Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[C:16]([C:20]4[O:24][C:23]([C:25]5[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=5)=[N:22][N:21]=4)[CH:17]=[CH:18][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:32]([O:37][CH2:38][CH2:39]Br)(=[O:36])[C:33]([CH3:35])=[CH2:34].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:32]([O:37][CH2:38][CH2:39][O:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:23]2[O:24][C:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([N:12]4[C:11]5[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=5[C:5]5[C:13]4=[CH:1][CH:2]=[CH:3][CH:4]=5)[CH:15]=3)=[N:21][N:22]=2)[CH:26]=1)(=[O:36])[C:33]([CH3:35])=[CH2:34]
Reactant: C=C(C)C(=O)OCCBr
Reactant: Oc1cccc(-c2nnc(-c3cccc(-n4c5ccccc5c5ccccc54)c3)o2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCOc1cccc(-c2nnc(-c3cccc(-n4c5ccccc5c5ccccc54)c3)o2)c1
Reaction time: 21 h

Procedure:
To a solution of 3-(5-(3-carbazol-9-ylphenyl)-1,3,4-oxadiazol-2-yl)phenol (0.80 g, 1.98 mmol) and 2-bromoethyl methacrylate (0.40 g, 2.07 mmol) in DMF (15.0 ml) was added K2CO3 (4.0 g, 28.94 mmol) at room temperature under stirring. The reaction was carried out at room temperature for 21 h. Water (100.0 ml) was added. Brown solid product was obtained by filtration. The crude product was purified by silica gel column chromatography using dichloromethane/ethyl acetate (9.5:0.5) as eluent. After removal of solvent, Methanol (120.0 ml) was added into this glass-like solid. After removal of methanol, White solid product was obtained and collected from water by filtration. After vacuum dry, the product as white solid in 038 g (76.4%) was obtained. 1H NMR (400 MHz, CDCl3, δ): 8.34 (m, 1H), 8.26 (m, 111), 8.15 (dd, J1=8.0 Hz, J2=0.8 Hz, 2H), 7.78-7.66 (m, 4H), 7.42 (m, 5H), 7.31 (m, 2H), 7.10 (m, 1H), 6.12 (t, J=1.2 Hz, 1H), 5.56 (m, 1H), 4.51 (m, 2H, OCH2), 4.27 (m, 2H, OCH2), 1.93 (t, 3=1.2 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3, δ): 167.25, 164.71, 163.88, 158.97, 140.61, 138.73, 135.86, 130.86, 130.37, 126.19, 125.85, 125.78, 125.43, 124.80, 123.56, 120.45, 120.37, 119.85, 118.88, 112.42, 109.54, 66.21, 62.84, 18.27. [M]+ calcd for C32H25N3O4, 515.2. found 515.2. Anal. Calcd for C32H25N3O4: C, 74.55; H, 4.89; N, 8.15. Found: C, 74.26; H, 4.83; N, 8.03.
Reaction SMILES: CC([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][CH:19]=[O:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])(C)C.[CH:21]([Mg]Cl)([CH3:23])[CH3:22].Cl.O>O1CCCC1>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([S:16][CH2:17][CH2:18][CH:19]([OH:20])[CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(SCCC=O)cc(C(C)(C)C)c1O
Reactant: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(O)CCSc1ccc(O)c(C(C)(C)C)c1
Temperature: 12.5 °C
Reaction time: 3 h

