Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[N:21][C:20]([N:23]4[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[N:24]4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH2:30](I)[CH3:31].C1COCC1.[H-].[Na+]>CCOCC.O.CN(C=O)C>[CH2:30]([O:29][CH2:28][C:26]1[CH:25]=[N:24][N:23]([C:20]2[N:21]=[N:22][C:17]([N:14]3[CH2:15][CH2:16][CH:11]([N:8]4[C:9]5[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=5)[CH2:6][CH2:7]4)[CH2:12][CH2:13]3)=[CH:18][CH:19]=2)[CH:27]=1)[CH3:31]
Reactant: OCc1cnn(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOCc1cnn(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of (1-(6-(4-(6-fluoroindolin-1-yl)piperidin-1-yl)pyridazin-3-yl)-1H-pyrazol-4-yl)methanol (59 mg, 0.15 mmol, 1 equiv) and ethyl iodide (93 mg, 0.6 mmol, 4 equiv) was added solvent THF (5 mL) and DMF (1 mL). NaH (36 mg, 60% in mineral oil, 0.9 mmol, 6 equiv) was then added. The resulting mixture was stirred at room temperature for 1.5 h and then poured into Et2O/H2O (20 mL/20 mL). The organic layer was washed with brine (20 mL), dried (Na2SO4), and filtered. The solvent was removed and the resulting residue was purified by column using 40-60% EtOAc/hexane as the eluent to yield 1-(1-(6-(4-(ethoxymethyl)-1H-pyrazol-1-yl)pyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline, which was then re-crystallized from CH2Cl2/hexane upon slow evaporation.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Br:15][C:16]1[S:20][C:19]([C:21](O)=[O:22])=[CH:18][CH:17]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:21]([C:19]2[S:20][C:16]([Br:15])=[CH:17][CH:18]=2)=[O:22])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1ccc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2ccc(Br)s2)C1

Procedure:
56.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 5-bromothiophene-2-carboxylic acid to give (R)-3-{[(5-bromo-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. Yellow oil. MS 389.0 ([M+H]+)
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8](Br)[C:9]=1[CH:10]=[N:11][NH:12][CH3:13]>O1CCCC1>[Br:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=12
Reactant: CNN=Cc1c(Br)cncc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc2c(Br)cncc21
Temperature: 25 °C
Reaction time: 90 h

Procedure:
Sodium hydride (60% in mineral oil, 0.524 g, 13.1 mmol) was added to a solution of C7 (3.20 g, 10.9 mmol) in tetrahydrofuran (20 mL), and the reaction mixture was heated at reflux for 1.5 hours, then allowed to sit at room temperature for 90 hours. Additional sodium hydride (1 equivalent) was added, and the reaction mixture was heated at reflux for 3 hours. After cooling to room temperature, the mixture was quenched with water, diluted with saturated aqueous sodium chloride solution, and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded the product as a solid. Yield: 1.51 g, 7.12 mmol, 65%. 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.38 (s, 1H), 8.03 (s, 1H), 4.19 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([NH2:9])=[O:8])=[CH:5][NH:4][N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CC(O)C>[C:19]1([NH:1][C:2]2[C:6]([C:7]([NH2:9])=[O:8])=[CH:5][NH:4][N:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Brc1ccccc1
Reactant: NC(=O)c1c[nH]nc1N
Agent: [Pd]
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: O
Solvent: CC(C)O
Product: NC(=O)c1c[nH]nc1Nc1ccccc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
3-Amino-1H-pyrazole-4-carboxamide (19.8 g, 157 mmol), K3PO4 (66.7 g, 314 mmol), bromobenzene (23.2 mL, 220 mmol) and 2-propanol (785 mL) were combined in a round bottom flask and purged with a stream of N2 gas for 40 minutes. Pd2(dba)3 (1.80 g, 1.96 mmol) and 2-di-t-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-i-propylbiphenyl (3.77 g, 7.85 mmol) were added and the reaction was purged for an additional 5 minutes. The reaction mixture was then heated to 80° C. and allowed to stir under a N2 atmosphere for 12 hours. The mixture was then allowed to cool to ambient temperature for an additional 16 hours. The reaction mixture was diluted with EtOAc (300 mL) and filtered through celite (slowly). The celite was washed with EtOAc (300 mL) and the combined filtrates were concentrated in vacuo to afford an oil which was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM). The major, low rf product, was isolated to afford a reddish-brown oily solid. The brown solid was suspended in 40 mL of warm MeOH, cooled to ambient temperature, and water (40 mL) was added. The mixture was stirred for 30 minutes and filtered. The solid was suction dried for 16 hours to afford the title compound as a peach-colored solid.
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:13])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>>[Cl:20][CH2:21][CH2:22][CH2:23][N:8]1[C:7]2[C:2]([F:1])=[CH:3][C:4]([F:13])=[CH:5][C:6]=2[O:11][CH2:10][C:9]1=[O:12]
Reactant: ClCCCI
Reactant: O=C1COc2cc(F)cc(F)c2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1COc2cc(F)cc(F)c2N1CCCCl
Yield: 50 %

