Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:12][N:11]([CH:10]=[N:9][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])[N:4]=1)[CH3:13]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN(C)C=Nc1nc(O)ncc1F
Solvent: c1ccncc1
Product: CN(C)C=Nc1nc(OS(=O)(=O)c2ccccc2)ncc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.8 %

Procedure:
To a suspension of N′-(5-fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformamidine (0.10 g, 0.54 mmol) in pyridine (2 mL) was added benzene sulfonyl chloride (0.106 g, 0.60 mmol) and the mixture was agitated on an orbital shaker for 16 h at room temperature. The reaction mixture was partitioned between EtOAc and saturated aq NaHCO3, and the organic phase was dried over solid MgSO4, filtered, and concentrated under reduced pressure. Purification by reverse phase chromatography (H2O/MeCN gradient) afforded the title compound (0.089 g, 46% yield) as a white solid: mp 124-125° C.; 1H NMR (300 MHz, CDCl3) δ 8.54 (s, 1H), 8.12-8.07 (m, 3H), 7.73-7.66 (m, 1H), 7.62-7.56 (m, 2H), 3.21 (s, 6H); HPLC-MS (ESI) m/z 325 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:14]I>CN(C=O)C>[CH3:14][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([S:2][CH3:1])[CH:11]=2)[CH:7]=[CH:8]1
Reactant: CSc1ccc2cc[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc2ccn(C)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of 6-methylsulfanyl-1H-indole (6.8 g, 42 mmol) in DMF (50 mL) was added to a slurry of NaH (55 mmol) in DMF(10 mL) at 0° C. over a period of 10 minutes. After stirring for 1 hour at 0° C., CH3I (4.0 ml,64 mmol) was added and the mixture stirred for 30 minutes at 0° C., then at room temperature for 1 hour, then poured into ice/H2O and extracted with EtOAc. The organic phase was washed with saturated NaCl solution, dried over MgSO4, filtered and evaporated to give 6.7 g (91.0%) of 1-methyl-6-methylsulfanyl-1H-indole as a yellow oil after flash column chromatography.
Reaction SMILES: [CH2:1]([O:6][C:7]1[C:8]([C:13]2(O)[CH:18]3[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]3)[CH2:14]2)=[N:9][CH:10]=[CH:11][N:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][C:13]1([C:8]2[C:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[N:12][CH:11]=[CH:10][N:9]=2)[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14]1
Reactant: O=S(Cl)Cl
Reactant: CCCCCOc1nccnc1C1(O)CN2CCC1CC2
Solvent: ClCCl
Product: CCCCCOc1nccnc1C1(Cl)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 30 ml of pentanol that had reacted with 0.5 g of Na (0.022 mol) was added 1.7 g of (7) (0.0071 mol). The reaction was heated to 70° C. for 2 h, the reaction cooled to ambient temperature, and 30 ml of 1 N HCl was added. The excess pentanol was azeotroped off with water and the residue made basic with 5 N NaOH. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts washed with brine, dried, and the solvent evaporated. The residue was purified by radial chromatography eluting with 5% ethanol-0.5% N and then with 10% ethanol-1% NH4OH-CHCl3 to give 1.68 g of 3-(3-pentyloxypyrazinyl)-1-azabicyclo[2.2.2]octan-3-ol. NMR ppm (CDCl3) 0.97 (3H, t), 1.2 (1H, m), 1.45 (6H, m), 1.87 (2H, m), 2.3 (1H, m), 2.4 (1H, t), 2.8 (1H, m), 2.93 (3H, m), 3.1 (1H, m), 3.98 (1H, s), 4.28 (1H, d), 4.42 (2H, m), 8.01 (1H, d), 8.11 (1H, d). A solution of 1.48 g of this alcohol (0.0051 mol) in 50 ml of CH2Cl2 was cooled to 0° C. as 1.1 ml of thionyl chloride in 5 ml of CH2Cl2 was added dropwise. The cooling was removed, the reaction stirred 1.5 h and then heated to reflux for 45 min. After cooling to ambient temperature, ice-water was added to the reaction and the reaction made basic with saturated aqueous K2CO3. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts washed with brine, and the solvent evaporated. The residue was purified by radial chromatography eluting with 5% ethanol- 0.5% N4OH-CHCl3 to give 1.27 g of 3-chloro-3-(3-pentyloxypyrazinyl)-1-azabicyclo[2.2.2]octane. NMR ppm (CDCl3) 0.99 (3H, t), 1.35-1.8 (7H, m), 1.9 (2H, m) 2.37 (1H, m), 2.6-2.82 (2H, m), 3.0 (1H, t), 3.15 (2H, m), 3.6-4.1 (2H, m), 4.42 (2H, t), 8.06 (2H, m). A mixture of 1.05 g of this chloride (0.0034 mol) and 0.4 g of 10% Pd on carbon in 50 ml of ethanol was hydrogenated 1 h at 60 psi of H2. The catalyst was filtered off, 25 ml of isopropanolic HCl was added, and the solvent was evaporated. The residue was recrystallized from ethyl acetate to give 0.28 g of (25), mp 166°-167° C. NMR ppm (CDCl3) 0.95 (3H, t), 1.41 (4H, m), 1.57-1.9 (5H, m), 2.13 (2H, m), 2.45 (1H, m), 3.12 (1H, m), 3.3-4.46 (3H, m), 3.55 (1H, m), 3.7 (1H, m), 4.3 (1H, q), 4.37 (2H, t), 8.03 (1H, d), 8.1 (1H, d). Anal. C16H25N3O-HCl requires C: 61.62; H: 8.40; N: 13.47%. Found C: 61.39; H: 8.07; N: 13.48%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:11][CH2:10][N:9]([C:12](=O)[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH2:8][CH2:7][C:6]=2[N:21]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH2:8][CH2:7][C:6]=2[N:21]=1
Reactant: Nc1cnc2c(n1)CCN(C(=O)c1ccc(Cl)cc1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cnc2c(n1)CCN(Cc1ccc(Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.7 gm (12.2 mmols) of 2-amino-7-(4-chloro-benzoyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]-azepine were dissolved in 50 ml of absolute tetrahydrofuran, and the solution was added dropwise to a suspension of 2.8 gm (73.3 mmols) of lithium aluminum hydride in tetrahydrofuran. The mixture was stirred for 3 hours at room temperature, and then the excess lithium aluminum hydride was decomposed with 2 N sodium hydroxide and the precipitated aluminate was filtered off. The filtrate was concentrated by evaporation and chromatographed on silicagel with ethyl acetate/methanol (5:1) as the mobile phase. Thereafter, the product was dissolved in absolute ether, and the solution was evaporated until crystallization commenced.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=O)=[CH:3][CH:2]=1.Cl>>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:5][CH:6]=1
Reactant: CCN(CC)C(=O)CCCc1ccc(-c2ccccc2)cc1
Agent: Cl
Product: CCN(CC)CCCCc1ccc(-c2ccccc2)cc1
Yield: 63.8 %

