Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(#N)C.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])=[N:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccccc1B(O)O
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(Br)cnc21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(Br)cc12
Yield: 65.2 %

Procedure:
A mixture of 5-bromo-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (1.606 g, 3.537 mmol), 2-methoxy-phenyl-boronic acid (575 mg, 3.78 mmol) and of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (145 mg, 0.178 mmol) in acetonitrile (8 mL) and aqueous solution of sodium carbonate (2M, 8 mL) was stirred in a closed vial at 85° C. for 100 min. The resulting mixture was then distributed between a saturated aqueous solution of sodium bicarbonate and dichloromethane and the aqueous phase extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes to afford 5-bromo-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (1.002 g, 65% yield) as an off-white oil. 1H-NMR (500 MHz, d6-DMSO) δ 8.70 (d, 1H), 8.40 (d, 1H), 7.61 (d, 1H), 7.50 (ddd, 1H), 7.23 (dd, 1H), 7.10 (ddd, 1H), 5.81 (s, 2H), 3.85 (s, 3H), 3.66 (t, 2H), 0.84 (t, 2H), −0.10 (s, 9H). MS: m/z 456, 458 [MNa+].
Reaction SMILES: [H-].[Na+].O1CCC[CH2:4]1.[C:8]([O:12][C:13]([NH:15][CH2:16][C@@:17]1([CH2:26][C:27]([OH:29])=[O:28])[CH2:23][C@H:22]2[C@@H:18]1[CH:19]=[C:20]([CH2:24][CH3:25])[CH2:21]2)=[O:14])([CH3:11])([CH3:10])[CH3:9].CI>O>[C:8]([O:12][C:13]([N:15]([CH2:16][C@@:17]1([CH2:26][C:27]([OH:29])=[O:28])[CH2:23][C@H:22]2[C@@H:18]1[CH:19]=[C:20]([CH2:24][CH3:25])[CH2:21]2)[CH3:4])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CCC1=C[C@H]2[C@@H](C1)C[C@@]2(CNC(=O)OC(C)(C)C)CC(=O)O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCC1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Sodium hydride (63%, 2.48 g, 65.0 mmol) was added in small portions to a tetrahydrofuran solution (25 mL) of [(1S,5R,6R)-6-{[(tert-butoxycarbonyl)amino]methyl}-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid (2.01 g, 6.50 mmol) and methyl iodide (4.05 mL, 65.0 mmol) with stirring at room temperature. The mixture was stirred at this temperature for 6 hours, and water (50 mL) was then added thereto while the reaction solution was cooled on ice, followed by washing with diethyl ether. The aqueous layer was made acidic using 1 M citric acid, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography to obtain the compound of interest as an oil substance (2.00 g, 95%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7](=[CH2:11])[C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[C:12]([OH:15])(=[S:14])[CH3:13].C(O)(C)C>>[NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]([CH2:11][S:14][C:12](=[O:15])[CH3:13])[C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1
Reactant: CC(O)=S
Reactant: C=C(C(=O)O)C1CCNCC1
Solvent: CC(C)O
Product: CC(=O)SCC(C(=O)O)C1CCNCC1

Procedure:
A solution of 2-(piperidin-4-yl)prop-2-enoic acid (0.30 g, 1.64 mmol) in 6 mL of 1:1 thioacetic acid/isopropanol was stirred for 24 hours. The reaction mixture was concentrated in vacuo to afford the crude product, 2-(piperidin-4-yl)-3-(acetylthio)propanoic acid. The product was dissolved in 2 mL of water, cooled to 0° C., degassed with nitrogen, and 2 mL of ammonium hydroxide was added. The reaction mixture was stirred for 1 hour, concentrated in vacuo and the residue was dissolved in 10% HCl and purified by preparative HPLC to afford 73 mg of pure 2-(piperidin-4-yl)-3-mercaptopropanoic acid, as a trifluoroacetic acid salt, NMR (D2O) 1.30-1.43 (m,2), 1.70-1.90 (m,3), 2.32-2.42 (m,1), 2.50-2.60 (m,1) 2.63-2.72 (m,1), 2.79-2.90 (m,2), 3.22-3.34 (m,2) ppm.
Reaction SMILES: C([O-])(=O)C(C)(C)C.[C:8]([CH2:10][CH2:11][Zn+])#[N:9].Br[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.[NH4+].[Cl-]>C1COCC1.CN1C(=O)CCC1>[C:8]([CH2:10][CH2:11][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)#[N:9]
Reactant: N#CCC[Zn+]
Reactant: N#Cc1ccc(Br)cc1
Agent: CC(C)(C)C(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: N#CCCc1ccc(C#N)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 78.6 %

