Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[S:30][C:11]3=[N:12][C:13]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:14][C:15](=[O:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:31]1[CH:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>O1CCCC1>[O:16]=[C:15]1[N:10]2[N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:37][C:34]4[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=4)[CH:3]=3)[S:30][C:11]2=[N:12][C:13]([N:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:21][CH2:22]2)=[CH:14]1
Reactant: O=Cc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)n3nc(-c4cccc(N)c4)sc3n2)CC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(=O)n3nc(-c4cccc(NCc5ccncc5)c4)sc3n2)CC1
Temperature: 100 °C

Procedure:
To a solution of tert-butyl 4-(2-(3-aminophenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (60 mg, 0.140 mmol, 1.0 equiv) and 4-pyridinecarboxaldehyde (0.013 mL, 0.140 mmol, 1.0 equiv) in 1 mL tetrahydrofuran in a microwave vial is added dibutyltin dichloride (4.25 mg, 0.014 mmol, 0.1 equiv) and Phenylsilane (0.035 mL, 0.280 mmol, 2.0 equiv). The mixture is heated in a microwave reactor for 10 min at 100° C. Upon completion, the reaction mixture is filtered through a thiol-SPE column (Stratospheres) and concentrated in vacuo to give crude tert-butyl 4-(5-oxo-2-(3-(pyridin-4-ylmethylamino)phenyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate as a yellow oil. The residue is then taken on crude to the next reaction, which followed the same procedure as above to give 7-(piperazin-1-yl)-2-(3-(pyridin-4-ylmethylamino)phenyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (10 mg, 18%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[F:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=3[F:20])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15]
Reactant: COc1cccc(B(O)O)c1F
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(I)c(F)ccc12
Product: COc1cccc(-c2c(F)ccc3c(N)c(C(=O)NC4CC4)nnc23)c1F
Yield: 56.3 %

Procedure:
Using Method A, 4-amino-7-fluoro-8-iodo-N-cyclopropyl-cinnoline-3-carboxamide (178 mg, 0.48 mmol) and 2-fluoro-3-methoxyphenylboronic acid (162 mg, 0.96 mmol) were reacted. After purification the title compound (100 mg, 56% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.04(d, J=4.8 Hz, 1H), 8.59 (m, 1H), 7.26 (m, 2H), 7.02 (m,1H), 3.90 (s, 3H), 2.93 (m, 1H), 0.69 (m, 4H). MS APCI, m/z=371.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:27])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.Cl>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:27])[CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([CH2:25][CH3:26])([CH3:23])[CH3:24])=[CH:20][CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(C(C)(C)CC)cc1)C(=O)c1cccc(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(C(C)(C)CC)cc1)C(O)c1cccc(Cl)c1
Reaction time: 0.33 h

Procedure:
While stirring zinc chloride (4.91 g, 36.0 mmol) in diethyl ether (50 ml), sodium borohydride (2.73 g, 72.0 mmol) was added at room temperature, and the mixture was stirred as it was for 2 hrs. Insoluble material in the mixture was removed by filtration and washed with diethyl ether to give a solution of zinc borohydride in diethyl ether. To the obtained solution was added a solution of ethyl 3-(3-chlorophenyl)-3-oxo-2-[4-(tert-pentyl)benzyl]propionate (6.969 g, 18.01 mmol) in diethyl ether (30 ml) under ice-cooling, and the mixture was stirred as it was for 20 min. To the reaction solution was added dilute hydrochloric acid by small portions to decompose excess zinc borohydride, and the mixture was extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1−6/1) to give the objective substance.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].Cl[C:12]1[C:13](Cl)=[C:14]([CH3:19])[CH:15]=[CH:16][C:17]=1[CH3:18]>>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:18][C:17]1[CH:16]=[CH:15][C:14]([CH2:19][O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]=[CH:2][CH3:3])=[CH:13][CH:12]=1)=[CH:2][CH3:3]
Reactant: C=CCc1ccccc1O
Reactant: Cc1ccc(C)c(Cl)c1Cl
Product: CC=Cc1ccccc1OCc1ccc(COc2ccccc2C=CC)cc1

