Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=2)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: OCc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OCc1cncc(-c2ccc(F)cc2)c1
Temperature: 85 °C
Yield: 84.4 %

Procedure:
To a solution of 3-bromo-5-hydroxymethyl-pyridine (3.3 g, 17.5 mmol) in toluene (35 ml) was added Pd(PPh3)4 (0.6 g, 0.52 mmol), an aqueous solution of Na2CO3 (17.5 ml of a 2M solution) and p-fluorphenylboronic acid (2.65 g, 19 mmol, dissolved in 8.5 ml EtOH). The mixture was heated at 80-90° C. for 1 hr and vigorously stirred. After the reaction was completed, the biphasic reaction mixture was cooled, the organic layer was collected and washed with saturated NaCl. The aqueous layer was washed with EtOAc and the combined organic layers were dried on Na2SO4. The drying agent was removed by filtration and the solvent was evaporated in vacuo to give a dark oil which was purified by flash chromatography on silica gel (eluent: CH2Cl2 /MeOH/NH4OH, 95/4.5/0.5) and yielded 3-(p-fluorophenyl)-5-hydroxymethyl-pyridine (3.0 g, 84%). The product was converted into its monohydrochloride salt; the residue was dissolved in Et2O and treated with 16.5 eq of ethanolic HCl. The product 3-(p-fluorophenyl)-5-hydroxymethyl-pyridinium hydrochloride Q4-OH.HCl precipitated as a white solid which was collected by filtration and subsequent drying.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:11])=[C:4]([NH2:10])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[CH:12]1([N:15]=[C:16]=S)[CH2:14][CH2:13]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[Br:1][C:2]1[C:3]2[N:11]=[C:16]([NH:15][CH:12]3[CH2:14][CH2:13]3)[NH:10][C:4]=2[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: Nc1cc(Cl)c(Cl)c(Br)c1N
Reactant: S=C=NC1CC1
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: Clc1cc2[nH]c(NC3CC3)nc2c(Br)c1Cl
Yield: 34.7 %

Procedure:
3-Bromo-4,5-dichloro-1,2-phenylenediamine (5.12 g, 20.0 mmol), cyclopropyl isothiocyanate (2.18 g, 21.98 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (11.0 g, 25.97 mmol) and pyridine (75 mL) were used according to general procedure I. The product was recrystallized from 1,4-dioxane to afford 2.23 g (53%) of a white solid. MS (CI): m/z 319 amu. Anal. Calcd for C10H8BrCl2N3-(0.35 C4H8O2): C, 38.92; H, 3.09; N, 11.94. Found: C, 39.17; H, 3.05; N, 11.94.
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[N:19]=[C:20]([I:21])[C:13]=12>ClCCl>[I:21][C:20]1[C:13]2[C:14](=[N:15][CH:16]=[N:17][C:12]=2[NH2:11])[N:18]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(I)nn2C1CCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.8 %

Procedure:
A mixture of trifluoroacetic acid/dichloromethane (20:80, 250 mL) was added to a solution of tert-butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (10.72 g, 24.1 mmol) in dichloromethane (100 mL) at 0° C. 15 minutes later, the ice-bath was removed and the reaction mixture was stirred at room temperature for 5 hours. The solvents were evaporated and the residue was dissolved in dichloromethane. Hydrochloric acid (5.0N) was added and the aqueous layer was washed with dichloromethane three times. Sodium hydroxide (50%) was added to adjust the pH to about 10. The suspension was lyophilized to reduce the volume to one third of the original volume. The solid was collect by filtration to give 3-iodo-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (8.109 g, 97%). 1H NMR (CDCl3) δ 1.81(m, 2H), 1.99 (m, 2H), 2.65 (m, 2H), 3.07 (m, 2H), 4.68 (m, 1H), 8.19 (s, 1H).
Reaction SMILES: [CH:1]1[C:15](=[O:16])[N:14]=[C:13]2[N:3]([C@@H:4]3[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@@H:5]3[O:12]2)[CH:2]=1.C1C=CN=CC=1.[FH:23].C([O-])([O-])=O.[Ca+2]>O1CCOCC1>[F:23][C@@H:5]1[C@H:6]([OH:11])[C@@H:7]([CH2:9][OH:10])[O:8][C@H:4]1[N:3]1[CH:2]=[CH:1][C:15](=[O:16])[NH:14][C:13]1=[O:12]
Reactant: F
Reactant: O=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Temperature: 0 °C
Yield: 79 %

