Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([CH3:22])[C:11](=[O:21])[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)=[CH:5][CH:4]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1)[NH2:29].[C:35]1([CH3:45])[CH:40]=[CH:39][C:38]([S:41]([OH:44])(=[O:43])=[O:42])=[CH:37][CH:36]=1>ClC1C=CC=CC=1>[C:35]1([CH3:45])[CH:36]=[CH:37][C:38]([S:41]([OH:44])(=[O:42])=[O:43])=[CH:39][CH:40]=1.[CH3:34][O:33][C:31]1[CH:30]=[C:28]([N:29]2[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:12][C:11](=[O:21])[C:10]([CH3:22])=[C:9]2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:27]=[C:26]([O:25][CH3:24])[CH:32]=1
Reactant: COc1ccc(C(=O)C(C)C(=O)CC(=O)c2ccccc2)cc1
Reactant: COc1cc(N)cc(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: COc1ccc(-c2c(C)c(=O)cc(-c3ccccc3)n2-c2cc(OC)cc(OC)c2)cc1

Procedure:
To 200 ml of chlorobenzene were added 3.1 g (0.01 mole) of 1-(4-methoxyphenyl)-2-methyl-5-phenyl-1,3,5-pentanetrione, 2.3 g (1.5 mole) of 3,5-dimethoxyaniline, 2.9 g (0.015 mole) of para-toluenesulfonic acid and 10 g of Molecular Sieves 5A, followed by refluxing the resulting mixture for 2 hours. After cooling the reaction mixture, solid matter was removed from the reaction mixture, followed by addition of 500 ml of chloroform thereto. The organic layer was washed first with 200 ml of 10% hydrochloric acid and then with water. The organic layer was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate by filtration, the solvent was distilled off and the residue was subjected to chromatography on a silica gel column (eluent: ethyl acetate). Upon washing the resultant crystals with ethyl acetate, 3.3 g of 1-(3,5-dimethoxyphenyl)-2-(4-methoxyphenyl)-3-methyl-6-phenyl-4(1H)-pyridinone p-toluenesulfonate having a melting point of 202°-204° C. was obtained.
Reaction SMILES: [C:1]1([C:7]2[C:8](O[C:11](=[O:13])[CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.O.C([O-])(=O)C.[Na+].O.[NH2:23][NH2:24]>C(O)(=O)C>[C:1]1([C:7]2[C:8](=[O:9])[NH:23][NH:24][C:11](=[O:13])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Reactant: NN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc(-c2ccccc2)c(=O)[nH][nH]1
Temperature: 7 °C
Yield: 34.4 %

Procedure:
Phenylmaleic anhydride (30 g, 0.17 mol), sodium acetate trihydrate (28 g, 0.21 mol) and hydrazine monohydrate (10 ml, 0.21 mol) were heated together at reflux in 40% acetic acid (600 ml) for 18 h. The mixture was cooled at 7° C. for 2 h, then filtered. The solid was washed with diethyl ether and dried in vacuo to give 11 g (34%) of the title compound: 1H NMR (250 MHz, DMSO-d6) δ 7.16 (1H, br s), 7.44 (5H, m), 7.80 (2H, br s); MS (ES+) m/e 189 [MH+].
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH:14]([C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1)[O:15][C:16](=[S:18])[CH3:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[CH:5]=1)[CH3:2].[CH2:28]([OH:30])[CH3:29]>C(OC(=O)C)(=O)C.[Pd]>[CH2:1]([N:3]([CH2:13][CH:14]([C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1)[O:15][C:16](=[S:18])[CH3:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:28](=[O:30])[CH3:29])[CH:5]=1)[CH3:2]
Reactant: CCN(CC(OC(C)=S)c1nc2ccccc2s1)c1cccc([N+](=O)[O-])c1
Reactant: CCO
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Product: CCN(CC(OC(C)=S)c1nc2ccccc2s1)c1cccc(NC(C)=O)c1