Procedure:
α,α'-bis-(ortho-propenylphenoxy)-para-xylene is prepared in a procedure similar to Example I, except that 459.3 grams (3.4 moles) of 2-allylphenol is employed along with 300 grams (1.7 mole) of dichloro-para-xylene to yield 597 grams (95% yield) of a white crystalline solid having a melting point of 50°-53° C.
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:16]([N:18]1[C@@H:30]2[C@@H:21]([C@H:22]([C:31]3[N:32](C(OCC4C=CC=CC=4)=O)[CH:33]=[CH:34][CH:35]=3)[NH:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=32)[CH2:20][CH2:19]1)=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[NH:32]1[CH:33]=[CH:34][CH:35]=[C:31]1[C@@H:22]1[C@@H:21]2[CH2:20][CH2:19][N:18]([C:16]([C@H:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C@H:10]3[NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:17])[C@@H:30]2[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH:23]1
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3cccn3C(=O)OCc3ccccc3)Nc3ccccc3[C@@H]21)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@H]2[C@@H](c3ccc[nH]3)Nc3ccccc3[C@H]21)c1ccccc1
Reaction time: 2 h
Yield: 20.4 %

Procedure:
Benzyl 2-((3aR*,4R*,9bR*)-1-{[(1S,2R)-2-(benzoylamino)cyclohexyl]carbonyl}-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-4-yl)-1H-pyrrole-1-carboxylate (407 mg, 0.67 mmol) was dissolved in methanol (3 ml), 10% palladium on carbon (50% aqueous, 240 mg) was added, and the mixture was stirred under hydrogen atmosphere for 2 hrs. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography using silica gel (30 g), and eluted with hexane-ethyl acetate (9:1-4:1, v/v). The title compound (3aR,4R,9bR) (64 mg, 20%) was obtained as a colorless amorphous form from the first eluted fraction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[C:12]([NH:15][NH2:16])(=[O:14])[CH3:13]>C1COCC1>[C:12]([NH:15][NH:16][C:10]([NH:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[Cl:1])=[S:11])(=[O:14])[CH3:13]
Reactant: CC(=O)NN
Reactant: Cc1ccc(Cl)c(N=C=S)c1
Solvent: C1CCOC1
Product: CC(=O)NNC(=S)Nc1cc(C)ccc1Cl

Procedure:
One tenth mole, 18.3 g., of 2-chloro-5-methylphenylisothiocyanate and 11.0 g. (0.15 mole) of acetylhydrazine were refluxed for 7 hours in 500 ml. of THF. After cooling, the insoluble product was collected by filtration. The crude product was collected by filtration. The crude product was washed with water, filtered and dried. The yield was 25 g. of 1-acetyl-4-(2-chloro-5-methylphenyl)-3-thiosemicarbazide, m.p. about 145°-157° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH2:16]O)[N:6]=1.P(Br)(Br)[Br:20]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]([CH2:16][Br:20])[N:6]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)Cc1nn(CO)c(=O)c2ccccc12
Solvent: ClCCl
Product: COC(=O)Cc1nn(CBr)c(=O)c2ccccc12

Procedure:
A solution of methyl-3-hydroxymethyl-4-oxophthalazin-1-ylacetate (0.49 g), phosphorous tribromide (0.54 g) and methylene chloride (10 ml) was stirred at room temperature for 2 hours. The solution was poured onto ice-water (5 ml) and the separated methylene chloride layer was collected, dried and evaporated to obtain a light yellow solid (yield: 0.43 g; m.p. 98°-104° C.).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+].[Cl-].[Ca+2:22].[Cl-]>O>[Ca:22].[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [Ca+2]
Agent: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: [Ca]
Reaction time: 0.5 h

Procedure:
2.0 g 2-butyl-5-methanesulfonamido-benzofuran II was added to the solution of 0.5 g 85% potassium hydroxide in 20 ml water. The reaction mixture was stirred for 30 minutes. To the obtained solution 0.89 g calcium chloride dissolved in 5 ml water was added in 10 minutes, the resulting suspension was stirred at 20-25° C. for 1 hour and then at 5° C. for 2 hours. The product was filtered off and dried.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][CH2:16][C:17](Cl)=[O:18].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:17](=[O:18])[CH2:16][O:15][CH3:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)N1CCN(Cc2ccccc2)CC1

