Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][N:8]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][O:11]3)[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ncc2c1
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1cnc2c(cnn2C2CCCCO2)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
To a solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (1.4 g, 7.2 mmol) and dihydropyran (3.3 mL, 36.0 mmol) in tetrahydrofuran (20 mL) was added (±)-camphorsulfonic acid (250 mg) and the reaction mixture was stirred at 65° C. for 16 hours. After cooling to room temperature it was diluted with ethyl acetate (250 mL), washed with saturated aqueous sodium bicarbonate (2×100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated. Gradient column chromatography (10% to 30% ethyl acetate in hexane) provided 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (1.8 g, 90%). MS (EI) for C11H12BrN3O: 283 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:23][C:24]2[CH:25]=[C:26]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:27]=[CH:28][CH:29]=2)=[N:4][CH:5]=[N:6][C:7]=1[N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:16]([N:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:7]1[N:6]=[CH:5][N:4]=[C:3]2[C:2]=1[NH:1][C:40](=[O:42])[N:23]2[C:24]1[CH:25]=[C:26]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])[CH:27]=[CH:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2N)c1
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)c1cccc(-n2c(=O)[nH]c3c(N(Cc4ccccc4)Cc4ccccc4)ncnc32)c1
Reaction time: 1 h
Yield: 230.1 %

Procedure:
To a stirred solution of tert-butyl 3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)phenyl(methyl)carbamate (22) (3.1 g, 6.08 mmol) and TEA (1.75 mL, 12.16 mmol) in dry DCM (40 mL) at 0° C. and under N2 atmosphere was added a solution of triphosgene (722 mg, 2.43 mmol) in dry DCM (20 mL) dropwise during 1 h. After the stirring was continued for 1 h, the reaction was quenched with water (10 mL). The organic layer was separated, washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0 to 20% ethyl acetate in petroleum ether) to give tert-butyl 3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (23) (3 g, 92%) as a light brown solid. LC-MS (ESI): m/z (M+1) 537.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[CH:7]=1)=[O:5].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][N:28]=1.C([Mg]Cl)(C)C>C1COCC1>[Cl:26][C:27]1[N:28]=[CH:29][C:30]([C:4]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=3)[CH:7]=2)=[O:5])=[CH:31][CH:32]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(C)n2)c2ccccc2c1=O
Reactant: Clc1ccc(I)cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1cccc(Cn2cc(C(=O)c3ccc(Cl)nc3)c(=O)c3ccccc32)n1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 800 mg (2.37 mmol) of 1-(6-methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 25 mL THF and 1.25 g (5.22 mmol) of 2-chloro-5-iodo-pyridine in 7 mL THF with 2.73 mL 2M isopropylmagnesium chloride. Yield: 635 mg of a white powder. LC-MSD, m/z for C22H16ClN3O2 [M+H]+=390.1, 392.0; HPLC retention time: 2.0 min.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][Cl:35].O>CN(C)C=O>[Cl:35][CH2:34][CH2:33][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
3-[7-Hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (45 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (187 mg) and 1-bromo-2-chloroethane (0.06 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (46 mg, yield 90%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:12][OH:13].[OH-].[Na+].Cl>O.CCO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[N:12][OH:13]
Reactant: O=Cc1cc(I)ccc1F
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1cc(I)ccc1F
Temperature: 0 °C
Yield: 82.7 %