Procedure:
5,7-Difluoro-4H-benzo[1,4]oxazin-3-one (0.24 g, 1.3 mmol), Cs2CO3 (1.08 g, 3.3 mmol), and 1-chloro-3-iodopropane (0.296 g, 1.45 mmol) were mixed according to GP2. Purified by column chromatography (SiO2; heptanes/EtOAc, gradient 0 to 30% EtOAc) to give the title compound (0.17 g, 49%). Rf=0.66 (heptanes/EtOAc 1:1); 1H NMR (CDCl3) δ 6.67-6.58 (m, 2H), 4.55 (s, 2H), 4.16-4.10 (m, 2H), 3.59-3.52 (m, 2H), 2.21-2.10 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][N:37]([CH2:39][C:40]1[O:44][C:43]([C:45]2[CH:51]=[CH:50][C:48]([NH2:49])=[C:47]([O:52][CH3:53])[CH:46]=2)=[N:42][N:41]=1)[CH3:38].Cl>C(O)C(F)(F)F>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:49][C:48]3[CH:50]=[CH:51][C:45]([C:43]4[O:44][C:40]([CH2:39][N:37]([CH3:36])[CH3:38])=[N:41][N:42]=4)=[CH:46][C:47]=3[O:52][CH3:53])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(-c2nnc(CN(C)C)o2)ccc1N
Agent: Cl
Solvent: OCC(F)(F)F
Product: COc1cc(-c2nnc(CN(C)C)o2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 85 °C
Yield: 48 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (0.12 g, 0.25 mmol) and 4-{5-[(dimethylamino)methyl]-1,3,4-oxadiazol-2-yl}-2-(methyloxy)aniline (0.069 g, 0.28 mmol) in trifluoroethanol (5 mL) was added HCl (0.050 mL, 4 M in dioxane, 0.20 mmol). The reaction was heated at 85° C. for 48 hours. Purification by flash chromatography followed by trituration with diethyl ether provided the title compound (0.089 g, 0.12 mmol, 51%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 6H), 3.76 (s, 2H), 3.96 (d, J=4.6 Hz, 6H), 6.76 (d, J=4.9 Hz, 1H), 7.03 (t, J=6.9 Hz, 1H), 7.15 (t, J=8.1 Hz, 2H), 7.26 (d, J=8.2 Hz, 1H), 7.30-7.40 (m, 1H), 7.42-7.50 (m, 1H), 7.51-7.59 (m, 2H), 7.71 (d, J=9.2 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 8.10 (br. s., 1H), 8.35 (d, J=8.6 Hz, 1H), 8.39 (d, J=5.5 Hz, 1H), 8.69 (br. s., 1H), 9.44 (d, J=6.8 Hz, 1H), 9.74 (s, 1H). MS (M+H, ES+) 704.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>>[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:26])([F:25])[F:27])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: Cn1ccnc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Product: Cn1ccnc1C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12f and 1-methylimidazole
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:16]3=[CH:25][C:26]([CH2:28][N:29]([CH3:31])[CH3:30])=[CH:27][N:15]3[N:14]=2)[CH:8]=1)(=O)=O.[CH3:32][S:33]([O-:35])=[O:34].[Na+].O>CN1CCCC1=O>[CH3:31][N:29]([CH3:30])[CH2:28][C:26]1[CH:25]=[C:16]2[N:15]([CH:27]=1)[N:14]=[C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][S:33]([CH3:32])(=[O:35])=[O:34])[CH:8]=1)[N:18]=[C:17]2[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3cccc(COS(C)(=O)=O)c3)nn2c1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN(C)Cc1cc2c(N3CCOCC3)nc(-c3cccc(CS(C)(=O)=O)c3)nn2c1
Yield: 27.9 %

