Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[CH:12]=[C:11]([O:23]CC2C=CC=CC=2)[CH:10]=1)[CH2:5][C:6]([CH3:8])=[CH2:7].[OH-].[Na+]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:31])[CH:4]([C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]([OH:23])[CH:10]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C(CC(C)C)c1cc(O)cc(O)c1
Reaction time: 2 h
Yield: 90.5 %

Procedure:
10% Pd/C (Aldrich cat no 205699, 214 mg) was added to a stirred solution of 2-(3,5-bis-benzyloxyphenyl)-4-methyl-pent-4-enoic acid methyl ester (2.14 g, 5.1 mmol) and NaOH (225 mg, 5.6 mmol) in MeOH (30 mL) at room temperature. Stirring was continued for 2 h under H2 (1 atm.) then the mixture was filtered through Celite, concentrated in vacuo, suspended in water (15 mL) and adjusted to pH 2 with 1M HCl. The mixture was extracted with DCM (3×60 mL); the combined organic layer washed with brine (20 mL), dried (MgSO4), concentrated in vacuo and purified by flash chromatography (silica, 0-20% EtOAc in petroleum ether) to give the title product as a white syrup (1.1 g, 90%).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([O:28][CH:29]([CH3:34])[C:30]([F:33])([F:32])[F:31])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=1)=[CH:15][C:14]([Cl:27])=[CH:13][CH:12]=2)=[O:7])(C)(C)C.Cl>O1CCOCC1>[Cl:27][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([O:28][CH:29]([CH3:34])[C:30]([F:33])([F:31])[F:32])[C:8]([C:6]([OH:7])=[O:5])=[C:17]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=1
Reactant: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(OC(C)C(F)(F)F)nc3ccc(Cl)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1cccc(-c2c(C(=O)O)c(OC(C)C(F)(F)F)nc3ccc(Cl)cc23)c1

Procedure:
The title compound was prepared in analogy to example 78 step E from 6-chloro-4-(3-isopropyl-phenyl)-2-(2,2,2-trifluoro-1-methyl-ethoxy)-quinoline-3-carboxylic acid tert-butyl ester (70 mg, 0.14 mmol) and 4N HCl in dioxane. Off white solid (44 mg, 71%). LC-MS (ESI): 438 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([CH3:13])=[C:4]([CH2:11][CH3:12])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[C:14]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)#[N:15].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].CO>[CH2:11]([C:4]1[C:3]([CH3:13])=[C:2]([C:20]2[CH:21]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C:14]#[N:15])[C:7]([CH3:8])=[N:6][C:5]=1[O:9][CH3:10])[CH3:12]
Reactant: CCc1c(OC)nc(C)c(Br)c1C
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCc1c(OC)nc(C)c(-c2cccc(C#N)c2)c1C
Yield: 9.4 %