Procedure:
2.0 g of the aldehyde of Example 4 was dissolved in 20 ml of dry tetrahydrofuran under argon and added to 8.5 ml of 2 M isopropylmagnesium chloride in tetrahydrofuran that had previously been added under argon gas to a flask that had been dried in vacuo overnight. Reaction temperature was maintained at 10-15° C. with an ice bath. When addition was complete, the reaction mixture was allowed warm to room temperature and stirred for 3 hours. 2 N hydrochloric acid (2 ml) was added followed by 50 ml of water and the mixture extracted with ethyl acetate three times. The organic extracts were combined, washed with water twice and dried over sodium sulfate. The solvent was removed in vacuo after filtration and the crude product chromatographed on silica to give the title compound.
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:20](Cl)=[O:21])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>O1CCCC1.C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2([C:20]([NH:5][CH3:3])=[O:21])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)C1(c2ccc(Cl)cc2)CC1
Agent: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methylamine in tetrahydrofuran (THF) (2.0 M, 3.5 mL) was mixed with triethylamine (2.1 mL, 15 mmol). The resulting mixture was added to a solution of 1-(4-chlorophenyl)cyclopropanecarbonyl chloride in methylene chloride (15.0 mL) at 0° C. The resulting mixture was stirred at room temperature (about 25° C.) for 30 min, and was then quenched with saturated sodium bicarbonate (25 mL). The quenched mixture was extracted with ethyl acetate (3×40 mL). The combined ethyl acetate extracts were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to provide the product, 1-(4-chlorophenyl)-N-methylcyclopropanecarboxamide, which was used in next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:11]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:22]([N:7]1[C:6]2[CH:11]=[C:2]([Cl:1])[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]=2[O:10][CH2:9][CH2:8]1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1cc(Cl)cc2c1OCCN2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCOc2c(C(=O)O)cc(Cl)cc21
Yield: 65.2 %

Procedure:
A solution of 10 g of 6-chloro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid and 6.5 ml of triethylamine in 100 ml of chloroform was cooled, and 4.4 g of acetyl chloride was added thereto with stirring. The resulting mixture was stirred at room temperature for 2 hours. To the liquid reaction mixture were added an aqueous solution of sodium hydrogen carbonate and chloroform, and the resulting organic layer was separated, washed with water, and then dried with magnesium sulfate. The solvent was distilled off under reduced pressure, thereby obtaining 7.8 g of 4-acetyl-6-chloro-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid. Melting point: 76°-77° C.
Reaction SMILES: Br[Si](C)(C)C.[P:6]([O:39]CC)([O:36]CC)([O:8][CH2:9][C@@:10]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:14](=[O:15])[N:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=2)[C:12](=[O:28])[N:11]1[CH3:29])=[O:7]>C(Cl)Cl>[P:6]([OH:39])([OH:36])([O:8][CH2:9][C@@:10]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:14](=[O:15])[N:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([C:24]([F:27])([F:25])[F:26])[CH:17]=2)[C:12](=[O:28])[N:11]1[CH3:29])=[O:7]
Reactant: CCOP(=O)(OCC)OC[C@@]1(c2ccccc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)[C@@]1(COP(=O)(O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under argon atmosphere, 2.5 mL of bromotrimethylsilane is added to a solution of 0.80 g of (S)-[1-(4-cyano-3-trifluoromethylphenyl)-2,5-dioxo-3-methyl-4-phenylimidazolidin-4-yl]methyl diethyl phosphate in 25 mL of DCM cooled at 0° C. The reaction is stirred for 1 hour at 0° C. then 18 hours at room temperature. The solvent is evaporated then the residue is dissolved in a mixture of water and methanol. Solvents are evaporated and this process repeated twice. The crude product is purified by chromatography over silica gel while eluting with 90/10/1/1 to 85/15/2/2 dichloromethane/methanol/acetic acid/water mixture to provide the desired compound.
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH2:15]>>[CH3:17][Si:16]([CH2:14][CH2:15][P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=C[Si](C)(C)C
Product: C[Si](C)(C)CCP(c1ccccc1)c1ccccc1