Procedure:
Compound 19 (45 mg, 0.1 mmol) and sodium methylsulfinate (41 mg, 0.4 mmol) were dissolved in 2 mL N-methylpyrrolidone. The mixture was under microwave irradiation for 30 minutes at 120° C. with the power of 100 watts. After completion of the reaction, the reaction mixture was poured into water, extracted for three times with ethyl acetate, and extracted for three times with dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to a small volume. The crude product was purified by a preparative plate (dichloromethane:methanol=6:1) to obtain 12 mg of white solid (28.0%). m.p. 143-144° C. 1H NMR (300 MHz, CDCl3): δ 8.32 (d, J=5.2 Hz, 1H), 8.29 (s, 1H), 7.63 (d, J=1.2 Hz, 1H), 7.50 (d, J=5.2 Hz, 2H), 6.78 (d, J=1.2 Hz, 1H), 4.34 (s, 2H), 4.11 (t, J=4.4 Hz, 4H), 3.88 (t, J=4.4 Hz, 4H), 3.66 (s, 2H), 2.78 (s, 3H), 2.36 (s, 6H). MS (EI) m/e (%): 429 (M+, 12).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](N(CC)CC)[CH3:25]>CO>[C:24]([C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)#[CH:25]
Reactant: Nc1nc2ccnc(-c3cccc(Br)c3)n2n1
Reactant: CCN(CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cccc(-c2nccc3nc(N)nn23)c1
Reaction time: 0.25 h

Procedure:
A suspension of 2.0 g of 5-(3-bromophenyl) [1,2,4]triazolo[1,5-c]pyrimidin-2-amine in 45 ml of triethylamine was flushed with argon and stirred 15 minutes. A 17 mg portion of palladium II acetate and 34 mg of triphenyl phosphine were added followed by 1.06 g of ethynyl trimethylsilane. The mixture was heated to reflux, then allowed to stand overnight under argon, then again heated at reflux for 5 hours and then cooled. A 34 mg portion of palladium II acetate, 68 mg of triphenyl phosphine and 2.12 g of ethynyl trimethylsilane were added and this mixture was refluxed 15 hours. The mixture was cooled, evaporated, taken up in 200 ml of chloroform, washed with 100 ml of saturated aqueous potassium bicarbonate, dried, filtered and evaporated giving a brown glass. This glass was taken up in 50 ml of methanol and 200 mg. of anhydrous potassium carbonate were added. This mixture was sealed, stirred overnignt and then evaporated. The residue was taken up in 100 ml of chloroform, washed with 50 ml of dilute aqueous potassium bicarbonate, dried, filtered through hydrous magnesium silicate and evaporated. This solid was crystallized from chloroform-cyclohexane, giving 300 mg of the desired product, mp 170°-172° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([O:13]C)=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.N1C=CC=CC=1.Cl[CH2:22][CH2:23][CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27].CCN(CC)CC.[OH-].[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[O:27]=[S:26]1(=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][N:1]1[C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: COC(=O)c1cc(N)c2cc[nH]c2c1
Reactant: O=S(=O)(Cl)CCCCCl
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(O)c1cc(N2CCCCS2(=O)=O)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.5 %

Procedure:
To a solution of methyl 4-amino-1H-indole-6-carboxylate (D201) (1.0 g, 5.3 mmol, 1 equiv) in CH2Cl2 (50 ml) were added pyridine (0.55 g, 6.5 mmol, 1.2 equiv), 4-chloro-1-butanesulfonyl chloride (1.14 g, 6 mmol, 1.1 equiv) and DMAP (300 mg, 2.45 mmol, 0.5 equiv) and the resulting mixture was stirred at room temperature for 5 h. NEt3 (1 ml, 7.2 mmol, 1.3 equiv) was added and the resulting solution stirred for 2 h then diluted with AcOEt, washed with a 2N aqueous solution, a saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in MeOH (20 ml) and treated with a 2N aqueous NaOH solution (10 ml, 20 mmol, excess). The resulting solution was stirred at room temperature for 15 h then most of the MeOH was removed in vacuo. The residue was partitioned between AcOEt and a 2N aqueous HCl solution. The two layers were separated and the organic phase was dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (CH2Cl2/MeOH: 9/1) gave 4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-1H-indole-6-carboxylic acid (A155) (320 mg, 20%) as a pale pink solid. [M+H]=295.0, RT=1.90 min.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([O:8][C:9]1[CH:24]=[C:23]2[C:12]([CH2:13][C:14]3[CH:18]=[N:17][N:16]([CH2:19][C@H:20](O)[CH3:21])[C:15]=32)=[CH:11][CH:10]=1)[CH3:7].C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:32]([C@@H:20]([CH3:21])[CH2:19][N:16]1[C:15]2=[CH:23][C:24]3[C:13]([CH2:12][CH:11]=[CH:10][C:9]=3[O:8][CH2:6][CH3:7])=[C:14]2[CH:18]=[N:17]1)=[N+:33]=[N-:34]
Reactant: CCOc1ccc2c(c1)-c1c(cnn1C[C@@H](C)O)C2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC1=C2C=c3c(cnn3C[C@H](C)N=[N+]=[N-])=C2CC=C1
Yield: 98.5 %