Procedure:
A mixture of 5-bromo-3-ethyl-2-methoxy-4,6-dimethylpyridine (254 mg, 1.75 mmol), 3-cyanophenylboronic acid (254 mg, 1.75 mmol), palladium tetrakis(triphenylphosphine) (81.2 mg, 0.07 mmol), 2M aq sodium carbonate (1.15 mL), toluene (10 mL) and methanol (0.7 mL) is reacted following the procedures of Step 4, Example 5. The crude product is purified by HPLC in two runs eluting with a gradient of acetonitrile-20 to 5% water ramping @ 0.5% per min. Product containing fractions from both runs are combined and concentrated to afford 3-(5-ethyl-6-methoxy-2,4-dimethylpyridin-3-yl)benzonitrile (44 mg, 14%) as an oil. LC/MS: MS m/e=267 (M+H); RT 4.41 min.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH:21]1([CH2:26][C:27]([OH:29])=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]1.[O:30]1CCCC1>CCCCCC.C1(C)C=CC=CC=1>[OH:30][CH:22]1[CH2:23][CH2:24][CH2:25][CH:21]1[CH2:26][C:27]([OH:29])=[O:28]
Reactant: C1CCOC1
Reactant: O=C(O)CC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: O=C(O)CC1CCCC1O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
In an atmosphere of argon, to a solution of LDA (lithium diisopropylamide) prepared with a solution of diisopropylamine (60 ml) in anhydrous tetrahydrofuran (500 ml) and a 1.45M solution of butyl lithium in n-hexane (297 ml), a solution of cyclopentylacetic acid (25 g) in anhydrous toluene (100 ml) was dropped. The solution was stirred for 30 min. at room temperature and for 1 hr at 45° C. With blowing of air dried through phosphorus pentaoxide, the solution was stirred for 16 hrs. After reaction, the supernatant separated by decantation was diluted with water. The diluted solution was washed with diethyl ether, adjusted pH 2 with 6N hydrochloric acid and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then concentrated under reduced pressure. The residue was purified by recrystallization to give the title compound (17.1 g) having the following physical data:
Reaction SMILES: C([NH:5][C:6]([NH:8][CH:9]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1OC)[CH2:10]O)=[S:7])(C)(C)C.[ClH:21].[OH2:22]>>[ClH:21].[NH2:5][C:6]1[S:7][CH2:10][CH:9]([CH2:12][C:13]2[CH:18]=[CH:17][NH:16][C:15](=[O:22])[CH:14]=2)[N:8]=1
Reactant: O
Reactant: COc1cnccc1CC(CO)NC(=S)NC(C)(C)C
Agent: Cl
Product: NC1=NC(Cc2cc[nH]c(=O)c2)CS1
Temperature: 100 °C

Procedure:
A suspension of 0.4 g of N-(tert-butyl)-N′-[2-hydroxy-1-(3-methoxy-pyridin-4-yl-methyl)ethyl]-thiourea in 4 mL of aqueous solution of 6N hydrochloric acid is heated at a temperature of about 100° C. for 18 hours. The reaction medium is then concentrated under reduced pressure (2 kPa) at a temperature of about 40° C. The residue obtained is taken up by 25 mL of distilled water and the mixture is washed with 2 times 20 mL of dichloromethane. The aqueous phase is evaporated under reduced pressure (2 kPa) at a temperature of about 40° C. The residue is taken up with 2 times 15 mL of ethanol and concentrated according to the conditions described above, then dried in an oven under reduced pressure (10 kPa) at a temperature of about 40° C. for 4 hours. About 0.31 g of racemic 4-(2-amino-4,5-dihydro-thiazol-4-ylmethyl)-1H-pyridin-2-one hydrochloride, are obtained in the form of a pale yellow solid melting at 124° C. This product is purified by chromatography on a column of CHIRALCEL OD 20μ in an heptane-ethanol-triethylamine mixture (80/20/0.1 by volume). The fractions containing the expected product are collected and concentrated under reduced pressure (1 kPa) at a temperature of about 40° C. and then the residue is dried in an oven under reduced pressure (10 kPa) at a temperature of about 40° C. About 0.0131 g of (+)-4-(2-Hydroxy-pyridin-4-ylmethyl)-4,5-dihydro-thiazol-2-ylamine, (αD2°=+12.1+/−0.7 in the 0.5% DMSO) are obtained. [1H NMR spectrum (300 MHz, (CD3)2SO d6, δ in ppm): 2.73 (dd, J=13.5 and 7 Hz, 1H); 2.80 (dd, J=13.5 and 7 Hz, 1H); 3.27 (dd, J=11.5 and 5.5 Hz, 1H); 3.62 (dd, J=11.5 and 7.5 Hz, 1H); 4.53 (mt, 1H); 6.13 (dd, J=6.5 and 1.5 Hz, 1H); 6.24 (s large, 1H); 7.34 (d, J=6.5Hz, 1H); from 8.90 to 9.40 (mf very broad, 2H); from 9.60 to 10.40 (mf very broad, 1H)].
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([N+:17]([O-])=O)[CH:11]=2)[CH:6]=[CH:5][N:4]=1>CO.CCOC(C)=O>[NH2:17][C:12]1[CH:11]=[C:10]([O:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([NH:2][CH3:1])[N:8]=2)[CH:15]=[CH:14][C:13]=1[OH:16]
Reactant: CNc1nccc(Oc2ccc(O)c([N+](=O)[O-])c2)n1
Solvent: CCOC(C)=O
Solvent: CO
Product: CNc1nccc(Oc2ccc(O)c(N)c2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(2-Methylamino-pyrimidin-4-yloxy)-2-nitro-phenol (Step D, 0.163 g, 0.620 mmol) was dissolved in 7 mL MeOH and 15 mL EtOAc. To the argon-degassed solution was added 10% by weight Pd/C (0.08 g). The reaction was stirred vigorously at RT under 1 atm H2 gas for 18 h. The reaction was filtered through a Celite® plug and concentrated to dryness to yield the title compound. MS (MH+)=233.1; MW Calc'd 232.24 for C11H12N4O2.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:13](Cl)(Cl)=[S:14]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][C:3]=1[N:4]=[C:13]=[S:14]
Reactant: S=C(Cl)Cl
Reactant: Cc1c(N)ccc([N+](=O)[O-])c1C
Solvent: Cc1ccccc1
Product: Cc1c(N=C=S)ccc([N+](=O)[O-])c1C
Yield: 48 %

