Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:7](=O)[CH:6]=[CH:5][CH2:4][O:3]1.[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[NH:10][NH2:11].C(O)(=O)C>[Pd].CO>[C:14]([O:13][C:9]([NH:10][N:11]=[C:7]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH3:1])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC1OCC=CC1=O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC1OCCCC1=NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A methanol (9 mL) solution of (±)-2-methyl-2H-pyran-3(6H)-one (370 mg, 3.30 mmol) was treated with a suspension of 10% palladium on carbon (185 mg) in methanol (3 mL). The mixture was sparged under hydrogen and stirred for 45 minutes at ambient temperature. The mixture was sparged under nitrogen, treated with tert-butyl carbazate (436 mg, 3.30 mmol, 1 equiv) and acetic acid (0.756 mL, 13.2 mmol, 4 equiv) and sparged under hydrogen. After stirring for 1 hour, the mixture was sparged under nitrogen and filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with sodium bicarbonate (30 mL, saturated aqueous) and the organic extract was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 20:80; hexanes:ethyl acetate) to provide the titled compound.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([C:15]2[S:16][C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19](=[O:21])[N:20]=2)[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1>FC(F)(F)C(O)=O>[O:8]=[C:9]1[NH:14][C:13]([C:15]2[S:16][C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19](=[O:21])[N:20]=2)=[CH:12][CH:11]=[CH:10]1
Reactant: O=c1nc(-c2cccc(OCc3ccccc3)n2)sc2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: O=c1cccc(-c2nc(=O)c3ccccc3s2)[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.5 %

Procedure:
2-(6-(Benzyloxy)-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.15 g, 0.43 mmol) was dissolved in trifluoroacetic acid (10 ml), and the mixture was stirred at room temperature for 15 hrs. The solvent was evaporated, and the residue was recrystallized from chloroform-hexane to give the titled compound (0.07 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]3[S:23][C:24]4[CH2:30][C:29]5(OCC[O:31]5)[CH2:28][CH2:27][C:25]=4[N:26]=3)=[O:21])[CH2:16][CH2:15]1)(=[O:13])=[O:12])=[CH:5]2>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]3[S:23][C:24]4[CH2:30][C:29](=[O:31])[CH2:28][CH2:27][C:25]=4[N:26]=3)=[O:21])[CH2:16][CH2:15]1)(=[O:13])=[O:12])=[CH:5]2
Reactant: O=C(c1nc2c(s1)CC1(CC2)OCCO1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Solvent: CO
Product: O=C1CCc2nc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3)sc2C1
Reaction time: 16 h

Procedure:
In a 300-mL egg-plant type flask was charged l-[(5-chloroindol-2-yl)sulfonyl]-4-[(6,6-ethylenedioxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)carbonyl]piperazine (740 mg), followed by dissolution in methanol (150 mL). To the resulting solution was added p-toluenesulfonic monohydrate (100 mg), followed by heating under reflux. After 16 hours, the reaction was terminated and the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (silica gel: 75 g, ethyl acetate:hexane=1:1), whereby the title compound (110 mg) was obtained as a pale yellow amorphous solid.
Reaction SMILES: [CH:1]1([S:6][CH2:7][CH2:8][CH2:9][OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:20][S:21]([O:10][CH2:9][CH2:8][CH2:7][S:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCSC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCCSC1CCCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 3-(cyclopentylthio)-1-propanol (for example, as prepared for Intermediate 23) (1.05 g, 6.56 mmol) in dry DCM (5 ml) was added diisopropylethylamine (1.37 ml, 7.87 mmol), and then methanesulfonyl chloride (commercially available, for example, from Aldrich) (0.609 ml, 7.87 mmol) at 20° C. The reaction mixture was stirred at room temperature, under nitrogen for 2.5 h and then diluted with DCM (10 ml) and saturated sodium bicarbonate solution (20 ml). The phases were separated using a hydrophobic frit. The organic phase was concentrated in vacuo to afford the title compound (1.74 g): LCMS RT=3.13 min, ES+ve m/z 239 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([NH:13]C(=O)C(C)(C)C)=[CH:9][CH:8]=1.[OH-].[Na+]>Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2ncccn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(-c2ncccn2)cc1
Yield: 88.5 %