Procedure:
Amine preparation: a mixture of benzylpiperazine, methoxyacetyl chloride and triethylamine was stirred in DCM for 2 h to yield 1-(4-benzyl-piperazin-1-yl)-2-methoxy-ethanone following standard work up.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[C:12](=O)[NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>C1COCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(N)=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H]1CN
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a cold (0° C.) solution of (2S)-carbamoyl-azetidine-1-carboxylic acid tert-butyl ester (8 g) in dry THF (200 mL) was added dropwise 1M BH3 solution in THF (160 mL). The reaction mixture was stirred at RT under nitrogen for 20 h and cooled to 0° C. Then was added carefully 1M HCl solution (200 mL) and brine and the mixture was extracted with EA (3×). The aqueous phase was basified with 2M NaOH solution (pH 10), extracted with EA (3×). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to yield the title compound light yellow oil (1.9 g, 25%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.[C:30](#[N:33])[CH:31]=[CH2:32]>CO>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([F:22])=[CH:11][C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:32][CH2:31][C:30]#[N:33])[CH2:20][CH2:21]3)=[C:13]([CH3:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: C=CC#N
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CO
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCC#N)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (20 mg, 0.048 mmol) in MeOH (0.5 mL) was added acrylonitrile (5 mg, 0.096 mmol). The resulting mixture was stirred at room temperature for 14 h and then purified directly by preparative RP-HPLC to provide 3-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-5-fluoro-2-methylphenyl)piperidin-1-yl)propanenitrile; ESMS m/z 469.2 (M+H+).
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[CH3:16][OH:17]>>[CH3:16][O:17][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CO
Agent: [Na]
Product: COc1ccc([N+](=O)[O-])cc1C(F)(F)F
Yield: 99 %

Procedure:
Sodium (11.78 g, 0.512 mol) was dissolved in dry methanol (1 l) and to the resulting solution was added a solution of 1-chloro-4-nitro-2-trifluoromethyl-benzene (96.22 g, 0.427 mol) in methanol (100 ml). The reaction mixture was refluxed for 3 h then cooled and evaporated in vacuo. The residue was partitioned between water (500 ml) and dichloromethane (3×400 ml). The combined organic extracts were dried (Na2SO4) and evaporated to give the title compound (93.76 g, 99%) as a white solid.
Reaction SMILES: [NH2:1][C:2]([CH2:40][CH3:41])([CH2:38][CH3:39])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[CH:18]3[CH2:19][CH2:20][CH:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4].[Cl:42][C:43]([Cl:48])([Cl:47])[C:44](Cl)=[O:45].CCN(C(C)C)C(C)C>>[Cl:42][C:43]([Cl:48])([Cl:47])[C:44]([NH:1][C:2]([CH2:40][CH3:41])([C:3]([N:5]1[CH2:10][CH2:9][C:8]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)([CH2:11][CH2:12][N:13]2[C@H:18]3[CH2:19][CH2:20][C@@H:14]2[CH2:15][CH:16]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[CH2:17]3)[CH2:7][CH2:6]1)=[O:4])[CH2:38][CH3:39])=[O:45]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CCC(N)(CC)C(=O)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2cccc(F)c2)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)(NC(=O)C(Cl)(Cl)Cl)C(=O)N1CCC(CCN2[C@@H]3CC[C@H]2CC(n2c(C)nc4ccccc42)C3)(c2cccc(F)c2)CC1
Yield: 54.2 %