Procedure:
To a solution of 2,3-dimethyl-4-nitroaniline (0.5 g, 1.0 equiv.) in toluene (50 mL) was added thiophosgene (0.3 mL, 1.3 equiv.) and the reaction mixture was heated at the reflux temp. overnight. The resulting mixture was concentrated under reduced pressure and the residue was purified by column chromatography (25% CH2Cl2/hex) to afford 2,3-dimethyl-4-nitrophenyl isothiocyanate as a light yellow solid (0.30 g, 48%): 1H NMR (CDCl3) δ2.39 (s, 3H), 2.41 (s, 3H), 7.20 (d, J=8.4 Hz, 1H); CI-MS m/z 200 ((M+H)+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:8][C:9]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:10]=1[CH2:11][NH:12][C:13]1[C:14]2[N:15]([C:19]([CH:23]=[O:24])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1)=[O:7].[BH4-].[Na+]>CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:8][C:9]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:10]=1[CH2:11][NH:12][C:13]1[C:14]2[N:15]([C:19]([CH2:23][OH:24])=[C:20]([CH3:22])[N:21]=2)[CH:16]=[CH:17][CH:18]=1)=[O:7]
Reactant: COCCOC(=O)Nc1cccc(C)c1CNc1cccn2c(C=O)c(C)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCOC(=O)Nc1cccc(C)c1CNc1cccn2c(CO)c(C)nc12
Yield: 81 %

Procedure:
2.8 g (7.06 mmol) of 8-{2-[(2-methoxyethoxy)carbonylamino]-6-methylbenzylamino}-2-methylimidazo[1,2-a]-pyridine-3-carboxaldehyde are reduced with sodium borohydride analogously to Example 2, methanol is distilled off in vacuo, and the residue is treated with water and ethyl acetate and adjusted to pH 9 using potassium hydrogen phosphate solution. The mixture is extracted several times with ethyl acetate, dried and concentrated in vacuo, and the residue is recrystallized from toluene/diisopropyl ether. 2.28 g (81%) of the title compound of m.p. 138°-140° C. are obtained.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:27][CH:28]([CH3:31])[CH2:29][NH2:30]>C(#N)C>[CH3:27][CH:28]([CH3:31])[CH2:29][NH:30][CH2:12][C@H:13]1[O:18][C:17]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1
Reactant: CC(C)CN
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CC(C)CNC[C@@H]1COc2ccc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [(2S)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.2 g, 0.5 mmol), 2-methylpropane-1-amine (1 ml) and ACN (2 ml) was heated under microwave radiation at 120° C. for 30 min. Purification on SCX-3 column (TEA/MeOH) and flash column chromatography (EtOAc/MeOH). Yield: 0.1 g, 77%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 213° C. MS m/z (rel. intensity, 70 eV) 299 (M+, 4), 256 (16), 207 (11), 86 (bp), 57 (8). [α]=+65° (MeOH).
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1.[CH3:24][O-:25].[Na+]>>[CH3:24][O:25][C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1
Reactant: C[O-]
Reactant: CCCOc1ccccc1-c1nc2nc(SC)nnc2c(=O)[nH]1
Agent: [Na+]
Product: CCCOc1ccccc1-c1nc2nc(OC)nnc2c(=O)[nH]1