Procedure:
To a mixture of 2-fluoro-5-iodobenzaldehyde (9.4 mmol) in H2O (5 ml), EtOH (5 ml), and ice (4.5 g) was added hydroxylamine hydrochloride (0.67 g, 10.3 mmol, 1.1 eq.). Then, 23.6 mmol of 50% NaOH (1 g in 1 ml H2O, 2.5 eq.) was added with stirring. Enough ice to keep the temperature at 25-30° C. was added. The reaction was stirred for 2 h, acidified with conc. HCl to pH 4 (ice was added to keep the temperature at 25-30° C.), and extracted with Et2O. The combined organic solution was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was chromatographed on silica gel using (1-10%) ethyl acetate in hexanes to give 2-fluoro-5-iodobenzaldehyde oxime (2.06 g, 78% over 2 steps).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([Cl:14])=[N:10][CH:11]=[CH:12][CH:13]=2)[C:5]([F:15])=[CH:4][N:3]=1.Cl.[CH3:17][NH2:18].C([O-])([O-])=O.[K+].[K+].C(O)(C(F)(F)F)=O>CCOC(C)=O.O.CS(C)=O>[Cl:14][C:9]1[C:8]([C:6]2[C:5]([F:15])=[CH:4][N:3]=[C:2]([NH:18][CH3:17])[N:7]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CN
Reactant: Fc1cnc(Cl)nc1-c1cccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CNc1ncc(F)c(-c2cccnc2Cl)n1
Temperature: 55 °C

Procedure:
To 2-chloro-4-(2-chloro-pyridin-3-yl)-5-fluoro-pyrimidine (178 mg, 0.73 mmol) and methylamine hydrochloride (74 mg, 1.1 mmol) was added K2CO3 (202 mg, 1.46 mmol) and DMSO (1.5 mL). The mixture was heated overnight in a sealed tube at 55° C. The mixture was cooled to RT, diluted with EtOAc and water, then neutralized with TFA (pH˜6-7). The organic layer was washed several times with water, dried over Na2SO4, filtered and concentrated to yield [4-(2-chloro-pyridin-3-yl)-5-fluoro-pyrimidin-2-yl]-methyl-amine. MS m/z=239 [M+1]+. Calc'd for C10H8ClFN4: 238.65.
Reaction SMILES: S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[C:12]([NH:31][C:32]1[S:33][CH:34]=[C:35]([C:37](=[N:41][O:42][CH3:43])[C:38]([OH:40])=O)[N:36]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[S:45]([CH2:48][C@H:49]1[NH:52][C:51](=[O:53])[C@H:50]1[NH2:54])[C:46]#[N:47]>C(Cl)Cl.C(N(CC)CC)C>[S:45]([CH2:48][C@H:49]1[NH:52][C:51](=[O:53])[C@H:50]1[NH:54][C:38](=[O:40])[C:37]([C:35]1[N:36]=[C:32]([NH:31][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[S:33][CH:34]=1)=[N:41][O:42][CH3:43])[C:46]#[N:47]
Reactant: N#CSC[C@H]1NC(=O)[C@H]1N
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1CSC#N)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
1 ml of triethylamine and then 1.38 g of tosyl chloride were added to a suspension of 3.19 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetic acid in 50 ml of methylene chloride and the mixture was stirred at room temperature for 40 minutes. A solution of 1.162 g of the product of Step C in 40 ml of methylene chloride and 2 ml of trietylamine were added to the mixture over 5 minutes and the mixture was stirred for 4 hours, was washed with water, then with water containing 4 ml of N hydrochloric acid, dried and evaporated to dryness. The residue was dissolved in ethyl acetate and the solution was iced and vacuum filtered. The product was washed with methanol and dried to obtain 0.709 g of racemate of syn isomer of cis 4-thiocyanatomethyl-3-[2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetamido]-2-oxo-azetidine. The mother liquors were evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 93-7 chloroform-methanol mixture yielded another 1.069 g of the said product.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[C:13]2[N:14]=[C:15]3[S:21][CH2:20][CH2:19][N:16]3[C:17](=[O:18])[C:12]=2[CH:11]=[N:10]1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:6]([CH2:8][N:9]1[C:13]2[N:14]=[C:15]3[S:21][CH2:20][CH2:19][N:16]3[C:17](=[O:18])[C:12]=2[CH:11]=[N:10]1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)Cn1ncc2c(=O)n3c(nc21)SCC3
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1ncc2c(=O)n3c(nc21)SCC3
Yield: 63.1 %