Procedure:
N-(4-(2-pyrimidinyl)phenyl)-2,2-dimethylpropanamide (1.41 g, 5.48 mmol) was boiled in 6 M hydrochloric acid (40 ml) for 2 h. The mixture was cooled and made strongly basic with NaOH (s) and extracted with CH2Cl2 (2×50 ml), dried (Na2SO4) and the solvent was removed in vacuo. Trituration with n-hexane gave 0.83 g (88%) of 4-(2-pyrimidinyl)aniline as a light-yellow powder. The product was further transformed by Method B and Method G (using cyclohexanecarboxaldehyde). M.p. 236-238° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[N:10][C:11]([O:16][CH2:17][C:18](=[O:20])[CH3:19])=[C:12]([CH:15]=2)[C:13]#[N:14])=[CH:4][CH:3]=1.[O-]CC.[Na+]>C(O)C>[NH2:14][C:13]1[C:12]2[C:11](=[N:10][C:9]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:15]=2)[O:16][C:17]=1[C:18](=[O:20])[CH3:19]
Reactant: CC(=O)COc1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Temperature: 25 °C

Procedure:
A solution of the product from Step A (0.126 g; 0.292 mmol) in ethanol (4 mL) was treated with sodium ethoxide (0.040 g; 0.584 mmol) and stirred at reflux for 1 hour. The reaction was allowed to cool to room temperature and quenched with saturated NaHCO3 solution. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethyl acetate-hexane gradient) gave the title compound. HPLC/MS: 430.9 (M+1), 432.9 (M+3); Rt=4.04 min.
Reaction SMILES: N#N.[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19].CCN(CC)CC>CN(C=O)C>[CH3:17][Si:18]([CH3:20])([CH3:19])[O:3][C:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH:9]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: N#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.00 g, 25.09 mmol) in dry DMF (25 mL) was added trimethylsilyl chloride (5.77 mL, 45.17 mmol) followed by Et3N (8.38 mL, 60.23 mmol) at rt. The reaction mixture was stirred at 80° C. for 24 h. The mixture was then cooled to rt, diluted with hexanes and washed with sat. aq. NaHCO3. The layers were separated and the org. layer dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (hexanes/EA, 9:1) to afford tert-butyl 4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate as a colorless oil. Rf (Hexanes/EA, 9:1)=0.50.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.[Cl:12][CH:13]([CH3:17])[C:14](Cl)=[O:15]>C1(C)C=CC=CC=1>[Cl:12][CH:13]([CH3:17])[C:14]([N:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]1[CH3:1])=[O:15]
Reactant: CC1NCCc2ccccc21
Reactant: CC(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: CC(Cl)C(=O)N1CCc2ccccc2C1C