Procedure:
In a similar manner to Example 78, 3-methylthio-8-oxo-6-(2-propoxyphenyl)-7,8-dihydropyrimido[4,5-e][1,2,4]triazine (0.5 g) was treated for 3 hours with sodium methoxide (prepared from sodium, 0.17 g, and methanol) to afford the title compound, 0.34 g, m.p. 234-235° C. (recrystallized from methanol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([S:13]([C:16]2[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[NH:10][CH:11]=O)=[CH:5][CH:4]=1)#[N:2].O(Cl)Cl>O1CCCC1>[N+:10]([CH:9]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH3:20])=[CH:21][CH:22]=1)(=[O:15])=[O:14])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)#[C-:11]
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2ccc(C#N)cc2)cc1
Agent: ClOCl
Solvent: C1CCOC1
Product: [C-]#[N+]C(c1ccc(C#N)cc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
To a stirred solution of N-((4-cyanophenyl)(tosyl)methyl)formamide (3 g, 9.54 mmol, 1.00 equiv) in tetrahydrofuran (30 mL) at −10° C. was added dropwise phorphorus oxychloride (4.4 g, 28.70 mmol, 3.00 equiv) and TEA (4.8 g, 47.44 mmol, 5.00 equiv). The reaction mixture was stirred at room temperature for 3 h and then concentrated under vacuum. The residue was diluted with 100 mL of dichloromethane then washed with 3×50 mL of water and 2×50 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-30% of ethyl acetate in petroleum ether to give 1.5 g (53%) of 4-(isocyano(tosyl)methyl)benzonitrile as an off-white solid. 1H-NMR (300 MHz, DMSO-d6): δ 8.00-7.90 (m, 3H), 7.80-7.70 (m, 4H), 7.50-7.44 (m, 2H), 2.42 (s, 3H) ppm.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[C:9]([C:10]#[N:11])[C:8]([NH2:13])=[CH:7][CH:6]=1)([O-])=O.[OH-].[Na+]>O>[NH2:13][C:8]1[CH:7]=[CH:6][C:5]([NH2:2])=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1cc(N)ccc1N
Reaction time: 4 h
Yield: 86.4 %

Procedure:
To a solution of 80 grams (0.356 mole) of stannous chloride dihydrate in 200 ml. of concentrated hydrochloric acid is added in portions over the course of about 5 minutes, 16.314 grams (0.1 mole) of 5-nitroanthranilonitrile. Water cooling is used and the internal temperature rises to about 50°. Stirring is continued for 4 hours and the mixture is allowed to stand overnight. The reaction mixture is cooled to 5° in an ice-bath and a cold 50% solution of sodium hydroxide added until the mixture is strongly basic. The mixture is extracted with methylene chloride. The methylene chloride extracts are washed with water and the solvent removed by distillation. There is obtained 11.51 grams (86.5%) of material melting at 85°-87°. Recrystallization from benzene-skellysolve B gives material melting at 86°-7°. The infrared spectrum is in agreement.
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[CH:6][N:7](C)C)C.[Cl:16][C:17]1[CH:22]=[C:21]([NH:23]N)[N:20]=[CH:19][N:18]=1.C(O)(C(F)(F)F)=O.Cl.C[O-].[Na+]>O1CCOCC1.C(O)C>[ClH:16].[Cl:16][C:17]1[N:18]=[CH:19][N:20]=[C:21]([N:23]2[C:4](=[O:15])[C:5]([N:10]3[CH:14]=[CH:13][N:12]=[N:11]3)=[CH:6][NH:7]2)[CH:22]=1
Reactant: NNc1cc(Cl)ncn1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: C1COCCO1
Product: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1