Procedure:
0.29 ml (3.79 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 0.49 g (1.9 mmol) of (R)-1-(7-ethoxy-1,4-dihydro-indeno[1,2-c]pyrazol-1-yl)-propan-2-ol and 1.06 ml (7.6 mmol) of triethylamine in 30 ml of dichloromethane and the mixture was stirred at this temperature for a further 50 minutes. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 50 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 50 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellowish solid obtained was dissolved in 25 ml of anhydrous dimethylformamide, treated with 0.25 g (3.8 mmol) of sodium azide and the reaction mixture was heated to 70° while stirring for 22 hours. After cooling, the solution was poured into 70 ml of semi-saturated sodium chloride solution and extracted twice with 70 mi of diethyl ether each time. The combined organic phases were washed once with 50 ml of water and once with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate). 0.53 g (99%) of (S)-1-(2-azido-propyl)-7-ethoxy-1,4-dihydro-indeno[2,1-c]pyrazole was obtained as a light yellow solid.
Reaction SMILES: S(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]1[C:25]2[C:20](=[CH:21][C:22]([O:26]C)=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH:17]1[C:28]1[CH:38]=[CH:37][C:31]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])=[CH:30][CH:29]=1)(C)(=O)=O.Br.[CH2:40]([S:46]C(=N)N)[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].B(Br)(Br)Br>CN(C)C=O>[CH2:40]([S:46][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]1[C:25]2[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH:17]1[C:28]1[CH:29]=[CH:30][C:31]([C:32]([N:34]([CH3:35])[CH3:36])=[O:33])=[CH:37][CH:38]=1)[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCSC(=N)N
Reactant: COc1ccc2c(c1)CCC(c1ccc(C(=O)N(C)C)cc1)C2CCCCCCCCCCOS(C)(=O)=O
Agent: Br
Agent: BrB(Br)Br
Solvent: CN(C)C=O
Product: CCCCCCSCCCCCCCCCCC1c2ccc(O)cc2CCC1c1ccc(C(=O)N(C)C)cc1
Reaction time: 2 h

Procedure:
Aqueous 1ON-sodium hydroxide solution (0.08 ml.) was added to a solution of p-[(1RS,2RS)-1-(10- mesyloxydecyl)-6-methoxy-1,2,3,4-tetrahydronaphth-2-yl]-N,N-dimethylbenzamide (0.107 g.) and S-n-hexylisothiourea hydrobromide (0.097 g.) in dimethylformamide (5 ml.) and the mixture was stirred at laboratory temperature for 2 hours and then evaporated to dryness. Water (5 ml.) was added to the residue and the mixture was extracted three times with diethyl ether (10 ml. each time). The combined extracts were dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column using initially cyclohexane and then toluene as eluent. The product thus obtained was demethylated with boron tribromide by a similar process to that described in the second paragraph of Example 1, and the product was purified by chromatography on a silica gel column using a 4:4 v/v mixture of toluene and ethyl acetate as eluent. There was thus obtained as an oil p-[(1RS,2RS)-1-(10-hexylthiodecyl)-6-hydroxy-1,2,3,4-tetrahydronaphth-2-yl]-N,N-dimethylbenzamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [Al].[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH2:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22]>>[CH2:12]([C:7]1[CH:6]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:10]=[CH:9][C:8]=1[OH:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23]
Reactant: C=CCCCCCCCC(C)C
Reactant: CC(C)c1ccc(O)cc1
Agent: [Al]
Product: CC(C)CCCCCCCCCc1cc(C(C)C)ccc1O
Yield: 75.4 %