Procedure:
A reaction vessel was charged with 50 ml toluene and 2.0 g 1-methyl-1,2,3,4-tetrahydroisoquinoline (prepared by procedure of Example 1--Procedure A). Then, 2.0 ml 2-chloropropionyl chloride was added gradually to the mixture. The reaction mixture was stirred and heated until a homogeneous solution appeared. The mixture was filtered, stripped of solvent, and subjected to Kugelrohr distillation (150° C. @ 0.25 mm Hg) to provide 2.8 g of a yellow oil product having the elemental analysis reported in Table I.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][NH:7][CH2:6][CH:5]([C:9]([OH:11])=[O:10])[CH2:4]1.[CH3:12][CH2:13]O>>[OH:2][CH:3]1[CH2:8][NH:7][CH2:6][CH:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4]1
Reactant: CCO
Reactant: O=C(O)C1CNCC(O)C1
Agent: Cl
Product: CCOC(=O)C1CNCC(O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Anhydrous HCl was bubbled through a suspension of (±)-5-hydroxypiperidine-3-carboxylic acid (5.6 g, 38.6 mmol) (according to the procedures as disclosed in J. Med. Chem., 25, 1157-1162, (1982)), cooled to 0° C. in EtOH (100 mL), until saturation was reached. The reaction mixture was warmed to room temperature, stirred overnight, then concentrated in vacuo. The crude salt was cooled to 0° C. in CHCl3 (80 mL), and anhydrous NH3 was bubbled through the solution. The resulting white precipitate was removed by vacuum filtration, and the filtrate was concentrated in vacuo to provide 6.6 g (99%) of (±) ethyl 5-hydroxypiperidine-3-carboxylate as a pale yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:10]([OH:36])=[C:11]2[C:16](=[CH:17][N:18]=1)[N:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14](=[O:26])[C:13]([C:27]1[CH:28]=[N:29][C:30]([N:33]([CH3:35])[CH3:34])=[N:31][CH:32]=1)=[CH:12]2)=[O:8].[OH-].[Na+].C1COCC1>CO>[CH2:19]([N:15]1[C:16]2[C:11](=[C:10]([OH:36])[C:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[O:8])=[N:18][CH:17]=2)[CH:12]=[C:13]([C:27]2[CH:32]=[N:31][C:30]([N:33]([CH3:35])[CH3:34])=[N:29][CH:28]=2)[C:14]1=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCNC(=O)c1ncc2c(cc(-c3cnc(N(C)C)nc3)c(=O)n2Cc2ccccc2)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)c1ncc(-c2cc3c(O)c(C(=O)NCCC(=O)O)ncc3n(Cc3ccccc3)c2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
A mixture of 3-{[1-benzyl-3-(2-dimethylamino-pyrimidin-5-yl)-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carbonyl]-amino}-propionic acid methyl ester (30 mg, 0.060 mmol), 2 M NaOH (2 mL), THF (2 mL) and MeOH (2 mL) was stirred at r.t. overnight. The mixture was concentrated to approximately one-third of its original volume. 1 M HCl was added until pH was about 4, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 16 mg of the title compound as a pale yellow solid. MS: (+) m/z 489.29 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].FC(F)(F)S(O[C:15]1[C:16]2[CH2:36][N:35]([C:37](=[O:39])[CH3:38])[CH2:34][CH2:33][C:17]=2[N:18]=[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[O:32][CH:31]=[N:30][CH:29]=3)=[CH:24][CH:23]=2)[N:20]=1)(=O)=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O>>[OH:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[C:15]1[C:16]2[CH2:36][N:35]([C:37](=[O:39])[CH3:38])[CH2:34][CH2:33][C:17]=2[N:18]=[C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[O:32][CH:31]=[N:30][CH:29]=3)=[CH:26][CH:27]=2)[N:20]=1
Reactant: OCC1CCCCN1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N3CCCCC3CO)c2C1
Yield: 56.4 %

Procedure:
1-(4-(2-(Hydroxymethyl)piperidin-1-yl)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (18.3 mg, 56.4%) was prepared from piperidin-2-ylmethanol and 6-acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (example 88a) according to the general procedure for amine substitution of tosylate on pyrimidines.
Reaction SMILES: CS([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][N:6]=1)(=O)=O.[NH2:15][NH2:16].[ClH:17]>C(O)C>[ClH:17].[NH:15]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][N:6]=1)[NH2:16]
Reactant: CS(=O)(=O)c1ccc(S(C)(=O)=O)nc1
Reactant: NN
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(NN)nc1
Temperature: 25 °C

Procedure:
The 2,5-bis-methanesulfonyl-pyridine and anhydrous hydrazine are stirred in ethanol for two hours between room temperature and reflux temperature. After cooling to room temperature the mixture is concentrated. The residual solid is washed with aqueous saturated NaHCO3 and water and collected by filtration to give a pale yellow solid. The solid is treated with 10% methanolic HCl and the precipitate is collected by filtration to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:24])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[C@H:13]([OH:25])[CH2:12][C@@H:11]1[OH:26].C(=O)([O-])[O-].[Ca+2].[OH-].[Na+].[BH4-].[Na+]>C([O-])(=O)C.[Hg+2].C([O-])(=O)C.O1CCCC1>[OH:25][C@@H:13]1[CH2:12][C@H:11]2[C@H:10]([CH2:9][C@H:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:27])[O:26]2)[C@H:14]1/[CH:15]=[CH:16]/[C@@H:17]([OH:24])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:22])[CH3:23]
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCC=C(C)C)[C@H](O)C[C@@H]1O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Product: COC(=O)CCCC[C@H]1C[C@@H]2[C@@H](/C=C/[C@@H](O)CCC=C(C)C)[C@H](O)C[C@@H]2O1
Reaction time: 0.17 h