Procedure:
A magnetically stirred mixture of 46.5 g (0.25 mole) diphenyl phosphine and 25 g (0.25 mole) of vinyl trimethyl silane, in a closed cylindrical quartz tube, was irradiated from about 3 cm distance with two 75 Watt Hanau tube immersion lamps, with a wide spectrum of ultraviolet irradiation, in a 15° C. water bath for 26 hours. A proton magnetic resonance spectrum of a sample of the resulting mixture exhibited no significant peaks in the vinyl region indicating a substantially complete addition.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][S:11]([OH:14])(=O)=[O:12])=[N:2]1.C(#[N:17])C.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C>[CH:8]1[CH:7]=[CH:6][C:5]2[O:1][N:2]=[C:3]([CH2:10][S:11]([OH:14])(=[O:12])=[NH:17])[C:4]=2[CH:9]=1
Reactant: CC#N
Reactant: O=S(=O)(O)Cc1noc2ccccc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: N=S(=O)(O)Cc1noc2ccccc12
Temperature: 65 °C

Procedure:
1,2-Benzisoxazole-3-methanesulfonic acid (1) (20.0 g, 93.8 mmol) was mixed with acetonitrile (60 mL) and heated to reflux. The clear solution was cooled to 65° C. and phosphorous oxychloride (5.7 mL; 62.3 mmol) was added. The mixture was heated to reflux for 10 hours and then cooled to room temperature. Ethyl acetate (100 mL) was added and the mixture was filtered through CELITE™, which was subsequently washed with ethyl acetate (40 mL). The filtrate was cooled in an ice bath and ammonia gas was bubbled through the solution for 1 hour. The mixture was concentrated and water (100 mL) was added. The mixture was heated to reflux and cooled. It was concentrated, cooled in an ice-bath and filtered to yield crude zonisamide. Purification was achieved by recrystallization from iso-propanol/water. The yield of purified product was 78.8%.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][CH2:17][CH:18]([CH2:28][CH3:29])[O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)[CH3:15]>>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([O:19][CH:18]([CH2:28][CH3:29])[CH2:17][O:16][CH2:14][CH3:15])=[CH:27][CH:26]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOCC(CC)Oc1ccc(CBr)cc1
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Product: CCOCC(CC)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Yield: 24.8 %

Procedure:
Procedures similar to those in Preparation Example 8 were carried out by using 2.0 g of 2-t-butyl-4-chloro-5-hydroxy-3(2H)-pyridazinone and 3.1 g of 4-(2-ethoxy-1-ethylethoxy)-benzyl bromide to obtain 1.0 g of the aimed compound as an oil.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[C:12](Cl)=[N:13][CH:14]=[C:15]([CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[CH:16]=1>>[N:18]1([CH2:17][C:15]2[CH:16]=[C:11]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:12]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:13][CH:14]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: Clc1ncc(Cn2ccnc2)cc1Br
Reactant: OB(O)c1ccccc1
Product: c1ccc(-c2cc(Cn3ccnc3)cnc2-c2ccccc2)cc1

Procedure:
Synthesized using phenylboronic acid (134 mg, 1.10 mmol) and 6 (150 mg, 0.55 mmol) according to Method C. Yellow solid. Yield: 79 mg, 0.25 mmol, 46%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.27 (s, 2H), 7.00 (brs, 1H), 7.11-7.13 (m, 2H), 7.16 (brs, 1H), 7.21-7.28 (m, 6H), 7.32-7.34 (m, 2H), 7.49 (d, J=2.1 Hz, 1H), 8.60 (d, J=2.1 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.3, 119.2, 127.6, 128.0, 128.1, 128.4, 129.2, 129.4, 129.8, 136.4, 137.1, 137.5, 139.0, 139.3, 147.1, 147.1, 157.6; MS (ESI): m/z=312.10 [M+H]+.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([OH:12])[CH3:11].[OH-].[K+].Cl>O>[CH2:10]([O:12][C:5]1[CH:6]=[CH:7][C:2]([C:1]([OH:9])=[O:8])=[CH:3][CH:4]=1)[C:11]#[C:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=C([O-])c1ccccc1
Reactant: CCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCC#CC#CCOc1ccc(C(=O)O)cc1
Temperature: 40 °C
Reaction time: 24 h
Yield: 89.3 %