Procedure:
2-Amino-2-ethyl-1-(4-(3-fluoro-phenyl)-4-{2-[3-(2-methyl-benzoimidazol-1-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-ethyl}-piperidin-1-yl)-butan-1-one (0.100 g, 0.178 mmol), trichloroacetyl chloride (0.032 g, 0.178 mmol) and DIEA (0.069 g, 0.534 mmol) as outlined in procedure for procedure for Example 890 to give title compound, 2,2,2-trichloro-N-{1-ethyl-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]propyl}acetamide (0.068 g, 54%). ES-LCMS m/z 706 (M+1).
Reaction SMILES: [C:1]([C:5]1[C:9]([Cl:10])=[C:8]([C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:17]=[C:16]([O:27][CH3:28])[C:15]=2[N+:29]([O-])=O)=[O:12])[N:7]([CH3:32])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C>[NH2:29][C:15]1[C:16]([O:27][CH3:28])=[N:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])=[CH:19][C:14]=1[NH:13][C:11]([C:8]1[N:7]([CH3:32])[N:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[C:9]=1[Cl:10])=[O:12]
Reactant: COc1nc(-c2ccccc2Cl)cc(NC(=O)c2c(Cl)c(C(C)(C)C)nn2C)c1[N+](=O)[O-]
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: COc1nc(-c2ccccc2Cl)cc(NC(=O)c2c(Cl)c(C(C)(C)C)nn2C)c1N
Reaction time: 3 h

Procedure:
A 2.25 L plastic coated Parr bottle was charged with 3-tert-butyl-4-chloro-N-(6-(2-chlorophenyl)-2-methoxy-3-nitropyridin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide (55.30 g, 0.115 mol) and ethyl acetate (0.55 L). To the resulting slurry was added a slurry of 5% Pt(Sulfided)/C (2.80 g) in ethyl acetate (˜20 mL). The resulting mixture was agitated under 35-40 psi hydrogen gas, recharging with hydrogen gas as needed. After 3 h, hydrogen uptake ceased. The resulting mixture was filtered through CELITE to remove catalyst and the filter cake washed with ethyl acetate. The filtrate was concentrated to yield N-(3-amino-6-(2-chlorophenyl)-2-methoxypyridin-4-yl)-3-tert-butyl-4-chloro-1-methyl-1H-pyrazole-5-carboxamide as a off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 1.42 (s, 9H), 3.98 (br. s., 2H), 4.06 (s, 3H), 4.15 (s, 3H), 7.27-7.35 (m, 2H), 7.44 (dd, J=7.83, 1.22 Hz, 1H), 7.55 (s, 1H), 7.63 (dd, J=7.58, 1.71 Hz, 1H), 8.54 (br. s., 1H)
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[N:4][CH:3]=1.[H][H]>CO.[Pd].CCOC(C)=O>[N:9]1[C:10]2[CH2:11][CH2:2][CH2:3][NH:4][C:5]=2[C:6]([O:12][C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: Nc1ccc(Oc2ccnc3cc(Br)cnc23)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccnc3c2NCCC3)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-(7-bromo-1,5-naphthyridin-4-yloxy)benzenamine (0.150 g, 0.474 mmol) in MeOH (7 mL) at RT was added a suspension of 10% palladium on carbon (0.0505 g, 0.474 mmol) in EtOAc (2 mL). The mixture was subjected to an atmosphere of hydrogen (balloon) and stirred overnight. After 18 hrs, the mixture was filtered over celite and concentrated in vacuo. The resulting tan foam, crude 4-(5,6,7,8-tetrahydro-1,5-naphthyridin-4-yloxy)benzenamine, was advanced without further purification. MH+=242.2@0.49 min
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27]N=4)[C:11]=3[N:12]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:31]([S-])C.[Na+].O.C(OCC)(=O)C>CN(C)C=O>[N:15]1([C:13]2[N:14]=[C:9]([C:5]3[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=3)[C:10]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]4[CH:31]=[CH:27][N:28]=[CH:29][CH:30]=4)[C:11]=3[N:12]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: CC[S-]
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCCN3c2ccncn2)c1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCCN3c2ccncc2)c1
Temperature: 150 °C
Yield: 43.5 %