Procedure:
A solution of 480 mg. of (5Z,13E)-(9S,11R,15S)-9,11,15-trihydroxy-19-methyl-5,13,18-prostatrienoic acid methyl ester (prepared according to DOS No. 2,635,985) and 530 mg. of mercury(II) acetate in 20 ml. of tetrahydrofuran is stirred with 200 mg. of pulverized calcium carbonate for 48 hours at 25°, and then combined in succession at 0° with 8 ml. of 1 N sodium hydroxide solution and a solution of 200 mg. of sodium borohydride in 8 ml. of 1 N sodium hydroxide solution. The mixture is stirred for 10 minutes and poured on 100 ml. of citrate buffer (pH 4), whereafter it is extracted three times with respectively 50 ml. of methylene chloride. The extract is shaken with sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated under vacuum. The residue shows, in the thin-layer chromatogram in the system ether/dioxane (9+1), two spots which are more nonpolar as compared to the starting material. For purposes of purification, the product is chromatographed on silica gel with the use of a hexane/ethyl acetate gradient, thus obtaining 100 mg. of the nonpolar isomer and 210 mg. of the polar isomer, both in the form of oils.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[N:12]1C=NC=N[CH:13]=1.N1CCCCC1>CO>[N:1]1[C:2]2[C:3](=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=2)[C:4]([OH:5])=[N:12][CH:13]=1
Reactant: c1ncncn1
Reactant: Nc1ccc(O)cc1C(=O)O
Solvent: C1CCNCC1
Solvent: CO
Product: Oc1ccc2ncnc(O)c2c1
Temperature: 0 °C
Yield: 72.3 %

Procedure:
A mixture of 2-amino-5-hydroxybenzoic acid (19.64 g, 128 mmol), 1,3,5-triazine (15.6 g, 192 mmol), and piperidine (9 mL, 92.4 mmol) were heated to 60° C. in methanol (60 mL) for 2 hours. After cooling to 0° C., the mixture was filtered. The solid was washed with cold methanol and dried under high vacuum to provide the product (15 g, 72%) as white solid.
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.Cl.[NH2:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[C:11](O)=[O:12]>C1COCC1>[NH2:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[CH2:11][OH:12]
Reactant: NC(C(=O)O)c1ccc(I)cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Product: NC(CO)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a stirred solution of lithium borohydride in THF (25.1 ml, 2 M solution) under an argon atmosphere was added dropwise chlorotrimethylsilane (12.7 ml). To the resulting suspension was added portionwise (RS)-amino-(4-iodo-phenyl)-acetic acid hydrochloride (6.30 g). Stirring was continued for 4 h and then the mixture was cooled to 0° C. and quenched by dropwise addition of methanol (4.5 ml). After stirring for 15 min at room temperature, water was added and the mixture was then diluted with ethyl acetate. Saturated brine was then added and the aqueous phase made alkaline (pH 14) by addition of 5 N aq NaOH. The phases were separated and the organic phase was washed with saturated brine and then dried over sodium sulphate and concentrated in vacuo to afford (RS)-2-amino-2-(4-iodo-phenyl)-ethanol (5.27 g, quant.) as a yellow solid. MS (ISP): 264.1 ([M+H]+).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH:9]([CH2:18][C:19]2[O:23][N:22]=[C:21]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[N:20]=2)[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>ClCCl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[C:1]1([S:7][CH2:8][CH:9]([CH2:18][C:19]2[O:23][N:22]=[C:21]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[N:20]=2)[CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)CC(CSc1ccccc1)Cc1nc(CCCCNc2ccccn2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC(CSc1ccccc1)Cc1nc(CCCCNc2ccccn2)no1
Yield: 99 %

Procedure:
The product from step 3 (50.4 mg, 0.10 mmoles) was stirred at RT in 1:1 mix of TFA and dichloromethane (2 mL) for 30 min. The solvent was removed under reduced pressure to give the product 56.2 mg (99%). 1H NMR (CD3OD) δ 7.84-7.79 (m, 2H), 7.39-7.35 (m, 2H), 7.32-7.26 (m, 2H), 7.22-7.17 (t, 1H), 6.95 (d, 1H), 6.82 (t, 1H), 3.37 (t, 2H), 3.22-3.02 (series of m, 4H), 2.81 (t, 2H), 2.65-2.57 (series of m, 2H), 2.49 (t, 1H), 1.92-1.82 (series of m, 2H), 1.80-1.72 (series of m, 2H); MS (ESI+) for C22H26N4O3S m/z 427 (M+H)+.
Reaction SMILES: C(OC(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH:11]1[CH:16]=[CH:15][CH2:14][N:13](C(OCC)=O)[N:12]1[C:22]([O:24]CC)=O)C.OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>O>[NH:13]1[CH2:14][CH2:15][CH:16]=[C:11]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:22](=[O:24])[N:12]12
Reactant: CCOC(=O)c1cccnc1C1C=CCN(C(=O)OCC)N1C(=O)OCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C1c2cccnc2C2=CCCNN12
Temperature: 0 °C