Procedure:
The title compound is prepared via a modification of a literature procedure, J. Fox, et al., J. Org. Chem., Vol. 29, pp. 558-564 (1964). Thus, 2,2′-cyclouridine (5.65 g, 25 mmol) is treated with a solution of 70% hydrogen fluoride/pyridine (65 mL) in anhydrous dioxane (500 mL) at 120° C. in a sealed steel vessel for twenty hours. The reaction mixture is cooled to ice temperature, poured into ice (400 mL), and the pH is adjusted to 7 by addition of solid CaCO3. After the solvent is evaporated in vacuo (1 torr), the residue is dissolved in methanol, adsorbed onto silica gel, and purified by column chromatography using silica and ethyl acetatemethanol (v/v, 20:1) as eluent to give 2′-deoxy-2′-fluoro-uridine as a white solid (4.81 g, 79%). The 5′-DMT and 3′-cyanoethoxy-diisopropyl phosphoramidite derivatized nucleoside are obtained in accordance with the procedures of examples 65 and 66.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Br[C:11]1[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][C:19]2[S:20][C:21]([C:24]([NH:26][C:27]3[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:34])=[O:25])=[CH:22][N:23]=2)[CH:12]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:33][C:32]1[C:27]([NH:26][C:24]([C:21]2[S:20][C:19]([NH:18][C:13]3[CH:12]=[C:11]([N:7]4[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]4)[N:16]=[C:15]([CH3:17])[N:14]=3)=[N:23][CH:22]=2)=[O:25])=[C:28]([Cl:34])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1nc(Br)cc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1
Reactant: OCCN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1nc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)cc(N2CCN(CCO)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
1-(2-hydroxyethyl)piperazine (Compound 3) (65 g, 0.5 mol), 2-(6-bromo-2-methylpyrimidin-4-ylamino)-N-(2-chloro-6-methylphenyl)thiazole-5-formamide (Compound 14) (43.9 g, 0.1 mol), n-butanol (670 mL) and DIPEA (28.3 g, 0.2 mol) were mixed in reaction flask and reacted by refluxing for 7 h. After the reactant was cooled down to room temperature, crystals precipitated overnight. After air pump filtration, the cake was rinsed with n-butanol (500 mL) by stirring for 30 min. Then filtrated and the cake was dried to give white solid target Compound 1 (42.9 g, yield: 87.9%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].[OH-].[Na+].COC1C=CC(O)=CC=1>O1CCOCC1.O>[C:1]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: NCCCCCCCCCCCC(=O)O
Agent: COc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)C(=O)NCCCCCCCCCCCC(=O)O

Procedure:
The same procedure as described above is utilized with 5.4 g (0.052 mol) of methacryloyl chloride, 10 g (0.047 mol) of 12-aminododecanoic acid, 4.4 g (0.01 mol) of sodium hydroxide, and p-methoxyphenol in a mixed solvent (H2O:Dioxane=50:50) at 0°-5° C. Yield after recrystallized from ethyl acetate is 10 g (75%). Melting point 70.8°-72.4° C. NMR (DMSO-d6), 7.8 gamma (br s, 1H, NH), 5.5 gamma (br s, 1H, =CH2), 5.2 gamma (br s, 1H, =CH2), 3.0 gamma (t, 2H, NCH2), 2.1 gamma (t, 2H, CH2COOH), 1.7 gamma (s, 3H, CH3), 1.2 gamma (br s, 18H, (CH2)9).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:36].C(O)C.C(=O)([O-])[O-].[NH4+:44].[NH4+]>ClCCl.C(O)C>[ClH:36].[ClH:36].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:44])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: [NH4+]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 90 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 90% of theory, C27H28N6O3 (484.6); Rf value: 0.17 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=485; (M+2H)++=243; (M+H+Na)++=254.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]1[CH:22]=[CH:21][C:7]([CH:8]=[N:9][NH:10][C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].CCN(C1C=CC(/C=N/NC(C2C=CC(O)=CC=2)=O)=CC=1)CC.Br[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=1>>[CH2:23]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[N:9][N:10]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=2)[C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:21][CH:22]=1)[CH3:24]
Reactant: CCN(CC)c1ccc(C=NNC(=O)c2ccc(OC)cc2)cc1
Reactant: Cc1ccc(CBr)cc1
Agent: CCN(CC)c1ccc(/C=N/NC(=O)c2ccc(O)cc2)cc1
Product: CCN(CC)c1ccc(C=NN(Cc2ccc(C)cc2)C(=O)c2ccc(OC)cc2)cc1