Procedure:
In a flask were placed 4.0 g (0.014 mole) of the benzoate derivative obtained and 18 ml of ethanol and while stirring the mixture at room temperature, an aqueous solution composed of 2.0 g (0.36 mole) of potassium hydroxide and 20 ml of water was added to the mixture. After stirring the mixture for 24 hours at 40° C. Twenty (20) ml of water was added to the mixture followed by ice-cooled. When the reaction mixture was acidified with concentrated hydrochloric acid, white crystals formed. The crystals were recovered by filtration, washed with water, and dried. Thus, 3.2 g (yield 89.3%) of the desired product could be obtained. The melting point was 165°-166° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[N:20]1([C:2]2[C:11]3[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=2)[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: c1nc[nH]n1
Reactant: FC(F)(F)c1cc(Cl)c2cccc(C(F)(F)F)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: FC(F)(F)c1cc(-n2cncn2)c2cccc(C(F)(F)F)c2n1
Reaction time: 23 h
Yield: 72.7 %

Procedure:
A mixture of 3.0 g of 4-chloro-2,8-bis-trifluoromethyl-quinoline, 1.38 g of 1,2,4-triazole, 1.38 g of potassium carbonate and 30 ml of acetone is heated to boiling for 23 hours whereupon the reaction mixture is poured into 100 ml of water. The precipitated product is filtered, dissolved in 5 ml of ethanol, whereupon 5 ml of water are added. The precipitated product is filtered. Thus 2.42 g of the desired compound are obtained, yield: 73%, mp.: 106°-107° C.
Reaction SMILES: P(=O)(O)(O)O.C(OC([NH:13][CH:14]1[CH2:17][N:16]([C:18]2[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([CH:23]([CH3:25])[CH3:24])[N:22]=2)[CH2:15]1)=O)(C)(C)C.O.[OH-].[Na+]>ClCCl>[NH2:13][CH:14]1[CH2:17][N:16]([C:18]2[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([CH:23]([CH3:25])[CH3:24])[N:22]=2)[CH2:15]1
Reactant: CCOC(=O)c1sc(N2CC(NC(=O)OC(C)(C)C)C2)nc1C(C)C
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1sc(N2CC(N)C2)nc1C(C)C
Reaction time: 15.5 h
Yield: 75 %

Procedure:
85% phosphoric acid (0.14 mL, 1.18 mmol) was added to a solution of ethyl 2-{3-[(tert-butoxycarbonyl)amino]azetidin-1-yl}-4-isopropyl-1,3-thiazole-5-carboxylate obtained in Example (221a) (175 mg, 0.47 mmol) in dichloromethane (1 mL) at room temperature, followed by stirring for 15.5 hours. Water and a 50% aqueous sodium hydroxide solution were added to the reaction solution, and then the mixture was extracted with a chloroform/methanol mixed solvent. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. Thereafter, the solvent was evaporated under reduced pressure to obtain 95 mg of the title compound as a colorless oily substance (74%).
Reaction SMILES: [C:1]([CH:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[Cl:25])[C:5](OCC)=[O:6])(=O)[CH3:2].[NH2:26][NH:27]C(N)=S.C[O-].[Na+]>CO>[Cl:25][C:18]1[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=1[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:4]1[C:1]([CH3:2])=[N:26][NH:27][C:5]=1[OH:6]
Reactant: CCOC(=O)C(CCCCCCOc1ccc(OC)cc1Cl)C(C)=O
Reactant: NNC(N)=S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(OCCCCCCc2c(C)n[nH]c2O)c(Cl)c1
Yield: 55.2 %