Procedure:
15 g of aluminium is dissolved in 2,720 g (20 moles) of para-isopropylphenol in a five-necked flask having an inner capacity of 5,000 ml, followed by reaction with 1,176 g (7 moles) of isododecene (propylene tetramer) in the same manner as in Example 2 to obtain 1,608 g of 2-isododecyl-4-isopropylphenol. This product has a hydroxyl value of 184.0 (the theoretical: 184.3) and a boiling point of 152° C. to 160° C. under a vacuum of 1.2 Torr.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][C:29]=2[CH3:38])O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C([O-])(O)=O.[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CCO>[F:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:35])=[O:36])=[CH:30][C:29]=2[CH3:38])=[N:3][N:4]=[CH:5]3)=[CH:14][CH:15]=1
Reactant: Cc1cc(S(C)(=O)=O)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: Fc1ccc(Nc2ccc3c(Cl)nncc3c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: Cc1cc(S(C)(=O)=O)ccc1-c1nncc2cc(Nc3ccc(F)cc3)ccc12
Temperature: 140 °C

Procedure:
A mixture of 1-chloro-N-(4-fluorophenyl)phthalazin-6-amine (200 mg, 0.73 mmol), 4,4,5,5-tetramethyl-2-(2-methyl-4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane (260 mg, 0.88 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (26 mg, 0.037 mmol), and sodium carbonate (232 mg, 2.19 mmol) in a 7:2:3 mixture of DME, EtOH and water (3 mL) was heated at 140° C. for 10 min in the Emrys Optimizer® microwave. After cooling to RT, the mixture was diluted with saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (3×). The combined organics were dried over Na2SO4, filtered and concentrated. The residue was purified using column chromatography (0-75% acetone in hexanes) to yield the title compound as a tan crystalline solid. MS (ESI, pos. ion) m/z: 408.1 (M+1).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12]([C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=2)=[C:16]([O:29][CH2:30][CH3:31])[CH:15]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.C(OCC)(=O)C>[CH2:30]([O:29][C:16]1[CH:15]=[C:14]([CH2:12][N:9]2[CH2:10][CH2:11][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8]2)[CH:28]=[CH:27][C:17]=1[O:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][N:20]=1)[CH3:31]
Reactant: CCOc1cc(C=O)ccc1Oc1ccc(C#N)cn1
Reactant: c1ccc(C2CCNC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOc1cc(CN2CCC(c3ccccc3)C2)ccc1Oc1ccc(C#N)cn1
Yield: 60.8 %

Procedure:
Using a method similar to Example 365 step 2, and using 3-phenyl-pyrollidine (0.150 g, 1.02 mmol), 6-(4-formyl-2-ethoxy-phenoxy)-nicotinonitrile (0.201 g, 0.749 mmol), sodium triacetoxyborohydride (0.237 g, 1.12 mmol), and acetic acid (0.064 mL, 1.12 mmol) in 1,2-dichloroethane (7.5 mL), after silica gel chromatography (1:1 hexanes:ethyl acetate), provides 0.182 g (61%) of the title compound as a clear syrup: mass spectrum (electrospray): m/z=400.2 (M+1); 1H NMR (CDCl3): 8.41 (d, 1H, J=2.0 Hz), 7.86 (dd, 1H, J=2.4, 9.3 Hz), 7.29-7.26 (m, 4H), 7.20-7.14 (m, 1H), 7.07-7.03 (m, 2H), 6.99 (d, 1H, J=7.8 Hz), 6.94 (dd, 1H, J=2.0, 7.8 Hz), 4.01-3.92 (m, 2H), 3.69 (d, 1H, J=13.2 Hz), 3.62 (d, 1H, J=13.2 Hz), 3.41-3.31 (m, 1H), 3.99 (dd, 1H, J=7.8, 8.8 Hz), 2.86-2.78 (m, 1H), 2.77-2.70 (m, 1H), 2.54 (dd, 1H, J=7.3, 9.3 Hz), 2.40-2.29 (m, 1H), 1.96-1.85 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:28])=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][C:20](O)=[O:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:29][NH2:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:28])=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][C:20]([NH:30][CH3:29])=[O:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)O)c1=O
Reactant: CN
Product: CNC(=O)Cn1c(=O)c(C(=O)NC)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from [7-[(4-fluorophenyl)methyl]-4-hydroxy-3-[(methylamino)carbonyl]-2-oxo-1,5-naphthyridine-1 (2H)-yl]acetic acid and methylamine employing methods similar to those described in example 558. The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.00 (1H, br s), 8.53 (1H, s), 8.03 (1H, br s), 7.79 (1H, s), 7.33-7.30 (2H, m), 7.15-7.05 (2H, m), 4.83 (2H, s), 4.11 (2H, s), 2.88 (3H, d, J=3.8 Hz), 2.52 (3H, d, J=4.4 Hz); HRMS calcd for C20H19FN4O4+H+: 399.1463. Found 399.1465.