Procedure:
Referring to FIG. 2, thus, a two-step procedure was explored whereby the amine of compound 1 was protected prior to conversion to compound 3. Specifically, the amino group of compound 1 was protected by reacting with α-bromo-p-xylene to give 4-methoxy-benzoic acid N′-(4-diethylamino-benzylidene)-N-(4-methyl-benzyl)-hydrazide (compound 2). This was followed by the simultaneous demethylation and deprotection of the N-benzyl group of compound 2 by ether cleavage with boron tribromide. This produced compound 3, with an overall yield of 27%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[S:12]([O:19]S(C(F)(F)F)(=O)=O)([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13]>N1C=CC=CC=1>[F:16][C:15]([F:18])([F:17])[S:12]([OH:19])(=[O:14])=[O:13].[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Oc1ccc2ccncc2c1
Solvent: c1ccncc1
Product: O=S(=O)(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.5 g (0.0103 mol) of 7-hydroxyisoquinoline and 5.3 ml of pyridine are cooled to 0° C. 1.86 ml of triflic anhydride are added thereto dropwise. The mixture is stirred at 0° C. for 1 hour and then at ambient temperature for 2 hours. It is poured into a water/ice mixture and extracted with ethyl acetate, the organic phase is dried and the solvent is evaporated under reduced pressure. The crude product is purified by chromatography on a column of silica gel, elution being carried out with a cyclohexane/ethyl acetate=7/3 mixture. 7-Hydroxyisoquinoline trifluoromethanesulfonate is obtained in the form of an oil. 1.65 g of this product are mixed under argon with 27.5 ml of anhydrous dimethylformamide, 41 mg of palladium acetate, 1.65 ml of anhydrous triethylamine and 1.38 g of N,N-diethylethanolamine vinyl ether. The mixture is heated at 80° C. for 36 hours. It is poured into a water/ethyl acetate mixture, the two phases are separated, the organic phase is washed with water and dried, and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elution being carried out with an ethyl acetate/methanol=9/1 mixture. 2-[2-(7-Isoquinolyl)ethenyl)oxy)]-N,N-diethyl-1-ethanamine is obtained. 1.5 g of this product are treated with 130 ml of water and 13 ml of 96% sulfuric acid. The mixture is heated at 60° C. for 4.5 hours and is poured into ice, a saturated aqueous NaHCO3 solution is added thereto and extraction is carried out with ethyl acetate. The organic phase is dried and the solvent is evaporated under reduced pressure. The title compound is obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#N.S(=O)(=O)(O)[OH:13].[OH2:17]>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:13])=[O:17]
Reactant: O=S(=O)(O)O
Reactant: O
Reactant: Cc1cccc(CC#N)c1Br
Product: Cc1cccc(CC(=O)O)c1Br
Yield: 90.8 %

Procedure:
2-(2-bromo-3-methylphenyl)acetonitril (8.0 g, 0.038 mol) was added to a mixture of water (60 ml) and sulfuric acid (50 ml) and the mixture was refluxed overnight. After cooling to room temperature water (200 ml) was added and the mixture was extracted twice with methylene chloride. The methylene chloride extracts were combined, washed twice with water, dried and evaporated under reduced pressure to give 7.9 g (90.8%) of the title compound.
Reaction SMILES: C(O)(C)C.[CH3:5][C:6]1([CH3:14])[CH:12]2[CH2:13][CH:7]1[CH2:8][CH2:9][C:10]2=[CH2:11].[S:15](=[O:18])([OH:17])[O-:16].[NH4+:19]>O>[C:10]1([CH2:11][S:15]([O-:18])(=[O:17])=[O:16])[CH2:12][CH2:13][C@H:7]([CH:6]([CH3:14])[CH3:5])[CH2:8][CH:9]=1.[NH4+:19]
Reactant: C=C1CCC2CC1C2(C)C
Reactant: O=S([O-])O
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)[C@@H]1CC=C(CS(=O)(=O)[O-])CC1
Reaction time: 22 h

Procedure:
Into a 1 liter flask equipped with magnetic stirrer were placed 450 ml isopropanol, 240 ml water and 54.4 grams (0.4 mole) β-pinene. Ammonium bisulfite, 105 grams (45%) was then added thereto. The mixture was stirred at 40°-45° C. for 22 hours. Thereafter, the solution was evaporated to dryness. Residue was extracted with methanol. The methanolic solution was filtered, and the resultant filtrate evaporated to dryness. Obtained were 84 grams product (85.8% purity; 77% yield).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10](/[C:13](/[CH3:18])=[CH:14]/[C:15]([OH:17])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:19].Cl.O.[CH3:22][N:23]([CH:25]=O)C>>[CH:22]1[C:11]2[C:10](=[C:9]([NH:19][C:15](=[O:17])/[CH:14]=[C:13](/[C:10]3[CH:9]=[CH:8][C:7]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:12][CH:11]=3)\[CH3:18])[CH:8]=[CH:7][CH:12]=2)[CH:13]=[CH:25][N:23]=1
Reactant: C/C(=C\C(=O)O)c1ccc(N2CCCCC2)cc1
Reactant: N
Reactant: CN(C)C=O
Agent: Cl
Solvent: O
Product: C/C(=C\C(=O)Nc1cccc2cnccc12)c1ccc(N2CCCCC2)cc1