Procedure:
4.17 Parts of N-ethyl-N-(benzthiazolyl-2-thioacetoxyethyl)m-nitroaniline are dissolved in 75 parts of absolute ethanol and 25 parts of acetic anhydride and hydrogenated at 45° using 10% Pd/C as catalyst. The catalyst is filtered off and worked up in the usual manner to furnish N-ethyl-N-(benzthiazolyl-2-thio acetoxyethyl) m-acetamido aniline having the formula ##STR22##
Reaction SMILES: C(OC([NH:11][CH:12]1[C:15](=[O:16])[NH:14][CH:13]1[O:17][C:18](=[O:20])[CH3:19])=O)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[NH2:11][CH:12]1[C:15](=[O:16])[NH:14][CH:13]1[O:17][C:18](=[O:20])[CH3:19]
Reactant: CC(=O)OC1NC(=O)C1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OC1NC(=O)C1N

Procedure:
Acetic acid 3-benzyloxycarbonylamino-4-oxo-azetidin-2-yl ester (100 mg, 0.36 mmol) was hydrogenated on a Parr shaker over 10% palladium on carbon (100 mg) in ethyl acetate (20 ml) at 50 psi for 5 h. The mixture was filtered through Celite and evaporated. Acetic acid 3-amino-4-oxo-azetidin-2-yl ester was obtained in quantitative yield.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.Cl.[F:54][C:55]1[CH:56]=[C:57]([C@H:62]2[CH2:66][CH2:65][CH2:64][NH:63]2)[C:58]([CH3:61])=[N:59][CH:60]=1>CN(C=O)C>[F:54][C:55]1[CH:56]=[C:57]([C@H:62]2[CH2:66][CH2:65][CH2:64][N:63]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[N:3]=2)[C:58]([CH3:61])=[N:59][CH:60]=1
Reactant: Cc1ncc(F)cc1[C@H]1CCCN1
Reactant: CCOC(=O)c1cnn2ccc(O)nc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3C)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
To a solution of ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, Step A, 372 mg, 1.8 mmol) in DMF (10 mL) was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (874 mg, 1.98 mmol). The mixture was stirred at ambient temperature for 10 minutes then treated with DIEA (1.57 mL, 8.99 mmol) and (R)-5-fluoro-2-methyl-3-(pyrrolidin-2-yl)pyridine dihydrochloride (455 mg, 1.80 mmol). After stirring at ambient temperature for 4 hours the mixture was partitioned between 10% citric acid (50 mL) and EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic phases were washed successively with water (30 mL), saturated NaHCO3 (30 mL), water (30 mL) and brine (2×30 mL), then dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 1% MeOH/DCM to afford the product as white foam (480 mg, 72% yield). MS (apci) m/z=370.0 (M+H).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:27]=3[CH3:26])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reactant: Cc1cc(Cl)ccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1cc(Cl)ccc1C(=O)OC1CCN(C)C(=O)N1c1nnc(C(C)(C)C)s1

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)- 3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Methyl-4-chlorobenzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product tetrahydro- 1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-(2-methyl- 4-chlorobenzoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[CH:12]([C:14]([CH2:16][CH3:17])=[O:15])=[CH2:13].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[F:1][C:2]([F:10])([F:11])[CH2:3][CH2:4][C:5]([CH2:13][CH2:12][C:14](=[O:15])[CH2:16][CH3:17])([C:8]#[N:9])[C:6]#[N:7]
Reactant: C=CC(=O)CC
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(=O)CCC(C#N)(C#N)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
3.2 g of 2-(3,3,3-trifluoropropyl)malononitrile and 1.7 g of ethyl vinyl ketone were dissolved in 30 ml of acetone, 3.3 g of potassium carbonate was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.3 g of 2-(3,3,3-trifluoropropyl)-2-(3-oxopentyl)malononitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:24]3[CH2:23][CH2:22][N:21]([C:16]4[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=4)[CH2:26][CH2:25]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Product: Clc1ccc2nc(CN3CCN(c4ccc(Cl)c(Cl)c4)CC3)cn2c1
Yield: 41.6 %