Procedure:
In 30 ml of trifluoroacetic acid was dissolved 1.18 g (3.83 mmol) of Compound 34 prepared in Example 26, followed by heating under reflux for one hour. After evaporation of the solvent, water was added to the residue. The precipitated crystals were collected by filtration, followed by washing with water to give 0.61 g (63%) of Compound 36. The compound was recrystallized from ethanol for purification.
Reaction SMILES: [CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([NH2:18])[C:6]=2[N:5]=1)([CH3:3])[CH3:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C@H:29]2[CH2:34]N[CH2:32][CH2:31][NH:30]2)=[CH:23][CH:22]=1>>[CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([N:18]3[CH2:32][CH2:31][NH:30][C@@H:29]([CH2:28][CH2:27][C:24]4[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=4)[CH2:34]3)[C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N
Reactant: COc1ccc(CC[C@H]2CNCCN2)cc1
Product: COc1ccc(CC[C@H]2CN(C3=Nc4ccccc4Nc4sc(C(C)C)nc43)CCN2)cc1
Yield: 38.4 %

Procedure:
By using a similar method of the method of Example 460, using 2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(1.48 g, 5.7 mmol) and (S)-2-[2-(4-methoxy-phenyl)-ethyl]-piperazine (1.26 g, 5.7 mmol) to give 1.01 g of the title compound as a yellow solid: mass spectrum (ion spray): m/z=462 (M+1); Analysis for C26H31N5OS(0.3 H2O): calcd: C, 66.87; H, 6.82; N, 15.00; found: C, 66.58; H, 6.35; N, 14.96.
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C@H:18]([NH2:20])[CH3:19]>>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C@H:18]([NH:20][C:5]([C:2]1([CH3:1])[CH2:4][CH2:3]1)=[O:7])[CH3:19]
Reactant: C[C@@H](N)c1ccc2ccccc2c1
Reactant: CC1(C(=O)O)CC1
Product: C[C@@H](NC(=O)C1(C)CC1)c1ccc2ccccc2c1
Yield: 76 %

Procedure:
Similarly to Example 1d), 1.5 g (15 mmol) of 1-methylcyclopropane-1-carboxylic acid were reacted with 2.6 g (15 mmol) of (1R)-1-naphth-2-ylethylamine to give the title compound. The product was isolated, after purification by silica gel chromatography (mobile phase: cyclohexane/ethyl acetate gradient), as a white solid (2.9 g; 76% yield, melting point 91° C.).
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:9][CH3:10])S(O)(=O)=O)#[N:2].[CH3:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH2:17][S:18][CH2:19][CH2:20][NH2:21]>C(O)C>[C:1]([N:3]=[C:4]([NH:21][CH2:20][CH2:19][S:18][CH2:17][C:13]1[N:14]=[CH:15][NH:16][C:12]=1[CH3:11])[NH:9][CH3:10])#[N:2]
Reactant: CNC(=NC#N)S(=O)(=O)O
Reactant: Cc1[nH]cnc1CSCCN
Solvent: CCO
Product: CNC(=NC#N)NCCSCc1nc[nH]c1C
Yield: 21.4 %

Procedure:
A solution of cyanoimino-methylaminomethanesulfonic acid (DBU salt) (0.70 g) and 2-(5-methylimidazol-4-ylmethylthio)ethylamine (0.57 g) in ethanol (14 ml) was heated under reflux for 7 hrs. After removal of the solvent under a reduced pressure, the residue was purified by column chromatography on SiO2 [eluant: CH3CN-CH3OH (4:1)]. After concentration of the eluate under a reduced pressure, the residue was subjected to preparative thin layer chromatography [SiO2, CH3COOCH3 -CH3OH- 28% NH3 (aq) (10:1:1)] and then recrystallized from CH3OH-CH3CN to give N"-cyano-N-methyl-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]guanidine (0.18 g). Yield 32.4%, m.p. 140°-141° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](/[CH:24]=[CH:25]/[C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][OH:43])=[CH:37][CH:36]=3)[CH2:30][CH2:29]2)=[O:27])[CH:5]=[C:6]([CH3:23])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:11][N:10]=1.[H-].[Na+].[Cl:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51]Cl)=[CH:49][CH:48]=1.[NH4+].[Cl-]>CN(C=O)C>[Cl:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][O:43][CH2:42][CH2:41][C:38]2[CH:37]=[CH:36][C:35]([CH2:34][N:31]3[CH2:32][CH2:33][N:28]([C:26](=[O:27])/[CH:25]=[CH:24]/[C:4]4[CH:3]=[C:2]([CH3:1])[C:7]([O:8][C:9]5[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]6[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=6)=[CH:11][N:10]=5)=[C:6]([CH3:23])[CH:5]=4)[CH2:29][CH2:30]3)=[CH:40][CH:39]=2)=[CH:49][CH:48]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Cc1cc(/C=C/C(=O)N2CCN(Cc3ccc(CCO)cc3)CC2)cc(C)c1Oc1ccc(OCc2ccncc2)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cc(/C=C/C(=O)N2CCN(Cc3ccc(CCOCc4ccc(Cl)cc4)cc3)CC2)cc(C)c1Oc1ccc(OCc2ccncc2)cn1