Procedure:
A solution of 4-(3-methoxyphenyl)-2-morpholin-4-yl-8-pyrimidin-4-yl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine (0.50 g, 1.24 mmol) in dimethylformamide (5 ml) was heated to 150° C., and sodium ethanethiolate (1.04 g, 12.4 mmol) was added for every 15 minutes in 3 portions. After heating at 150° C. for 2 hours, sodium ethanethiolate (1.04 g, 12.4 mmol) was added, followed by heating for further 15 minutes. After cooling the reaction mixture, water (5 ml) and ethyl acetate (20 ml) were added, to filter off the deposited precipitate. The crude product was purified by silica column chromatography (dichloromethane/methanol=95/5), to obtain the desired compound as a pale brown solid (0.21 g, 43% yield).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1>O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]=1[N+:6]([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(C)c1ccc(Br)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of sulfuric acid (5.79 g, 59.03 mmol, 2.25 equiv) and nitric acid (2.48 g, 39.37 mmol, 1.50 equiv) was added into 1-bromo-4-tert-butylbenzene (5.6 g, 26.28 mmol, 1.00 equiv) while maintaining the temperature below 10° C. The resulting solution was stirred for 20 h at 25° C., poured into water and extracted with ether. The organic phase was dried over anhydrous sodium sulfate. After filtered and concentrated under reduced pressure, the residue was purified through a silica gel column with ethyl acetate/petroleum ether (1:200-1:50) to afford the title compound as a yellow liquid. 1H-NMR (400 MHz, DMSO-d6): δ ppm 1.361(s, 9H), 7.454(dd, J=2.4 Hz, J=8.4 Hz, 1H), 7.65(d, J=8.4 Hz, 1H), 7.848(d, J=2.4 Hz, 1H).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[N:5][C:4]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23](C)([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>O1CCOCC1>[CH3:2][C:3]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][C:4]=1[N:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nnn1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(N2CCN(C(=O)OC(C)C)CC2)nnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.8 %

Procedure:
4N hydrochloric acid solution in dioxane (3 ml) was added to 7 mg of 1-tert-butyl 4-[5-methyl-1-phenyl-1H-[1,2,3]triazol-4-yl]-piperazine-1-carboxylate followed by stirring at room temperature for 3 hours, the solvent was evaporated in vacuo therefrom, the resulting residue was dissolved in 1 ml of chloroform and, in a nitrogen atmosphere, 0.1 ml of isopropyl chloroformate and 0.2 ml of triethylamine were added thereto followed by stirring for one night at room temperature. After the solvent was evaporated in vacuo, the resulting residue was purified by a preparative thin-layer silica gel chromatography (chloroform:methanol=9:1) to give 2 mg of the title compound as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][N:9]=1.CS(C)=O.C(N(CC)CC)C.[NH4+].[Cl-]>ClCCl>[Cl:7][C:8]1[CH:13]=[C:12]([CH:14]=[O:15])[CH:11]=[CH:10][N:9]=1
Reactant: OCc1ccnc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1ccnc(Cl)c1
Temperature: -78 °C
Yield: 76 %

Procedure:
In a 250 mL tricol equipped with a low temperature thermometer and two equalizing dropping funnels was charged oxalyl dichloride (1.24 g, 9.81 mmol) in dichloromethane (15 mL) and this solution was stirred under N2 at −78° C. The first equalizing dropping funnel was connected to a nitrogen flow line and was charged with a solution of (2-chloropyridin-4-yl)methanol SLA 07152 (0.94 g, 6.54 mmol) with dichloromethane (15 mL). The other was charged with a solution of dimethyl sulfoxide anhydrous (1.7 mL, 19.63 mmol) in dichloromethane (2 mL) and this solution was added dropwise (25 min) in order to stabilize the temperature between −60° C. and -70° C. At the end of the addition the reaction solution was warmed to −60° C. over a period of 20 min then the solution of (2-chloropyridin-4-yl)methanol SLA 07152 was added dropwise (50 min) keeping the temperature between −50° C. and -60° C. in the reactor then the mixture reaction was warmed to −45° C. over a period of 30 min. The dropping funnel was washed with dichloromethane (2×5 mL) and charged with a solution of triethylamine (480 μl, 6.51 mmol) in dichloromethane (4 mL) which was added (10 min) to the reaction mixture and finally the reaction flask was allowed to warm to 0° C. over 10 min. The reaction solution was transferred to a 500 mL separatory funnel charged with 130 mL of a 5% aqueous NH4Cl solution. The two phases were separated the aqueous phase was extracted with dichloromethane (3×50 mL) and the combined organic phases were washed with 1 M aqueous phosphate buffer (pH=7; 4×100 mL), then dried over MgSO4, filtered and evaporated. 2-Chloropyridine-4-carbaldehyde SLA 07156 was obtained as an orange solid (0.740 g, 76% yield).