Procedure:
Following the general procedure of Example 11 and making non-critical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4, Step 1; 0.493 g) and 1-(3,4-dichlorophenyl)piperazine (Aldrich; 0.636 g) are converted to 0.404 g of the title compound after chromatography on silica gel and crystallization from ethyl ether/hexane; mp 122.5-123.5° C.; MS m/z 394; IR (mineral oil) 1339, 1488, 804, 1072, 2807 cm-1 ; 1H NMR (CDCl3) δ2.72, 3.21, 3.77, 6.72, 6.94, 7.13, 7.26, 7.52, 8.14.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5](/[C:8](=[N:10]/[S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])/[CH3:9])=[CH:4][CH:3]=1.[CH3:17][Mg]Br.[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH:10][S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])([CH3:17])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: C/C(=N\S(=O)C(C)(C)C)c1ccc(Cl)nn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(NS(=O)C(C)(C)C)c1ccc(Cl)nn1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 24.7 %

Procedure:
Crude 2-methyl-propane-2-sulfinic acid[1-(6-chloro-pyridazin-3-yl)-eth-(E)-ylidene]-amide (56 mg, 0.22 mmol) was dissolved in dry THF (2.2 mL) and cooled to −20° C. under an atmosphere of inert gas. Methylmagnesium bromide (1.0 M in MePh/THF, 0.26 mL, 0.26 mmol) was added in one portion via syringe and the reaction was stirred −20° C. for 1.5 h. To the reaction mixture was added saturated aqueous NH4Cl (4 mL) and EtOAc (7 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×5 mL). The combined organic layers were dried over Na2SO4, concentrated and then purified by flash chromatography (silica, 0→4% MeOH/CH2Cl2). 15 mg of impure 2-methyl-propane-2-sulfinic acid[1-(6-chloro-pyridazin-3-yl)-1-methyl-ethyl]-amide was isolated as a light brown solid. This material was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[S:25][C:24]([CH3:26])=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[ClH:36]>C(Cl)Cl.O1CCOCC1>[ClH:34].[ClH:36].[NH2:7][CH:8]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[S:25][C:24]([CH3:26])=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1cc2ncnc(N3CCN(C(=O)C(Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)CC3)c2s1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc2ncnc(N3CCN(C(=O)C(N)Cc4ccc(Cl)cc4)CC3)c2s1
Reaction time: 4 h

Procedure:
To a solution of {1-(4-chlorobenzyl)-2-[4-(6-methylthieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred for 4 hours. The solvent was removed to afford the product 2-Amino-3-(4-chlorophenyl)-1-[4-(6-methylthieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride quantitatively. MS (ESI+) [M+H]+ 416.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([I:11])[CH:3]=1.O.O.Cl[Sn]Cl.[OH-].[Na+]>C(O)C>[I:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([I:11])[CH:3]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(I)cc(I)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(I)cc(I)c1
Temperature: 80 °C
Yield: 75.9 %

Procedure:
To a solution of 1,3-diiodo-5-nitro-benzene (15.80 g, 0.042 mol) in ethanol (200 mL) was added SnCl2.2H2O (28.50 g, 0.13 mol) portion wise at room temperature. The reaction mixture was heated under reflux at 80° C. for 1.5 h. After cooling to room temperature, the solvent was evaporated under reduced pressure and the crude solid thus obtained was basified with 4N NaOH solution to pH 12. The mixture was extracted with ethyl acetate (×3) and the combined organic layer was washed with brine solution and dried over Na2SO4. The solvent was removed under reduced pressure, to give the desired compound as a yellow solid (11.0 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:12][C:11]=2[C:21]2[NH:25][CH:24]=[N:23][N:22]=2)[OH:9])=[CH:4][CH:3]=1.Cl.[CH3:27]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:9][CH3:27])[C:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)[S:12][C:11]=2[C:21]2[NH:25][CH:24]=[N:23][N:22]=2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)c1cc(-c2ccncc2)sc1-c1nnc[nH]1
Reactant: CO
Agent: Cl
Product: COC(c1ccc(Cl)cc1)c1cc(-c2ccncc2)sc1-c1nnc[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of (4-chlorophenyl)[5-pyridin-4-yl-2-(4H-1,2,4-triazol-3-yl)-3-thienyl]methanol (100 mg, 0.271 mmol) in methanol (10 mL) was added conc. HCl (2.0 mL, 24 mmol) and the mixture was stirred at rt overnight. The reaction mixture was concentrated and basified by sodium bicarbonate, loaded on silica gel and purified by column chromatography (SiO2, elution with 0-5% MeOH in DCM) to afford the title compound (80 mg, 78%). LCMS: (AA) ES+ 383.3, 385.2; 1H NMR (300 MHz, d6-DMSO) δ: 8.70 (s, 1H), 8.57 (d, J=4.80 Hz, 2H), 7.79 (s, 1H), 7.68 (d, J=4.79 Hz, 2H), 7.56 (d, J=8.25 Hz, 2H), 7.38 (d, J=8.30 Hz, 2H), 6.50 (s, 1H), 3.31 (d, J=9.06 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=1.Cl[C:11]1[N:16]=[C:15]2[NH:17][N:18]=[CH:19][C:14]2=[CH:13][N:12]=1>>[NH:17]1[C:15]2=[N:16][C:11]([NH:1][C:2]3[CH:3]=[N:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=3)=[N:12][CH:13]=[C:14]2[CH:19]=[N:18]1
Reactant: Clc1ncc2cn[nH]c2n1
Reactant: Nc1cnn(CCO)c1
Product: OCCn1cc(Nc2ncc3cn[nH]c3n2)cn1