Procedure:
To a DMF (5 mL) solution of (E)-3-(3,5-dimethyl-4-{[5-(pyridin-4-ylmethoxy)-pyridin-2-yl]oxy}phenyl)-1-{4-[4-(2-hydroxyethyl)benzyl]piperazin-1-yl}prop-2-en-1-one (400 mg) was added NaH (35.9 mg, 60% in mineral oil) at 0° C., then the resultant mixture was stirred for 1 hour. To the mixture was added 4-chlorobenzyl chloride (0.093 mL) at 0° C., then the resultant mixture was stirred at room temperature for 3 hours. The mixture was poured into saturated aqueous NH4Cl, and extracted with AcOEt. The organic layer was washed with H2O and saturated aqueous NaCl, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/1 to 1/0 and then AcOEt/MeOH=4/1) to afford (E)-1-[4-(4-{2-[(4-chlorobenzyl)oxy]ethyl}benzyl)piperazin-1-yl]-3-(3,5-dimethyl-4-{[5-(pyridin-4-ylmethoxy)pyridin-2-yl]oxy}phenyl)prop-2-en-1-one as a pale yellow amorphous powder (91 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([O:16]CC)=[O:15])=[CH:5]2.O.[OH-].[Li+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([OH:16])=[O:15])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(F)cnc2n(C)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c(=O)c(C(=O)O)cc2cc(F)cnc21
Reaction time: 2 h

Procedure:
To a stirred suspension of ethyl 6-fluoro-1-methyl-2-oxo-1,2-dihydro[1,8]-naphthyridine-3-carboxylate (0.46 g) in ethanol (15 ml) was added a solution of lithium hydroxide monohydrate (0.10 g) in water (5 ml) at ambient temperature. The mixture was stirred for 2 hours, evaporated under reduced pressure to a small volume, diluted with water then acidified with aqueous 2M hydrochloric acid. The solid formed was filtered from solution and sucked to dryness to give the required product as a colourless solid, 0.39 g. 1H NMR (CDCl3+d6-DMSO) δ: 14.4 (1H, s), 8.92 (1H, s), 8.72 (1H, d), 7.94 (1H, m), 3.98 (3H, s).
Reaction SMILES: N[C:2]1[C:3]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:4][C:5]([O:8][C:9]2[CH:14]=[C:13]([N:15]3[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]3=[O:27])[C:12]([F:28])=[CH:11][C:10]=2[Cl:29])=[CH:6][CH:7]=1.COCCOC.ClCCl.N(OC(C)(C)C)=O>CCCCC>[Cl:29][C:10]1[CH:11]=[C:12]([F:28])[C:13]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])=[CH:14][C:9]=1[O:8][C:5]1[CH:6]=[CH:7][CH:2]=[C:3]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:4]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(N)c(OCc4ccccc4)n3)c(Cl)cc2F)c1=O
Agent: CC(C)(C)ON=O
Solvent: COCCOC
Solvent: CCCCC
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(OCc4ccccc4)n3)c(Cl)cc2F)c1=O
Reaction time: 0.25 h
Yield: 30.3 %