Procedure:
In a dry and argon-flushed Schlenk-flask, equipped with a magnetic stirring bar and a septum, (2-cyanoethyl)zinc pivalate (1t) (2.35 g, 2150 mg/mmol, 1.09 mmol) was dissolved in a mixture of THF (3.0 mL) and NMP (1.0 mL). 4-Bromobenzonitrile (168 mg, 0.92 mmol) was added followed by PEPPSI-iPr (14 mg, 0.02 mmol) and the mixture was stirred for 12 h at 50° C. Then sat. aq. NH4Cl (10 mL) was added and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic phases were dried (Na2SO4). Evaporation of the solvents in vacuo and purification by flash chromatography (silica gel, ihexane/Et2O=3:1) afforded 4-(2-cyanoethyl)benzonitrile (entry 26) (113 mg, 80%) as a pale yellow oil.
Reaction SMILES: [Cl-].[CH3:2][NH:3][C:4](=O)[CH3:5].N1C(C)=CC=CC=1C.C(OC([N:22]1[CH2:29][CH2:28][C@:27]2([CH3:32])[C@H:30]([CH3:31])[C@H:23]1[CH2:24][C:25]1[CH:36]=[CH:35][C:34]([C:37]([NH:39][NH2:40])=O)=[CH:33][C:26]=12)=O)(C)(C)C>ClCCl>[CH3:2][N:3]1[C:4]([CH3:5])=[N:40][N:39]=[C:37]1[C:34]1[CH:35]=[CH:36][C:25]2[CH2:24][C@@H:23]3[C@@H:30]([CH3:31])[C@:27]([CH3:32])([C:26]=2[CH:33]=1)[CH2:28][CH2:29][NH:22]3
Reactant: C[C@@H]1[C@H]2Cc3ccc(C(=O)NN)cc3[C@]1(C)CCN2C(=O)OC(C)(C)C
Reactant: CNC(C)=O
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1nnc(-c2ccc3c(c2)[C@]2(C)CCN[C@H](C3)[C@H]2C)n1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Oxalylic chloride (0.12 mL) is added to a solution N-methylacetamide (102 mg) and 2,6-lutidine (0.33 mL) in dichloromethane (5 mL) chilled in an ice bath. After stirring the solution for 15 min, (2R,6R,11S)-8-hydrazinocarbonyl-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester (0.50 g) is added and the cooling bath is removed. The resulting solution is stirred at ambient temperature for 1 h and then neutralized with aqueous NaHCO3 solution. The resulting mixture is extracted with dichloromethane, the combined organic extracts are dried (MgSO4), and the solvent is evaporated. The residue is taken up in acetic acid (3 mL) and stirred at 120° C. for 2.5 h. After cooling to room temperature, the mixture is concentrated under reduced pressure and the residue is taken up in trifluoroacetic acid (1 mL) and dichloromethane (5 mL) to cleave off the tert-butoxycarbonyl group. The solution is stirred at room temperature overnight and then concentrated. The residue is dissolved in little methanol/acetonitrile, neutralized with aqueous ammonia, and purified by HPLC on reversed phase (MeCN/H2O/NH4OH) to give the title compound.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.CN(C)P(=O)(N(C)C)N(C)C>C([O-])(O)=O.[Na+].O>[C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: O=C(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 83.6 %