Procedure:
4-(4-biphenylyl)-N,N-diethyl-butylamine was prepared by the procedure of Example IV except that 4-(4-biphenylyl)-N,N-diethyl-butyramide (b.p. 181.3° C. -- 10.05 mm) is also convertible to a non-toxic acid addition salt by reaction with a suitable acid such as hydrochloric acid. A yield of 63.8% was obtained having an m.p. of 133.4° C.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1>O.[OH-].[Na+]>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)=[O:2])=[CH:10][CH:9]=1
Reactant: O=C(O)Cc1ccc(Sc2ccc(Cl)cc2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccc(S(=O)c2ccc(Cl)cc2)cc1
Reaction time: 8 h

Procedure:
To a solution of 4.49 g of sodium metaperiodate in 80 ml of water is added a solution of 5.57 g of [p-(p-chlorophenylthio)phenyl]acetic acid in 75 ml of 1.75% NaOH. A white solid precipitates immediately. After stirring overnight the mixture is filtered and the filtrate is acidified with concentrated HCl to give a white solid. This product, which contains some starting material, is reworked, as above, to yield the pure product. Recrystallization from chloroform-hexane affords white crystals, mp 139°-141° C and 144°-148.5° C.
Reaction SMILES: [Br-].[N:2]1([CH2:7][CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C([Li])CCC.[Br:33][C:34]1[C:39]2[O:40][CH2:41][C:42]3[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=3[C:44](=O)[C:38]=2[CH:37]=[CH:36][CH:35]=1>CCCCCC.O1CCCC1>[Br:33][C:34]1[C:39]2[O:40][CH2:41][C:42]3[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=3/[C:44](=[CH:8]/[CH2:7][N:2]3[CH2:3][CH2:4][CH2:5][CH2:6]3)/[C:38]=2[CH:37]=[CH:36][CH:35]=1
Reactant: O=C1c2ccccc2COc2c(Br)cccc21
Reactant: c1ccc([P+](CCN2CCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Brc1cccc2c1OCc1ccccc1/C2=C/CN1CCCC1