Procedure:
The title compound was prepared using the procedure described in 142D using the product from Example 147A instead of the product from Example 142C. 1H NMR (300 MHz, d6-DMSO) 10.50 (s, 1H), 9.82 (s, 1H), 8.71 (d, 1H), 8.58 (d, 1H), 8.47 (d, 1H), 8.26 (d, 1H), 7.95 (m, 2H), 7.62 (m, 2H), 6.80 (s, 1H), 3.20 (m, 4H), 2.58 (s, 3H), 1.90-1.56 (m, 6H); MS (DCI/NH3) m/e 372 (M+H)+; Anal. Calcd. For C24H25N3O. 2.0 HCl. 2.0 H2O. 0.3 DMF: C 59.24; H 6.69; N 9.27. Found: C 59.44; H 6.83; N 9.24.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH3:19])=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.CCOC(C)=O>C(Cl)(Cl)(Cl)Cl.CCCCCC>[Br:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH2:19][Br:27])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)c(Oc2cc(Cl)cc(C#N)c2)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CBr)c2F)c1
Yield: 32.3 %

Procedure:
A mixture of 3-[(6-bromo-2-fluoro-3-methylphenyl)oxy]-5-chlorobenzonitrile (3.39 g, 9.95 mmol), NBS (1.949 g, 10.95 mmol) and AIBN (0.082 g, 0.498 mmol) in carbon tetrachloride (45 ml) was heated at reflux overnight. The reaction mixture was filtered through Celite and the filtrate was evaporated to dryness. Chromatography of the residue (EtOAc:hexane) gave 3-{[6-bromo-3-(bromomethyl)-2-fluorophenyl]oxy}-5-chlorobenzonitrile (1.35 g, 32.3% yield) as a colorless oil which crystallized to a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.44 (dd, 1H), 7.34 (s, 1H), 7.19-7.27 (m, 1H), 7.10-7.15 (m, 1H), 6.97 (s, 1H), 4.45 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.Cl.[CH:32]12[CH2:37][CH:36]1[CH2:35][NH:34][CH2:33]2>C1COCC1.C(N(CC)CC)C>[CH:32]12[CH2:37][CH:36]1[CH2:35][N:34]([C:9]1[N:8]=[C:7]([NH:6][CH2:5][C:4]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:13]([NH:15][CH2:16][C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[O:14])=[CH:11][N:10]=1)[CH2:33]2
Reactant: C1NCC2CC12
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ncccn2)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCc2ncccn2)cc1Cl
Yield: 39 %

Procedure:
In absolute anhydrous THF (10 mL) was dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulphinyl)-N-(pyrimidin-2-ylmethyl) pyrimidine-5-formamide (100 mg, 0.22 mmol). Several drops of triethylamine were added, then 3-azabicyclo[3.1.0]hexan hydrochloride salt (42 mg, 0.35 mmol) was added. The reaction mixture was heated to reflux overnight. The solvent was removed by rotary evaporation, and water was added, followed by extraction with DCM. The organic phase was dried over sodium sulfate and purified by silica gel column chromatography (DCM/methanol=20/1 to 10/1). 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide as a white solid was obtained (40 mg, 39% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](=[S:5])[S-:4].C[NH2+]C.C(=S)=S.[N+:13]([CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:15])=[O:14]>CO>[CH3:1][N:2]([CH3:6])[C:3](=[S:4])[S:5][CH:17]([CH2:16][N+:13]([O-:15])=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])C=Cc1ccccc1
Reactant: CN(C)C(=S)[S-]
Agent: C[NH2+]C
Solvent: S=C=S
Solvent: CO
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1ccccc1
Yield: 51 %