Procedure:
A mixture of uridine (14; 13.25 g, 54.5 mmol), diphenyl carbonate (15.48 g, 72.5 mmol), anhydrous NaHCO3 (349 mg, 4.15 mmol), and hexamethylphosphoric triamide (50 mL) was heated with stirring at 150° C. under nitrogen for 20 min, and then cooled to room temperature. The mixture was poured into cold water (400 mL), and washed with CHCl3. Et3N (25 mL) was added, and the aqueous solution was heated at 70° C. for 5 h. The solvent was evaporated in vacuo, and the residue was crystallized from MeOH/water to give the title compound 15 as a white solid (11.13 g, 84%). 1H NMR (DMSO-d6) δ 11.2 (s, 1H, NH), 7.60 (d, J=7.5 Hz, 1H, H-6), 5.95 (d, 1H, H-1′), 5.51 (d, J=7.5 Hz, 1H, H-5), 6.30-5.30 (br, 2H, 2 OH), 4.10-3.50 (m, 6H, H-2′, H-3′, H-4′, H-5′, OH).
Reaction SMILES: CN(C)[CH:3]=[O:4].S(Cl)(Cl)=O.[Cl:10][C:11]([Cl:24])([Cl:23])[CH:12]1[NH:17][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[O:13]1>O>[CH:3]([N:17]1[C:16](=[O:18])[C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[O:13][CH:12]1[C:11]([Cl:10])([Cl:23])[Cl:24])=[O:4]
Reactant: O=C1NC(C(Cl)(Cl)Cl)Oc2ccccc21
Reactant: CN(C)C=O
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=CN1C(=O)c2ccccc2OC1C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Dimethylformamide (20 ml.) and thionyl chloride (5 ml.) were stirred together, 3,4-dihydro-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one (2.0 g.) was added in small portions over 15 minutes, and the mixture was stirred at ambient temperature for 48 hours. The reaction mixture was added to water (100 ml.), stirred for 1 hour and filtered. The solid product was dissolved in toluene, and purified by column chromatography on "Kieselgel"-60 (trade mark), eluting with a mixture of 5% by volume of ethyl acetate in toluene. The solvent was evaporated, and the product was crystallised from petroleum ether (b.p. 60°-80° C.) to give 3-formyl-3,4-dihydro-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one, m.p. 114° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH3:5].[OH-].[Na+]>O.C(O)C>[CH2:4]([O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[N:2][OH:3])=[CH:9][CH:8]=1)[CH3:5]
Reactant: NO
Reactant: CCOc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.8 %

Procedure:
A solution of 34.8 g of hydroxylamine hydrochloride in 50 ml of water was added in one portion to a solution of 37.5 g of 4-ethoxybenzaldehyde in 100 ml of ethanol in a 500-ml Erlenmeyer flask equipped with a magnetic stirrer. The reaction mixture was stirred for approximately 5 minutes, until clear. A room-temperature solution of 15.2 g of sodium hydroxide in 20 ml of water was added in several portions during 15 minutes. The reaction mixture was stirred for 5 minutes and then heated to boiling. After the cloudy reaction mixture had cooled to room temperature, water was added and product separated from solution as an oil. The mixture was extracted four times with 50-ml portions of chloroform. The chloroform extracts were combined, washed twice with 75-ml portions of saturated aqueous sodium chloride solution and dried over sodium sulfate. The dry chloroform solution was filtered, the filtrate was evaporated, and the residue crystallized with a slight amount of cooling. The crude solid was recrystallized from cyclohexane to give 35.4 g of 4-ethoxybenzaldoxime, m.p. 81°-86°. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][CH2:11][CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[S:28]([O:13][CH2:12][CH2:11][CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:30])(=[O:29])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC(CCCO)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CCCOS(C)(=O)=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. solution of 4-[(t-butoxycarbonyl)-amino]-4-phenylbutanol (133 mg, 0.5 mmol) in dichloromethane (8 mL) was added triethylamine (0.140 mL, 1.0 mmol), followed by methanesulfonylchloride (0.057 mL, 0.75 mmol). The solution was then stirred at 0° C. for 15 minutes before being quenched with an aqueous ammonium chloride solution (2 mL). The aqueous and organic layers were then separated, the aqueous layer extracted twice with dichloromethane, and the combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 4-[(t-butoxycarbonyl)-amino]-4-phenylbutanol mesylate as a yellow oil, which was used immediately in the next reaction without further purification. 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.67-2.00 (m, 4H), 2.95 (s, 3H), 4.18 (t, 2H, J=7.1 Hz), 4.20 (m, 1H), 4.92 (br s, 1H(NH)), 7.21-7.33 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]2[C:15]([CH3:16])=[CH:14][N:13](O)[CH2:12][C:11]=2[CH3:18])=[C:5]([CH3:19])[CH:4]=1.O.[PH2]([O-])=O.[Na+]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:19])[C:6]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[CH:12][C:11]=2[CH3:18])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(C2=C(C)CN(O)C=C2C)c(C)c1
Agent: [Pd]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C)c(-c2c(C)cncc2C)c(C)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 97.7 %

