepared as in Example 10, was dissolved in trifluoroacetic acid (5 mL) and the solution was subjected to hydrogenation at 50 psi over PtO2 catalyst for 12 hours. The mixture was concentrated in vacuum and product was purified from the residue by reverse phase HPLC (acetonitrile gradient) to give 2-[3′-amino-2-hydroxy-5-(3-piperidin-3-yl-propionylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (0.01 g). MS: found (M+H+) 562.4, (M−H+) 560.6, calc. 561.22.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]2[C:12]3[N:13]([C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=3)[N:14]=[C:15]([CH3:22])[C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(OCC)(=O)C.Cl>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]([C:11]2[C:12]3[N:13]([C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=3)[N:14]=[C:15]([CH3:22])[C:16]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: CCOC(=O)c1c(C)nn2c(CC)ccc2c1-c1ccc(C(=O)O)c(Br)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nn2c(CC)ccc2c1-c1ccc(CO)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 112 %

Procedure:
To a solution of 2-bromo-4-[3-(ethoxycarbonyl)-7-ethyl-2-methylpyrrolo[1,2-b]pyridazin-4-yl]benzoic acid (50.0 mg) in tetrahydrofuran (1 mL) was added a solution of 1 M borane-tetrahydrofuran complex (0.348 mL) in an ice bath. After stirring for 2 hours at room temperature, additional solution of the borane-tetrahydrofuran complex (0.348 mL) was added. The mixture was stirred for 15 hours at room temperature. The mixture was parititioned between ethyl acetate and 1 N hydrochloric acid. The organic layer was washed with water, saturated sodium bicarbonate, and brine, dried over magnesium sulfate, and evaporated to give ethyl 4-[3-bromo-4-(hydroxymethyl)phenyl]-7-ethyl-2-methylpyrrolo[1,2-b]pyridazine-3-carboxylate as an yellow oil (54.2 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[O:12]1[CH:16]=[N:15][N:14]=[C:13]1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(N(CC)CC)C.O=O>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[O:12][CH:16]=[N:15][N:14]=3)=[CH:22][CH:21]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Oc1ccc(-c2nnco2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2ccc(-c3nnco3)cc2)cc1
Yield: 72.1 %

Procedure:
A mixture of 4-methoxybenzeneboronic acid (1.9 g, 12 mmol), 4-(1,3,4)oxadiazol-2-yl-phenol (1.0 g, 6.2 mmol), copper(II)acetate (1.1 g, 6.2 mmol), crushed 4-Angstrom molecular sieves (0.65 g), triethylamine (4.2 mL) and methylene chloride (22.7 mL) was stirred under 1 atm of oxygen gas for 48 hours. The mixture was filtered through a pad of Celite®, concentrated in vacuo and purified by radial chromatography (2:1 hexane-ethyl acetate), affording 1.2 g of 2-[4-(4-Methoxy-phenoxy)-phenyl]-[1,3,4]oxadiazole.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH:19]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:15][CH2:14]3)=[O:12])[O:7][C:6]=2[CH:34]=1.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1>>[C:35]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH:19]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH2:15][CH2:14]3)=[O:12])[O:7][C:6]=2[CH:34]=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1
Reactant: O=C(C1=COc2ccc(O)cc2O1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: O=C(Cl)c1cccnc1
Product: O=C(Oc1ccc2c(c1)OC(C(=O)N1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)=CO2)c1cccnc1
Yield: 78 %

Procedure:
That compound is obtained in a yield of 78% starting from 7-hydroxy-2-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-ylcarbonyl}-1,4-benzodioxin and nicotinoyl chloride by proceeding as for Example 53. ##STR78##
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10]C)=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.C1OCCOCCOCCOCCOCCOC1.[CH3:34][S-:35]>CC(C)=O>[CH3:34][S:35][C:2]1[CH:3]=[C:4]([C:12]([F:15])([F:14])[F:13])[C:5]([C:8]([OH:10])=[O:9])=[CH:6][N:7]=1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Reactant: C[S-]
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CC(C)=O
Product: CSc1cc(C(F)(F)F)c(C(=O)O)cn1