Procedure:
10.0 g (47.7 mmol) of the compound from Example 3A and 8.3 g (57.1 mmol) of the compound from Example 7A are initially introduced into 100 ml ethanol and 1.5 ml (2.2 g, 19.0 mmol) TFA are added. The mixture is stirred under reflux for 12 h. A 4 M solution of hydrogen chloride in dioxane is then added in excess to the cooled reaction mixture, the mixture is extracted by stirring for approx. 1 h, the crystals which have precipitated out are filtered off and the residue on the filter is washed with dioxane and ethanol. The intermediate product obtained in this way is dissolved in 150 ml ethanol, 50 ml of a 25% strength methanolic sodium methylate solution are added and the mixture is stirred at RT for 2 h. The reaction mixture is then adjusted to pH 5 with 1 N hydrochloric acid and extracted by stirring at RT for a further 2 h, the solid is filtered off, the residue on the filter is washed with ethanol and the product is dried in vacuo.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:21]([C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26])=O>>[F:20][C:17]([F:18])([F:19])[C:14]1[N:12]2[N:13]=[C:8]([N:1]3[CH2:7][CH2:6][CH2:5][N:4]([CH2:21][C:23]4[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=4[C:25]#[N:26])[CH2:3][CH2:2]3)[CH:9]=[CH:10][C:11]2=[N:16][N:15]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCCNCC3)nn12
Reactant: N#Cc1ccccc1C=O
Product: N#Cc1ccccc1CN1CCCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-formylbenzonitrile was carried out according to General Synthetic Method 8. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 2-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-1,4-diazepan-1-yl]methyl]benzonitrile.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.Cl.Cl.[S:20]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[O:11])[CH:2]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)NCCCCCCN)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)NCCCCCCNC(=O)C=Cc2cccnc2)cc1

Procedure:
Batch size: 4.1 g (27.5 mmol) 3-(3-pyridyl)-acrylic acid, 4.7 g (37.0 mmol) oxalyl chloride, 5.0 g (49.4 mmol) TEA and 8.6 g (25.0 mmol) 6-(tosylamino)-hexylamine.dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH:21]([CH3:23])[CH3:22])[N:15]=2)[CH:3]=1.[NH3:24].CO>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:24])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH:21]([CH3:23])[CH3:22])[N:15]=2)[CH:3]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(OC(C)C)n1
Reactant: N
Solvent: CO
Product: CC(C)Oc1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Temperature: 40 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
To a solution of give ethyl 6-chloro-4-(6-isopropoxypyridin-2-ylamino)pyridazine-3-carboxylate (530 mg, 1.57 mmol) was added 7N ammonia in MeOH (16.9 mL, 118 mmol). The mixture was stirred at 40° C. for 18 h, after which the solvent was removed to give 6-chloro-4-(6-isopropoxypyridin-2-ylamino)pyridazine-3-carboxamide (470 mg, 97%) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 11.57 (s, 1H), 9.08 (s, 1H), 8.17 (s, 1H), 7.58 (t, J=7.8 Hz, 1H), 6.50 (d, J=7.3 Hz, 1H), 6.44 (d, J=8.0 Hz, 1H), 5.69 (s, 1H), 5.23 (m, 1H), 1.47 (d, J=6.3 Hz, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][CH2:13][C:12]2=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][C:23]=1[C:30]([O:32][CH3:33])=[O:31]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][C:13](=[CH:26][C:25]1[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[C:23]([C:30]([O:32][CH3:33])=[O:31])[CH:24]=1)[C:12]2=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCOc2ccc(OCc3ccccc3)cc21
Reactant: COC(=O)c1cc(C=O)ccc1OC
Product: COC(=O)c1cc(C=C2COc3ccc(OCc4ccccc4)cc3C2=O)ccc1OC

Procedure:
By the method of Example 44, 6-benzyloxy-4-chromanone (20.95 g) and 4-methoxy-3-methoxycarbonylbenzaldehyde were converted to present title product, 25.75 g (73%); tlc (19:1 CH2Cl2 :ether) Rf 0.70.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH2:24]([S:27](Cl)(=[O:29])=[O:28])[CH2:25][CH3:26]>>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:11][CH2:12][N:13]([S:27]([CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28])[CH2:14][CH2:15]2)=[N:4][CH:3]=1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)N1CCC(N(C(=O)Nc2ncc(Cl)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared in a similar manner to Example 554 using 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea and propanesulfonylchloride
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11](O)[C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>[Cl-].C[N+](C)(C)C>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([Cl:22])[C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(NCc2ccccc2)c([N+](=O)[O-])c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: C[N+](C)(C)C
Agent: [Cl-]
Product: Cc1cc(NCc2ccccc2)c([N+](=O)[O-])c(Cl)n1