Procedure:
Anhydrous 2-(N-pyrrolidinyl)ethyltriphenylphosphonium bromide (20 g, 45 mmole), 45 mmole of n-butyl lithium in hexane (1.6 M), and 4-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one (10 g, 35 mmole) were reacted in 550 mL dry tetrahydrofuran by the procedure in Example 1, Step a. This offered a (Z)/(E) (60:40) isomeric product as a light brown oil. pmr (DMSO-d6)δ: 7.28-7.56 (m, 5H, aromatic H); 7.15-7.26 (2 dd, 1H, H1); 6.88 (t, H3 of 60% Z); 6.84 (t, H3 of 40% E); 6.16 (t, CH= of 40% E): 5.86 (t, CH= of 60% Z); 5.30 (br s, 2H, ArCH2O); 2.28-2.54 (m, 6H, N(CH2)3); 1.66 (m, 4H, 2CH2).
Reaction SMILES: [C:1]1(=[O:5])[CH2:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][Si](C)(C)C)=[CH2:14])=[CH:9][CH:8]=1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH2:14][C:1]2([OH:5])[CH2:4][CH2:3][CH2:2]2)=[CH:9][CH:8]=1
Reactant: C=C(O[Si](C)(C)C)c1ccc(F)cc1
Reactant: O=C1CCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(CC1(O)CCC1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
Under nitrogen, 11.0 g (100 mmol) of titanium(IV) chloride in 140 mL of methylene chloride at 0° C. was slowly treated with a solution of 8.2 mL (110 mmol) of cyclobutanone in 30 mL of methylene chloride prior to the dropwise addition of a solution of 21.1 g (100 mmol) of 1-fluoro-4-[1[(trimethylsilyl)oxy]ethenyl]benzene (obtained from Step 2 ) in 15 mL of methylene chloride. The reaction was stirred for 15 minutes and then poured into 200 mL of ice/water; the phases were separated. The aqueous phase was extracted twice with 30 mL of methylene chloride and combined with the original methylene chloride phase. The combined extracts were washed 3 times with 120 mL of saturated sodium carbonate/water (1:1) and once with brine, dried (MgSO4), and concentrated in vacuo to give 20.4 g (98%) of crude 1-(4-fluorophenyl)-2-(1-hydroxycyclobutan-1-yl) ethan-1-one as an oil: NMR (CDCl3) δ1.53-1.70 (m, 1H), 1.80-1.94 (m, 1H), 1.99-2.10 (m, 2H), 2.17-2.31 (m, 2H), 3.31 (s, 2H), 7.10-7.19 (m, 2H), 7.95-8.03 (m, 2H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][N:12]([CH3:33])[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[N:19][C:20]([C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=2)[C:26](OC)=[O:27])=[N:21][CH:22]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:33][N:12]([CH3:11])[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[N:21][C:20]([C:23]2[CH:24]=[C:25]([CH2:26][OH:27])[CH:30]=[CH:31][CH:32]=2)=[N:19][CH:18]=1
Reactant: COC(=O)c1cccc(-c2ncc(OCCCN(C)C)cn2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Product: CN(C)CCCOc1cnc(-c2cccc(CO)c2)nc1

Procedure:
200 ml of a 1 M solution of diisobutylaluminium hydride in THF are added dropwise with stirring to a solution, kept under nitrogen, of 12.6 g (40.0 mmol) of methyl 3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzoate in 200 ml of THF. After the mixture has been stirred at room temperature for 1 hour, 10 ml of a saturated aqueous sodium sulfate solution are added dropwise. The resultant precipitate is filtered off with suction and washed with dichloromethane. The filtrate is dried over sodium sulfate and evaporated. The residue is taken up in a mixture of diethyl ether and petroleum ether. The resultant precipitate is filtered off with suction, washed with petroleum ether and dried in vacuo: {3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]phenyl}methanol as colourless crystals; m.p. 95-97° C.; ESI 288 (M+H); HPLC: Rt=2.35 min (method B).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH:10]([CH2:19][CH2:20][CH:21]=C)[C:11]([N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[O:12])[O:6][CH2:5][CH2:4][O:3]1.[O:23]=[O+][O-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH:10]([C:11]([N:13]2[CH2:17][CH2:16][O:15][C:14]2=[O:18])=[O:12])[CH2:19][CH2:20][CH:21]=[O:23])[O:3][CH2:4][CH2:5][O:6]1
Reactant: O=[O+][O-]
Reactant: C=CCCC(CCCC1(C)OCCO1)C(=O)N1CCOC1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(CCCC(CCC=O)C(=O)N2CCOC2=O)OCCO1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-4 (1.8 g, 5.8 mmol), sudan III (10 mg) and CH2Cl2 (150 mL) at −78° C. under argon was bubbled ozone until the red solution changed to yellow-orange. The solution was purged with argon for 30 minutes. PPh3 (2.26 g, 8.7 mmol) was added followed by the removal of the cooling bath. After 1.5 h, the reaction was concentrated. Flash chromatography (silica, 20%-50% EtOAc/hexanes) gave 2-5 as a yellow solid.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH2:30]Br)=[O:26])=[CH:23][CH:22]=1>CN(C=O)C.O>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH2:30][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)=[O:26])=[CH:35][CH:36]=1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(ncn2Cc2cccc(C(=O)c3ccc(Cl)cc3)c2)n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.2 %