Procedure:
The title compound was made following Procedure D (Step i) using 2-(4-amino-1H-pyrazol-1-yl)ethanol and 6-chloro-1H-pyrazolo[3,4-d]pyrimidine to form 2-(4-((1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)ethanol. This was followed by Procedure D (Step ii) using 4-(3-(bromomethyl)-2,4-difluorophenyl)morpholine. 1H NMR (d6-DMSO) δ 9.86 (s, 1H), 8.88 (s, 1H), 8.17 (br s, 1H), 7.98 (s, 1H), 7.65 (s, 1H), 7.14-6.97 (m, 2H), 5.56 (s, 2H), 4.88 (t, 1H), 4.18-4.09 (m, 2H), 3.77-3.73 (m, 2H), 3.70 (t, 4H), 2.92 (t, 4H); LC-MS method B, (ES+) 457.2, RT=6.98 min.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:15][CH2:14][C:8]2[N:9]=[N:10][C:11](Cl)=[CH:12][C:7]=2[CH2:6]1)=[O:4].O.[NH2:17][NH2:18]>>[CH3:1][O:2][C:3]([N:5]1[CH2:15][CH2:14][C:8]2[N:9]=[N:10][C:11]([NH:17][NH2:18])=[CH:12][C:7]=2[CH2:6]1)=[O:4]
Reactant: COC(=O)N1CCc2nnc(Cl)cc2C1
Reactant: NN
Solvent: O
Product: COC(=O)N1CCc2nnc(NN)cc2C1

Procedure:
16.5 g of 3-chloro-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid methyl ester and 70 cc of hydrazine hydrate are heated in a water bath for 1 hour. The title compound has a M.P. of 178°-180° (decomp., from acetonitrile).
Reaction SMILES: [S:1]1[C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[Cl:13][CH2:14][C:15]([CH2:17]Cl)=O>>[S:1]1[C:5]([C:6]2[O:7][CH:17]=[C:15]([CH2:14][Cl:13])[N:8]=2)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1cc2ccccc2s1
Product: ClCc1coc(-c2cc3ccccc3s2)n1
Yield: 33 %

Procedure:
In substantially the same manner as in Reference Example 31, 2-benzo[b]thiophenecarboxamide was allowed to react with 1,3-dichloroacetone to give 2-(2-benzo[b]thienyl)-4-chloromethyloxazole. The yield was 33%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 150-151° C.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[C:26]([O:30][C:31](=[O:51])[NH:32][C:33]([CH3:50])([CH3:49])[CH2:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:51])[NH:32][C:33]([CH3:50])([CH3:49])[CH2:34][N:35]1[CH:39]=[C:38]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]([F:23])([F:21])[F:22])[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:37]=[N:36]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1)NC(=O)OC(C)(C)C
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)(Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1)NC(=O)OC(C)(C)C