Procedure:
A mixture of 11.1 g (0.03 m) of ethyl 2-acetyl-8-(2-chloro-4-methoxyphenoxy)octanoate, 2.73 g (0.03 m) of thiosemicarbazide and 1.62 g (0.03 m) of sodium methoxide in 15 ml of methanol was heated at reflux for 24 hours. The solid product was collected, washed with 50% aqueous ethanol and recrystallized from ethanol to give 5.6 g of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3-methyl-1H-pyrazol-5-ol, m.p. 145°-146° C.; MIC=6 microg/ml (herpes 2). (During this reaction the thiocarbamyl group (CSNH2) of the thiosemicarbazide was cleaved so that the reaction product is the same as that obtained when unsubstituted hydrazine is used.)
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH2:31]([N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1)[CH:32]([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].O>COCCOC>[CH2:31]([N:35]1[CH:39]=[C:38]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[N:7][C:8]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH2:23][CH2:24][CH2:25][N:26]5[CH2:30][CH2:29][CH2:28][CH2:27]5)(=[O:20])=[O:21])=[CH:15][CH:14]=4)=[N:9]3)=[CH:4][CH:3]=2)[CH:37]=[N:36]1)[CH:32]([CH3:34])[CH3:33]
Reactant: O=S(=O)(NCCCN1CCCC1)c1ccc(Nc2ncc3ccc(Br)cc3n2)cc1
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)Cn1cc(-c2ccc3cnc(Nc4ccc(S(=O)(=O)NCCCN5CCCC5)cc4)nc3c2)cn1

Procedure:
Pd(dppf)2Cl2CH2Cl2 (0.05 eq) was added to a 0.05M mixture of 4-(7-bromoquinazolin-2-ylamino)-N-(3-(pyrrolidin-1-yl)propyl)benzenesulfonamide (eq), 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3 eq), 2.0M potassium carbonate/water (2 eq) in DME. The mixture was microwaved at 120° C. for 10 min
Reaction SMILES: [BrH:1].O[C:3]([CH3:10])([CH2:7][C:8]#[N:9])[CH2:4][C:5]#[N:6].C(=O)([O-])O.[Na+]>>[Br:1][C:5]1[N:6]=[C:8]([NH2:9])[CH:7]=[C:3]([CH3:10])[CH:4]=1
Reactant: Br
Reactant: CC(O)(CC#N)CC#N
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(N)nc(Br)c1