Procedure:
To a solution of theophylline (1.80 g) in DMF (50 ml) were added potassium carbonate (1.66 g) and 3-(4-chlorobenzoyl)benzyl bromide (3.10 g) and the mixture was stirred at room temperature for 24 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was recrystallized (acetone-hexane) to provide the title compound as white powder (1.64 g, 40%). 1H-NMR (CDCl3) δ: 3.40(3H,s), 3.60(3H,s), 5.57(2H,s), 7.42-7.79(9H,m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([CH:24]=[O:25])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CCOCC>[C:13]([O:17][C:18]([N:20]1[CH2:23][CH:22]([CH:24]([OH:25])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC(C(O)c2ccccn2)C1
Temperature: -78 °C

Procedure:
To 1.51 g (9.55 mmol) bromopyridine in 50 mL ether at −20° C. was added 6 mL (1.6 M in hexane, 9.6 mmol) n-butyl lithium, after 10 minutes the mixture was cooled to −78° C. and 1.61 g (8.7 mmol) 3-formyl-azetidine-1-carboxylic acid tert-butyl ester in 20 mL ether was added. The mixture was stirred and allowed to warm to room temperature, quenched with 50 mL 1 M sodium bicarbonate solution and then extracted with 50 mL DCM. The organic layer was dried over Na2SO4. After filtration and evaporation of the solvent the desired product was purified by column chromatography (silica, heptane/EtOAc 1:1 to EtOAc).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[N:10]=[C:11]([CH2:14][N:15]3[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[N:16]3)[S:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[N:10]=[C:11]([CH2:14][N:15]3[CH:19]=[C:18]([NH2:20])[CH:17]=[N:16]3)[S:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2csc(Cn3cc([N+](=O)[O-])cn3)n2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1(c2csc(Cn3cc(N)cn3)n2)OCCO1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 4-(2-methyl-[1,3]dioxolan-2-yl)-2-(4-nitro-pyrazol-1-ylmethyl)-thiazole (595 mg, 2.01 mmol), iron powder (340 mg, 6.02 mmol) and NH4Cl (542 mg, 10.04 mmol) in a mixture of EtOH (10.0 mL) and water (5.0 mL) was stirred at 75° C. for 1 h. The reaction mixture was filtered while hot and the filter cake rinsed with EtOH. The filtrate was concentrated under reduced pressure and the residue partitioned between CH2Cl2 (10 mL) and aq. 1M NaOH (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a red oil. TLC: rf (1:2 hept-EA)=0.10. LC-MS-conditions 02: tR=0.51 min, [M+H]+=267.18.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Br:22][C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[C:2]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: C1CNCCN1
Reactant: Brc1ccc2c(c1)C(c1ccccn1)=NCc1nnc(Br)n1-2
Product: Brc1ccc2c(c1)C(c1ccccn1)=NCc1nnc(N3CCNCC3)n1-2

Procedure:
In the manner given in Example 1, 1,8-dibromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with piperazine to give 8-bromo-1-piperazino-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH3:42][Mg]Br>O1CCCC1>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)([OH:26])[CH3:42])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(=O)C2CCCCC2)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(C)(O)C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 108 %