Procedure:
To a mixture of 3 (6.55 g, 25.5 mmol) and palladium (10 wt. % on activated carbon; 3.05 g, 2.8 mmol) in acetic acid (150 mL) was added sodium hypophosphite hydrate (6.7 g, 63 mmol) in a single portion at 80° C. The reaction mixture was stirred at 80° C. under N2 for 12 h, then filtered and concentrated in vacuo. The resulting light-yellow oil was dissolved in chloroform (250 mL) and washed successively with saturated NaHCO3 (aq.), water, and brine. The organic layer was then separated, dried over MgSO4, filtered, and concentrated in vacuo. The resulting pale-yellow solid was purified by flash chromatography on silica gel eluting with 1:1 hexane: ethyl acetate, to give 6.01 g (97.9%) of the title compound as colorless solid: mp 87-88° C.; 1H NMR (400 MHz, CD2Cl2): δ 8.334 (s, 2H), 6.707 (s, 2H), 3.804 (s, 3H), 1.892 (s, 6H), 1.851 (s, 6H); 13C NMR (100 MHz, CD2Cl2): δ 159.330, 148.939, 148.420, 136.373, 131.905, 129.958, 113.489, 55.556, 20.188, 16.831; MS (APCI): m/z 242.2 [(M+H)+, 100]; Anal. Calcd. For C16H19NO: C, 79.63; H, 7.94; N, 5.80. Found: C, 79.39; H, 7.94; N, 5.75.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[Br:11]Br>C(Cl)(Cl)Cl.[OH-].[NH4+].C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[C:10]=1[Br:11]
Reactant: Nc1ccc2scnc2c1
Reactant: BrBr
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Nc1ccc2scnc2c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
To a cooled (5° C.) solution of 2.04 g of 5-aminobenzothiazole in 60 mL of chloroform are added dropwise 2.15 g of bromine while maintaining the temperature below 10° C. After completion of the addition, the reaction mixture is stirred for 30 minutes at room temperature, then diluted with 14 mL of concentrated ammonium hydroxide and 16 mL of methylene chloride. The aqueous layer is washed with methylene chloride (2×16 mL) and the combined organic layers are rotary evaporated. The residue is purified by an aspirator vacuum-filtration through silica gel, eluting with 15% to 30 ethyl acetate in hexanes to provide 2.44 g of 5-amino-4-bromobenzothiazole as a reddish solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO.O>[CH2:10]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[N:7]=[C:6]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([O:17][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[C:19]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:20][C:19]=1[C:25]([F:26])([F:27])[F:28])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: O
Solvent: CO
Product: Fc1cnc(Nc2ccc(OCc3ccccc3)c(C(F)(F)F)c2)nc1Nc1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) was dissolved in a mixture of MeOH (1 ml) and H2O (0.1 ml). 4-benzyloxy-3-trifluoromethylaniline (481 mg, 1.8 mmol) was added and the mixture was refluxed for 2 days (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 9:1) to give N2,N4-bis(4-benzyloxy-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.51 (s, 1H), 8.05 (s, 1H), 7.38-7.64 (m, 5H), 6.94-7.14 (m, 11H), 6.44-6.73 (m, 4H), 4.84 (s, 2H), 4.79 (s, 2H); LCMS purity: 94.7%; MS (m/e): 628.93 (M+, 100).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[C:24]([Cl:25])=[CH:23][C:12]2[C:13](=O)[CH2:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[S:17][C:11]=2[CH:10]=1.O>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:8][C:9]1[C:24]([Cl:25])=[CH:23][C:12]2[C:13]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[S:17][C:11]=2[CH:10]=1
Reactant: O=C1Cc2ccccc2Sc2cc(Cl)c(Cl)cc21
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: CN1CCN(C2=Cc3ccccc3Sc3cc(Cl)c(Cl)cc32)CC1
Reaction time: 28 h

Procedure:
1-Methylpiperazine (15.0 g), followed by titanium tetrachloride (3.1 g) in benzene (45 ml), was added to a warm solution of 7,8-dichlorodibenzo(b,f)thiepine-10(11H)-one (8.85 g) (its preparation is described in Example 8) in benzene (75 ml). The mixture was refluxed while stirring for 28 hours, cooled and decomposed with water (100 ml). The resultant precipitate was filtered and washed with benzene and water. The benzene layer in the filtrate was separated, washed with water, dried over magnesium sulfate and taken down. The enamine base, obtained in nearly quantitative yield, was purified by crystallization from ethanol, m.p. 157°-159° C. Neutralization with maleic acid in ethanol yields the maleate, C23H22Cl2N2O4S, which is crystallized from ethanol; m.p. 229°-232° C.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][CH2:5][CH2:4][CH:3]1[CH2:13][C:14]([OH:16])=O.Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1.C([O-])(=O)C.[Na+]>C(O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:14](=[O:16])[CH2:13][CH:3]3[CH2:4][CH2:5][S:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:2]3=[N:27]2)=[CH:22][CH:21]=1
Reactant: O=C(O)CC1CCSc2ccccc2C1=O
Reactant: COc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(N2N=C3c4ccccc4SCCC3CC2=O)cc1
Yield: 33.2 %