Procedure:
6.6 g of 2-(1,2-diethoxycarbonyl-1,2,3,6-tetrahydropyridazin-3-yl)nicotinic acid ethyl ester are mixed with 15 ml water and 60 ml of H2SO4 added with cooling. The reaction mixture is heated under nitrogen to 120° over 1 hr in a hot oil bath. The mixture is slowly poured into 125 g Na2CO3 and 250 g of ice and 125 ml of water. The alkaline mixture is filtered through celite and repeatedly extracted with ethylacetate (8×100 ml) and the extracts dried over MgSO4. After filtration the solvent is removed by evaporation under vacuum to yield the title compound which is recrystalized from CH3CN.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[OH:10][CH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=Cc1ccc(CO)cc1
Yield: 50.7 %

Procedure:
First, 2.06 g of terephthalaldehyde and 20 ml of ethanol were placed in a reaction vessel, to which 0.15 g of sodium borohydride was slowly added with stirring under ice cooling. After stirring at room temperature for 12 hours, the ethanol was evaporated. The residue was poured into diluted hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed twice with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 1.06 g (yield, 51%) of p-(hydroxymethyl)benzaldehyde.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:20]C.B(Br)(Br)Br>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:20]
Reactant: COc1cccc(-c2ccc3c(Br)c(OC)ccc3c2)c1
Agent: BrB(Br)Br
Product: Oc1cccc(-c2ccc3c(Br)c(O)ccc3c2)c1

Procedure:
The compound is prepared by reaction of 1-bromo-2-methoxy-6-(3-methoxyphenyl)naphthalene (500 mg, 1.46 mmol, 1 eq) with boron tribromide solution (7.3 ml, 7.3 mmol, 5 eq) according to method G. Purification of the raw product was not necessary. The desired product was obtained in quantitative yield (460 mg).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22]C)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([O:17]C)[CH:10]=1.Br.C(=O)([O-])O.[Na+]>O>[OH:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[OH:22])[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:17])[CH:10]=1
Reactant: COc1ccc(CNCc2ccc(OC)c(OC)c2)cc1OC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(CNCc2ccc(O)c(O)c2)cc1O
Temperature: 145 °C
Reaction time: 1 h

Procedure:
The crude bis(3,4-dimethoxybenzyl)amine (0.6 g) was combined with hydrobromic acid (6 ml of 48% w/w solution in water) and slowly heated with stirring, to 145° C. over 1 h. The reaction was maintained at 145° C. for 12 h, allowed to cool to room temperature, and poured into water (25 ml). The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate (25 ml). The organic layer was washed into water (2×25 ml), dried (Na2SO4) and the solvent removed under reduced pressure to afford DC-0073 as a solid, 160 mg.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OC)(C)(C)C.O>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1nccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Temperature: 110 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
Charge a 2 L 3-neck round bottom flask with 2,3-dichloropyrazine (78.7 g, 0.532 mol), piperazine-1-carboxylic acid t-butyl ester (100 g, 0.537 mol), potassium carbonate (88.2 g, 0.638 mol) followed by N,N-dimethylacetamide (0.780 L), and heat the resultant slurry to 110° C. under nitrogen with vigorous stirring. Cool to room temperature, add water (0.390 L) and methyl t-butyl ether (0.390 L), and stir the mixture for 60 min. Stop stirring and separate the layers. Wash the organic layer with water (2×200 mL), dry over MgSO4, filter and concentrate to give 145 g of 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester as a yellow syrup (91% yield). 1H NMR (400 MHz, chloroform-d) δ ppm-8.10 (s, 1H), 7.91 (s, 1H), 3.59 (m, 4H), 3.40 (m, 4H), 1.48 (s, 9H)