Procedure:
To a solution of (2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanone (143 mg; 0.241 mmol) in tetrahydrofuran (2.5 mL) at 0° C. was added 3.0M methylmagnesium bromide in tetrahydrofuran (0.25 mL; 0.75 mmol). After 15 minutes, the bath was removed and reaction was stirred at room temperature for 3 hours. The reaction was quenched with 2 drops of water. The reaction was diluted with ethyl acetate and dried over sodium sulfate and concentrated under reduced pressure. The residue was purified over 12 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10-50% ethyl acetate in heptane) to give 158 mg (108% yield) of a colorless oil. MS (ES+): Calc: 609.5, Found: 610.4 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 7.77 (s, 1H), 7.74 (s, 1H) 7.42 (m, 2H), 7.34 (d, J=8.30 Hz, 1H), 5.46 (d, J=16.18 Hz, 1H), 4.93 (d, J=16.60 Hz, 1H), 4.82 (q, J=16.18 Hz, 2H), 4.18 (s, 3H), 1.78-1.6 (m, 6H), 1.58 (s, 3H), 1.40 (m, 1H), 1.13-0.94 (m, 4H).
Reaction SMILES: [CH3:1][N:2]([CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)[S:3]([C:6]1[CH:25]=[CH:24][C:9]2[N:10]([CH3:23])[C:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)=[N:12][C:8]=2[CH:7]=1)(=[O:5])=[O:4].[ClH:33].C(=O)([O-])[O-].[NH4+:38].[NH4+]>>[ClH:33].[CH3:1][N:2]([CH:26]1[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]1)[S:3]([C:6]1[CH:25]=[CH:24][C:9]2[N:10]([CH3:23])[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21](=[NH:38])[NH2:22])=[CH:19][CH:20]=3)=[N:12][C:8]=2[CH:7]=1)(=[O:4])=[O:5]
Reactant: CN1CCC(N(C)S(=O)(=O)c2ccc3c(c2)nc(COc2ccc(C#N)cc2)n3C)CC1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Product: CN1CCC(N(C)S(=O)(=O)c2ccc3c(c2)nc(COc2ccc(C(=N)N)cc2)n3C)CC1

Procedure:
Prepared analogously to Example 25d from 400 mg of 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulphonic acid-N-methyl-N-(1-methylpiperidin-4-yl)-amide with ethanolic hydrochloric acid and ammonium carbonate. Yield: 370 mg (83% of theory), C23H30N6O3S (470.6) ##EQU13##
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]=[CH:9]N(C)C)=[CH:4][CH:3]=1.[Na+].[I-].Cl[CH2:16][C:17](=[O:19])[CH3:18]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:16]([C:17](=[O:19])[CH3:18])=[CH:9][N:8]=2)[N:7]=1
Reactant: CN(C)C=Nc1ccc(Cl)nn1
Reactant: CC(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cnc2ccc(Cl)nn12
Temperature: 80 °C
Yield: 51.1 %

Procedure:
To a solution of N′-(6-chloro-pyridazin-3-yl)-N,N-dimethyl-formamidine (1.3 g, 7 mmol) in DMF (60 mL) was added NaI (1 g, 6.7 mmol) and chloroacetone (1 mL, 12.6 mmol). The mixture was heated at 80° C. overnight and concentrated under reduced pressure. The residue was purified by column chromatography to afford 1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethanone (0.7 g) in 51% yield. 1H-NMR (400 MHz, CDCl3) δ ppm 8.42 (s, 1H), 8.05 (d, 1H), 7.31 (d, 1H), 2.77 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:37]1[NH:42][C@@H:41]([CH2:43][OH:44])[CH2:40][N:39]2C[CH2:46][CH2:47][CH2:48][C@H:38]12.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=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]>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:42]3[C@@H:41]([CH2:43][OH:44])[CH2:40][N:39]4[CH2:46][CH2:47][CH2:48][C@@H:38]4[CH2:37]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OC[C@H]1CN2CCCC[C@@H]2CN1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(F)ccc1-c1cc(N2C[C@H]3CCCN3C[C@@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 4 h
Yield: 27.8 %

Procedure:
The title compound was prepared starting from 323 mg (0.608 mmoles) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl) -3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577),1.216 mg (0.160 mmol) of (3R,9aR)-octahydro-2H-pyrido[1,2-a]pyrazin-3-ylmethanol (Tetrahedron Asymmetry, 1996, 7(7), 1999-2005), 35 mg of bis(dibenzylideneacetone)palladium (0.061 mmol), 57 mg of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.145 mmol), 297 mg (0.912 mmol) of cesium carbonate; the reagents were dissolved in 10 ml of toluene and stirred at 140° C. in a closed vial for 4 hours. More dicyclohexylphosphino-2′-(N,N -dimethylamino)biphenyl (57 mg 0.145 mmol), and bis(dibenzylideneacetone)palladium (35 mg, 0.061 mmol) were added and the reaction kept at 140° C. for additional 4 hours. The crude material was loaded on a SCX cartridge, the neutral fractions were washed with methanol and the basic eluted with 2M ammonia in methanol and collected. The solvent was removed and the residue purified by chromatography (Silica) eluting with ethyl acetate, followed by a gradient from methylene chloride to methylene chloride: methanol 95:5. The cleanest fractions were purified further by chromatography on an NH2 silica cartridge with a gradient cyclohexane to cyclohexane:ethyl acetate 70:30, affording 29 mg of the title compound as pale yellow solid.