Procedure:
In boiling acetone, 0.70 g (2.9 mol) of methyl 6-chloro-4-trifluoromethylpyridin-3-ylcarboxylate is treated in the presence of a catalytic amount of 18-crown-6 with methanethiolate (0.33 g) until no further conversion can be detected by gas chromatographic analysis. The mixture is then filtered through silica gel and evaporated. This gives 0.73 g of methyl 6-methylthio-4-trifluoromethylpyridin-3-yicarboxylate; 1H NMR (CDCl3, ppm): 8.98, s, 1H; 7.48, S, 1H; 3.94, s, 3H; 2.64, s, 3H. Hydrolysis under the conditions mentioned above gives 6-methylthio-4-trifluoromethylnicotinic acid: 1H NMR (CDCl3, ppm): 9.02, s, 1H; 7.46, s, 1H; 2.64, s, 3H.
Reaction SMILES: Br[C:2]1[C:3]([C:24]#[N:25])=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[N:20][CH:19]=2)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:8]=1.[Br-].[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[CH2:37][Zn+].O1CCCC1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[CH2:37][C:2]1[C:3]([C:24]#[N:25])=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[N:20][CH:19]=2)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:8]=1
Reactant: N#Cc1c(-c2ccnnc2)sc(-c2ncn(C3CCCCO3)n2)c1Br
Reactant: [Zn+]Cc1ccc2ccccc2c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: N#Cc1c(-c2ccnnc2)sc(-c2ncn(C3CCCCO3)n2)c1Cc1ccc2ccccc2c1
Temperature: 70 °C
Yield: 72 %

Procedure:
Bis(tri-t-butylphosphine)palladium(0) (4.92 mg, 0.00963 mmol), 4-bromo-2-pyridazin-4-yl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]thiophene-3-carbonitrile (0.0402 g, 0.0963 mmol), 2-naphthylmethylzinc bromide in tetrahydrofuran (0.50M, 0.578 mL, 0.289 mmol) and tetrahydrofuran (4.0 mL, 49 mmol) were added to a microwave tube. The tube was sealed under a nitrogen atmosphere and heated at 70° C. for 2 h then cooled to rt. The mixture was concentrated in vacuo and the residue was purified by chromatography on a silica gel column eluting with 0-100% EtOAc in hexane to afford a solid product (0.0332 g, yield 72%). LCMS: (AA) ES+, 479. 1H NMR (300 MHz, d4-methanol) δ: 9.63 (s, 1H), 9.28-9.35 (m, 1H), 8.68 (s, 1H), 8.13-8.15 (m, 1H), 7.69-8.00 (m, 4H), 7.37-7.48 (m, 3H), 5.62-5.66 (m, 1H), 3.94-4.08 (m, 1H), 3.69-3.80 (m, 1H), 3.30 (s, 2H), 2.07-2.22 (m, 1H), 1.95-2.07 (m, 2H), 1.61-1.79 (m, 3H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH3:21])[C:16]([O:18]CC)=O)[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:28][C:16](=[O:18])[CH:15]([C:7]2[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([OH:4])[CH:6]=2)[CH3:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)C(C)c1ccc(OC(C)=O)c(OC(C)=O)c1
Reactant: NC1CCCCC1
Product: CC(C(=O)NC1CCCCC1)c1ccc(O)c(O)c1

Procedure:
Ethyl 3,4-diacetoxyphenylpropionate and cyclohexylamine were used to obtain N-Cyclohexyl-3,4-dihydroxyphenylpropionamide by carrying out the same procedures as described in Example 1 as an fatty product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[C:15]([NH:23][NH2:24])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:5]2[N:4]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:23][N:24]=2)[N:3]=1
Reactant: Clc1cc(N2CCCCC2)c(Cl)nn1
Reactant: NNC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Solvent: O
Product: Clc1nn2c(-c3ccccc3)nnc2cc1N1CCCCC1
Yield: 50.9 %

Procedure:
A mixture of 3,6-dichloro-4-(piperidin-1-yl)pyridazine (0.55 g, 2.4 mmol), benzoyl hydrazine (370 mg, 2.7 mmol), triethylamine (375 ml, 2.7 mmol) and p-toluenesulphonic acid monohydrate (510 mg, 2.7 mmol) in xylene (mixture of isomers, 10 ml) was stirred and heated at reflux under nitrogen for 24 hours. Upon cooling the xylene was removed in vacuo and the residue was partitioned between dichloromethane and water. The aqueous was further extracted with dichloromethane (×3). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with 30% ethyl acetate/dichloromethane to afford the undesired regioisomer (less polar) (177 mg, 23%) and the title compound (383 mg, 50%) (more polar). Data for the title compound: 1H NMR (250 MHz, CDCl3) δ 1.62-1.86 (6H, m), 3.09-3.13 (4H, m), 7.42 (1H, s), 7.50-7.60 (3H, m), 8.40-8.44 (2H, m).