Procedure:
Heat a solution of 4-benzylamino-6-methyl-3-nitro-pyridin-2-ol (13.70 g, 52.8 mmol) and tetramethylammonium chloride (6.0 g, 52.8 mmol) to reflux in phosphorus oxychloride (15 mL) for 5 h. After cooling, remove the excess phosphorus oxychloride in vacuo. Triturate the residue in ice-water (400 mL) to obtain the title compound as a brown solid.
Reaction SMILES: N([O-])=O.[Na+].S1C=CC=C1/C=C/C1N=CNC=1N.[CH3:18][O:19][CH2:20][N:21]=[C:22]=[O:23].[N+:24](=[C:26]1[C:30](/[CH:31]=[CH:32]/[C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[N:29][CH:28]=[N:27]1)=[N-:25]>O.[H+].[B-](F)(F)(F)F.CS(C)=O>[CH3:18][O:19][CH2:20][N:21]1[C:22](=[O:23])[N:27]2[CH:28]=[N:29][C:30](/[CH:31]=[CH:32]/[C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)=[C:26]2[N:24]=[N:25]1
Reactant: [N-]=[N+]=C1N=CN=C1/C=C/c1cccs1
Reactant: COCN=C=O
Agent: F[B-](F)(F)F
Agent: Nc1[nH]cnc1/C=C/c1cccs1
Agent: O=N[O-]
Solvent: O
Solvent: CS(C)=O
Product: COCn1nnc2c(/C=C/c3cccs3)ncn2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 11.8 %

Procedure:
Sodium nitrite (150 mg, 2.1 mmol) in water (1 mL) was added to a suspension of (E)-4-(2-(thiophen-2-yl)vinyl)-1H-imidazol-5-amine (0.35 g, 1.8 mmol) in 10% HBF4 (4 mL) at 0° C. After stirring at 0° C. for 60 minutes, the precipitate was filtered from solution and dried over P2O5. This diazo compound (IR stretch 2193 cm−1) was used without further purification. Methoxymethyl isocyanate (0.43 g, 4.9 mmol) was added to a solution of (E)-4-diazo-5-(2-(thiophen-2-yl)vinyl)-4H-imidazole (0.3 g, 1.47 mmol) in dry DMSO (2 mL) under nitrogen. The resulting solution was stirred at room temperature for 48 hours, then purified by column chromatography (DCM) to give the title compound as a yellow solid (50 mg, 12%). δH (CDCl3) 8.44 (1H, s), 7.95 (1H, d, J=15.6), 7.34 (1H, d, J=5.1), 7.31 (1H, d, J=15.6), 7.26 (1H, d, J=3.6), 7.08 (1H, dd, J=5.1, 3.6), 5.69 (2H, s), 3.57 (3H, s).
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][C:9]([N:15]3[CH:19]=CN=C3)=[N:10][CH:11]=2)[N:6]([CH:20]([CH3:22])[CH3:21])[C:5]1=[O:23])[CH:2]=[CH2:3].NC1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][C:9]([NH:15][C:19]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[N:10][CH:11]=2)[N:6]([CH:20]([CH3:22])[CH3:21])[C:5]1=[O:23])[CH:2]=[CH2:3]
Reactant: C=CCn1c(=O)c2cnc(-n3ccnc3)nc2n(C(C)C)c1=O
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: ClC(Cl)Cl
Product: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc2n(C(C)C)c1=O
Temperature: 180 °C
Yield: 60 %

Procedure:
A mixture of 300 mg (0.96 mmol) of 3-allyl-7-(imidazol-1-yl)-1-isopropyl-1H-pyrimido[4,5-d]pyrimidine-2,4-dione and 551 mg (2.88 mmol) of 1-(4-aminophenyl)-4-methylpiperazine is heated at 180° C. for 2 hours. The reaction mixture is cooled, dissolved into chloroform, and chromatographed on silica eluting with 4:96 methanol/chloroform. The resulting material is crystallized from methanol/water to give 251 mg (60%) of the title compound: mp 176-177° C.