Procedure:
Hydrogen bromide solution (33 wt. % in acetic acid) (17.8 ml, 98.92 mmol) was added dropwise to 3-hydroxy-3-methyl-pentanedinitrile (3.07 g, 24.73 mmol) with stirring. The reaction was stirred overnight at room temperature. Saturated aqueous sodium hydrogencarbonate was added until neutralised. The resulting white precipitate was collected by filtration, washed with water and dried under vacuum to give the desired product. Yield 2.55 g, 55%. LCMS MI: 186.89+188.91, RT: 3.16 min, Method: 2.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]([O-])=[O:20])[S:18][C:11]=12.[Li+]>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:19]([C:17]1[S:18][C:11]2[C:12](=[N:13][CH:14]=[CH:15][C:10]=2[Cl:9])[CH:16]=1)=[O:20]
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: NCc1ccccn1
Agent: [Li+]
Product: O=C(NCc1ccccn1)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 2-aminomethylpyridine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: 304/306 (MH+); HPLC Rf: 4.36 min.; HPLC purity: 97%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:33]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: CC(C)=CCCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Product: CC(C)=CCCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384 substituting 2-(3,4-difluorophenyl)-4-(4-methyl-3-pentenyloxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone. mp 70–73° C. 1H NMR (300 MHz, DMSO-d6) δ 1.5 (d, 6H), 2.27 (m, 2H) 4.43 (t, 2H), 4.5 (m, 1H), 7.5 (m, 2H), 7.6 (m, 1H), 7.8 (m, 2H), 7.92 (d, J=2 H, 2H), 8.2 (s, 1H). MS (DCI/NH3) m/z 462 (M+H)+, 479 (M+NH4)+. Anal. calc. for C22H21F2N3O4S: C, 57.26; H, 4.59; N, 9.11. Found, : C, 56.96; H, 4.70; N, 9.01.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][NH:25][C:26]([O:28][CH3:29])=[O:27])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH3:29][O:28][C:26]([NH:25][CH2:24][CH2:23][O:22][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:10]1)=[O:27]
Reactant: [H][H]
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)NCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Yield: 50.7 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (3 g, 7.04 mmol) in MeOH (60 mL) was added wet Pd(OH)2/C (300 mg). The reaction mixture was stirred under 50 of hydrogen psi at 50° C. for 3 hr. The suspension was filtered and the filtrate was concentrated hydrogen in vacuo. The crude product was purified by preparative HPLC to afford (R)-tert-butyl 3-((R)-(2-(methoxycarbonylamino)ethoxy)(phenyl)methyl)piperidine-1-carboxylate (1.4 g, 51%). 1H NMR (CD3OD) δ 7.40-7.22 (m, 5H), 4.20 (m, 1H), 4.01 (m, 1H), 3.81 (m, 1H), 3.6 (s, 3H), 3.27 (m, 3H), 2.84 (m, 2H), 1.8-1.5 (m, 2H), 1.45 (s, 9H). MS ESI +ve m/z 393 (M+1).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][N:13]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=[N:17][S:16](=[O:27])[N:15]=[C:14]1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=1>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:12][N:13]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=[N:17][S:16](=[O:9])(=[O:27])[N:15]=[C:14]1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccc(OC2=NS(=O)N=C(Oc3cccc(C)c3)N2C)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1cccc(OC2=NS(=O)(=O)N=C(Oc3cccc(C)c3)N2C)c1

Procedure:
A solution of m-chloroperbenzoic acid (4.7 g) in chloroform (30 ml) is added at RT to a stirred solution of 4-methyl-3,5-bis-(3-methylphenoxy)1,2,4,6-thiatriazine-1-oxide (3.1 g) in chloroform (15 ml). The reaction mixture is refluxed for about 5 minutes and the precipitate taken up in methylene chloride, washed with sat'd aq. Na2CO3, brine, dried, filtered and evaporated to a solid. The solid is recrystallized from isopropyl acetate using charcoal, affording the desired product, M.P.=221°-223° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([N:13]2[CH:18]([CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:17][CH2:16][C:15](=[O:25])[CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:37](O)([OH:39])[CH3:38]>C1(C)C=CC=CC=1.ClCCl>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([N:13]2[CH:18]([CH2:19][N:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[CH2:17][CH2:16][C:15]3([O:39][CH2:37][CH2:38][O:25]3)[CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC(O)O
Reactant: O=C1CCC(CN2CCCC2)N(C(=O)Cc2ccc(Cl)c(Cl)c2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CC2(CCC1CN1CCCC1)OCCO2
Yield: 135.3 %

Procedure:
A mixture of the product of Example 25 (0.16 g) p-toluenesulphonic acid (0.14 g) and ethanediol (0.1 g) in dry toluene (10 ml) was heated under Dean and Starke conditions for 2 hours. The cooled reaction mixture was diluted with dichloromethane (50 ml) and the organic solution was washed with aqueous sodium carbonate solution (1M; 2×15 ml). The organic solution was dried and evaporated in vacuo. The residue was purified by flash chromatography eluting with dichloromethane/methanol/ammonia (200:8:1) to give the free base of the title compound as a gum (0.12 g). A solution of the free base in dry diethyl ether (10 ml) was treated with ethereal hydrogen chloride. The resulting precipitate was washed with diethyl ether (10 ml) to give the title compound as a solid (0.10 g) m.p. 255° dec. T.l.c. SiO2 (dichloromethane/methanol/ammonia 150:8:1) Rf 0.3.