Procedure:
Dimethylammonium dimethyldithiocarbamate (16.6 grams, 0.10 mole), carbon disulfide (7.6 grams, 0.10 mole), and β-nitrostyrene (14.9 grams, 0.10 mole) were dissolved in methanol (50 ml.). A rapid exothermic reaction ensued and the product precipitated. The reaction temperature was held to 35° C. with ice cooling. After several hours at 25° C., the product was filtered off, washed with methanol, and dried in air. The crude product melted at ca. 103° C.-110° C. and weighed 22.9 grams (85%). Recrystallizations from hot methanol and from acetone-2-propanol solution (without heating) gave 13.8 grams of α-(nitromethyl)-benzyl dimethyldithiocarbamate melting at 104° C.-108.5° C. (prior sintering). The infrared spectrum was essentially identical to the spectrum of analytically pure material.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32](O)=[O:33])=[CH:26]2.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl.CN(C=O)C>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=4)[N:13]=[CH:12][C:11]3=[O:21])[CH2:6][CH2:7]1)=[O:33])=[CH:26]2
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=C(NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1)c1cc2cc(F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.6 %

Procedure:
A mixture of 1-[2-(4-aminopiperidin-1-yl)ethyl]-7-fluoroquinoxalin-2(1H)-one (Intermediate 140, 130 mg, 0.448 mmol), 5-fluoro-1H-indole-2-carboxylic acid (96.3 mg, 0.538 mmol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) (124 mg, 0.645 mmol) and 1-Hydroxybenzotriazole hydrate (HOBT) (87 mg, 0.645 mmol) in dichloromethane/DMF (4:1, 10 mL) was stirred for 2.5 hours at room temperature. The solvent was removed under reduced pressure and the residue was suspended in methanol, stirred for 45 minutes and then filtered to give title compound (161 mg).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([OH:12])[CH:6]=1)#[N:4].[CH2:13](I)[CH3:14].O>CN(C=O)C>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=1)#[N:4]
Reactant: Cc1ccc(C#N)cc1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C#N)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Into a reaction vessel was charged sodium hydride (4.8 g, 0.12 mol) and N,N′-dimethylformamide (40 ml), and a solution obtained by dissolving 4-cyano-2-hydroxytoluene (14) (13.3 g, 0.1 mol) in N,N′-dimethylformamide (40 ml) in an ice bath was dropped on this, and the solution was stirred for 1.0 hour at room temperature. Subsequently, ethyl iodide (18.7 g, 0.12 mol) was dropped in an ice water, and the solution was stirred for 1.5 hours at room temperature. To the reaction liquid was added water and extracted with ethyl acetate, then, washed with saturated saline, dried, and the solvent was distilled off under reduced pressure, to obtain 4-cyano-2-ethoxytoluene (15) (16.1 g, yield from (14) is 99%).
Reaction SMILES: [CH2:1]([NH:5][CH3:6])[CH2:2][CH2:3][CH3:4].[Cl:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:1]([N:5]([CH3:6])[S:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][Cl:7])(=[O:15])=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(Cl)CCCCCCl
Reactant: CCCCNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCN(C)S(=O)(=O)CCCCCCl
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
0.47 ml of N-butylmethylamine were added under an inert gas atmosphere to a solution of 410 mg of 5-chloropentane sulfonyl chloride in 10 ml of methylene chloride. The temperature rose from 13° C. to 26° C., and then after cooling to 0 to 5° C., 0.55 ml of triethylamine were added. The mixture was stirred at ambient temperature for 2 hours and the reaction medium was poured into an aqueous solution of 1M hydrochloric acid, extracted with methylene chloride, washed with water, then with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness under reduced pressure to obtain 486 mg of the expected product.
Reaction SMILES: [OH-].[Mg+2:2].[OH-].[C:4]([NH:7][C@H:8]([C:16]([OH:18])=[O:17])[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])(=[O:6])[CH3:5].CC(C)[O-].[Al+3:23].CC(C)[O-].CC(C)[O-]>O.C(O)(C)C>[Mg:2].[Al:23].[C:4]([NH:7][C@H:8]([C:16]([OH:18])=[O:17])[CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])(=[O:6])[CH3:5]
Reactant: [Mg+2]
Reactant: [Al+3]
Agent: CC(=O)NCCC[C@H](NC(C)=O)C(=O)O
Agent: CC(C)[O-]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: [Al]
Product: [Mg]
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Magnesium hydroxide (11.66 g.; 0.2 mole) suspended in water (20 cc.) is added to N,N'-diacetylornithine (172.8 g.; 0.8 mole) dissolved in distilled water (1,200 cc.) at 60° C. The reaction mixture is heated and stirred at 60° C for 30 minutes. Aluminium isopropoxide (81.6 g.; 0.4 mole) suspended in isopropanol (100 cc.) is added, and the mixture is then stirred and heated at 60° C for 30 minutes. After treatment of the reaction mixture as in Example 1, a mixed aluminium magnesium salt of N,N'-diacetyl-ornithine (175 g.) is obtained in the form of a white powder corresponding to the formula: ##EQU6## Al% = 5.45 (theory: 5.35) and Mg% = 2.36 (theory: 2.42).