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with {1,1-Dimethyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-ethyl}-carbamic acid tert-butyl ester to give [1,1-Dimethyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethyl]-carbamic acid tert-butyl ester. MS (ESI+) 590.2.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]2[C:44]([CH:45]=1)=[N:43][N:42]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:41]=2>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:38]=[CH:39][C:40]3[C:44]([CH:45]=2)=[N:43][N:42]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:41]=3)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCn1cc2ccc(CCl)cc2n1
Product: COCCCn1cc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc2n1

Procedure:
Analogously to Method D, 0.178 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.090 g of 6-chloromethyl-2-(3-methoxypropyl)-2H-indazole are reacted. The title compound is obtained as a colourless oil. Rf=0.15 (2:1 EtOAc-heptane); Rt=5.80.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](OCC)[N:7]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13]>C1(C)C(C)=CC=CC=1>[NH2:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([NH:13][CH2:12][CH2:11][NH2:14])[N:7]=1
Reactant: NCCN
Reactant: CCOc1cnnc(N)n1
Solvent: Cc1ccccc1C
Product: NCCNc1cnnc(N)n1
Temperature: 120 °C
Reaction time: 3.5 h

Procedure:
To a slurry of 3-amino-5-ethoxy-1,2,4-triazine (1.40 g, 0.0100 mol) in xylene (5 ml) was added ethylenediamine (1.00 ml, 0.0150 mol). The mixture was stirred at 120° C. for 3.5 hours, cooled, and concentrated to dryness in vacuo. The residue was stirred under ether, filtered off, and dried to give the title product, 16, (1.47 g, 95%, m.p. 186°-191° C.). TLC (20% methanol/chloroform/ammonia, silica): Rf =0.14.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[CH2:30]([OH:34])[CH2:31][CH2:32][CH3:33]>O1CCOCC1.CN(C=O)C>[CH2:30]([O:34][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1)[CH2:31][CH2:32][CH3:33]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Reactant: CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cn1

Procedure:
From 6-chloro-N-(4-methoxy-7-mopholin-4-yl-benzothiazol-2-yl)-nicotinamide with sodium hydride and butanol in dioxane and DMF. ES-MS m/e (%): 465 (M+Na+, 40), 443 (M+H+, 100).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH2:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=2[C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[N:31][CH:32]=2)=[CH:13][CH:12]=1>C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH2:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=2[C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[N:31][CH:32]=2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2ccc(OC)cc2CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C(=O)NCCC(=O)O)nc2)c(CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)c1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.20 mL, 0.60 mmol) was added to a THF solution (3 mL) of ethyl 3-(5-(2-(((2′,4′-dichloro-[1,1′-biphenyl]-4-yl)amino)methyl)-4-methoxyphenyl)picolinamido)propanoate (116 mg, 0.20 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off and dried in vacuo to yield the title compound.
Reaction SMILES: [N:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][N:11]3[CH:19]=[C:18]4[C:13]([N:14]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:15](=[O:22])[N:16]([CH3:21])[C:17]4=[O:20])=[N:12]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH3:30][S:31]SC.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C(Cl)Cl.C1COCC1>[N:1]1([C:6]2[CH:29]=[CH:28][C:9]([CH2:10][N:11]3[C:19]([S:31][CH3:30])=[C:18]4[C:13]([N:14]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:15](=[O:22])[N:16]([CH3:21])[C:17]4=[O:20])=[N:12]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cn1c(=O)c2cn(Cc3ccc(-n4cncn4)cc3)nc2n(CC(C)(C)C)c1=O
Reactant: CSSC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CSc1c2c(=O)n(C)c(=O)n(CC(C)(C)C)c2nn1Cc1ccc(-n2cncn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(4-(1H-1,2,4-triazol-1-yl)benzyl)-5-methyl-7-neopentyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (52 mg, 0.132 mmol) and methyl disulfide (12 μL, 0.13 mmol) are dissolved in 2 mL of anhydrous CH2Cl2, and then 1.0 M LiHMDS (190 μL, 0.19 mmol) in THF is added dropwise. The reaction mixture is stirred at room temperature for 30 min, and then quenched with saturated ammonium chloride aqueous solution. After routine workup, the obtained crude product is purified by silica gel column chromatography to give pure product as off-white solids. MS (ESI) m/z 440.2 [M+H]+.