Procedure:
A mixture of 4 g of 5-oxo-2,3,4,5-tetrahydro-[1]benzothiepine-4-acetic acid, 3.5 g of 4-methoxyphenylhydrazine hydrochloride and 1.8 g of sodium acetate in 100 ml of ethanol is refluxed under heating for 12 hours and then the solvent is distilled off. To the residue is added 20 ml of acetic acid and the mixture is refluxed under heating for 2 hours. The solvent is distilled off, and the mixture of the residue in water is extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and the solvent is distilled off. The crude product obtained is purified by column chromatography and recrystallized from ethanol to give 1.9 g of 2-(4-methoxyphenyl)-4,4a,5,6-tetrahydro-[1]benzothiepino[5,4-c]pyridazin-3(2H)-one, melting at 143°-145° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])[CH3:2].Cl[C:13]1[N:18]=[N:17][C:16]([C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:1]([N:3]([C:13]1[N:18]=[N:17][C:16]([C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11])[CH3:2]
Reactant: NC(=O)c1ccc(Cl)nn1
Reactant: CCNCc1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(Cc1ccccc1N)c1ccc(C(N)=O)nn1
Reaction time: 24 h
Yield: 39.2 %

Procedure:
N-Ethyl-N-(2-aminobenzyl)amine (707 mg, 4.7 mmol) in DMF (11 ml) was treated with 6-chloropyridazin-3-amide (4.7 mmol) followed by diisopropylethylamine (15.4 mol) and the reaction stirred at 140° under argon for 24 hours. The reaction was evaporated in vacuo (cold-finger) and the residue partitioned between water and ethyl acetate. The combined organic extracts were dried and evaporated to give a brown gum. The gum was purified by medium pressure chromatography to give 6-(N-ethyl-N-(2-aminobenzyl)amino)-pyridazine-3-carboxamide (500 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:12]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(Cl)CCl>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:29][S:26]([C:23]1[CH:22]=[CH:21][C:20]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])=[CH:25][CH:24]=1)(=[O:27])=[O:28])=[O:6]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(S(=O)(=O)NC(=O)c2ccc(Cl)cc2Cl)cc1
Reaction time: 16 h

Procedure:
To a stirring solution of 2,4-dichlorobenzoic acid (1.25 eq) in dry dichloromethane (10 mL/mmol), 4-(tert-butyl-dimethylsiloxy)phenylsulfonamide (1.0 eq) is added in one portion followed by EDC (1.25–1.5 eq) and finally, NN-dimethyl-4-aminopyridine (1.2 equiv). The mixture is vigorously stirred under nitrogen for 16 hr, concentrated under reduced pressure, and the residue partitioned between ethyl acetate and water. The organic layer is washed with 1N hydrochloric acid (4 times, 20 mL/mmol), then the combined aqueous phases extracted with ethyl acetate (twice, 20 mL/mmol). The combined organic layers are finally washed with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel chromatography or crystallization if necessary or desired. ESI-MS m/e 458.0 (M+−H; 460.0 (M++H).
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:8][CH2:7][C:6]([CH3:10])([CH3:9])[CH2:5][NH:4][C:3]1=[O:11].[H][H]>C(O)(=O)C.[Pd]>[Cl:1][CH:2]1[CH2:8][CH2:7][C:6]([CH3:9])([CH3:10])[CH2:5][NH:4][C:3]1=[O:11]
Reactant: [H][H]
Reactant: CC1(C)CCC(Cl)(Cl)C(=O)NC1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)CCC(Cl)C(=O)NC1
Yield: 99.5 %

Procedure:
3.0 g (14.3 mmoles) of 3,3-dichloro-6,6-dimethyl-2-oxoperhydroazepine were dissolved in 300 ml of glacial acetic acid and shaked at 40 psi of hydrogen with 1.9 g of 10% Pd/C. When the theoretical amount of hydrogen was consumed the catalyst was filtered off and the filtrate evaporated in vacuo to yield 2.5 g of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Cl:19][C:20]1[S:24][C:23]([S:25](Cl)(=[O:27])=[O:26])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[S:24][C:23]([S:25]([NH:18][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=2[NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])(=[O:27])=[O:26])=[CH:22][CH:21]=1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Product: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)c1ccc(Cl)s1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene1,2-diamine was reacted with 5-chlorothiophene-2-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.38 (dd, J=1.5 & 10.2 Hz, 1H), 7.32 (ddd, J=2.1, 5.1 & 9.3 Hz, 1H), 7.25 (d, J=3.9 Hz, 1H), 7.10 (dd, J=9.0 & 18.6 Hz, 3H), 6.84 (d, J=4.2 Hz, 1H), 5.86 (dt, J=1.8, 8.7 & 17.4 Hz, 1H), 5.49 (br s, D2O exchangeable, 1H).