Procedure:
1.38 g of boron trifluoride diethyl ether complex was added to a mixture of 2.55 g of 3-amino-6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-benzyloxypyridine, 6 ml of 1,2-dimethoxyethane and 2 ml of dichloromethane dropwise at −5° C. The mixture was stirred for 15 minutes at the same temperature, then, to the reaction solution was added 0.59 g of t-butyl nitrite dropwise at −5° C. The mixture was stirred for 1 hour at the same temperature, then, into the mixture was poured n-pentane. The solvent was removed by decantation. 15 ml of ethanol, and 2.3 g of zinc (dust) was added to the residue, and it was stirred at reflux temperature for 1.5 hour. The reaction solution was filtrated through Celite, and the solvent was distilled off, then, the resulted residue was subjected to silica gel chromatography to obtain 0.75 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-benzyloxypyridine.
Reaction SMILES: CO[C:3](=[O:22])[CH2:4][CH2:5][N:6]([CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=1)=[O:12])[CH3:7].[CH2:23]([NH2:26])[CH2:24][NH2:25]>>[NH2:19][C:18]1[C:13]([C:11]([NH:10][CH2:9][CH2:8][N:6]([CH2:5][CH2:4][C:3]([NH:25][CH2:24][CH2:23][NH2:26])=[O:22])[CH3:7])=[O:12])=[N:14][C:15]([Cl:21])=[C:16]([NH2:20])[N:17]=1
Reactant: COC(=O)CCN(C)CCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCN
Product: CN(CCNC(=O)c1nc(Cl)c(N)nc1N)CCC(=O)NCCN
Yield: 72 %

Procedure:
A solution of 20.4 g (61.7 mmol) of N-[2-[[(3,5-diamino-6-chloropyrazinyl)carbonyl]amino]ethyl]-N-methyl-beta-alanine methyl ester and 36.0 g (0.6 mol) of ethylenediamine was heated at 40° C. fdr 2 days under an inert atmosphere. The excess ethylene diamine was evaporated. The residue was triturated with 2-propanol. There was obtained 15.2 g (44.4 mmol 72%) of 3,5-diamino-N-[2-[[3-[(2-aminoethyl)amino]-3-oxopropyl]methylamino]ethyl]-6-chloropyrazinecarboxamide as a white solid; mp 140°-142° C.; Rf =0.27, Solvent System A.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8]Br.C(N(CC)CC)C.[I-].C([NH3+])(C)(C)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1>C1COCC1>[CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:31][C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: COC(=O)C=CC=CCBr
Agent: CC(C)(C)[NH3+]
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C=CC=CCSc1ccc(Cl)cc1
Yield: 63 %

Procedure:
To a solution of 6-bromohexa-2,4-dienoic acid methyl ester (1.03 g, 5 mmol), triethylamine (1.4 mL, 10 mmol) and tert-butylammonium iodide (92 mg, 0.25 mmol) in freshly distilled THF (25 mL) was added 4-chlorothiophenol under an atmosphere of nitrogen. The mixture was stirred at reflux for 2 hours after which it was concentrated under reduced pressure. The oil was dissolved in, ethyl acetate (100 mL) and then washed successively with saturated aqueous sodium hydrogen carbonate (50 mL), distilled water (50 mL) and brine (50 mL). The organic layer was then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give an oil that was purified by flash chromatography (1:9 diethyl ether:40-60° C. petroleum ether). The resulting yellow solid was recrystallised from diethyl ether/40-60° C. petroleum ether to give the title compound (0.85 g, 63%) as a white solid, mp 75-77° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]([CH2:14][P:15]([O:19]Cl)([O:17]Cl)=[O:16])[CH2:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])=[O:4].[CH2:23]([NH2:26])[CH:24]=[CH2:25]>CCOCC>[F:1][C:2]([F:22])([F:21])[C:3]([N:5]([CH2:14][P:15]([O:19][NH:26][CH2:23][CH:24]=[CH2:25])([O:17][NH:26][CH2:23][CH:24]=[CH2:25])=[O:16])[CH2:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])=[O:4]
Reactant: CCCCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Reactant: C=CCN
Solvent: CCOCC
Product: C=CCNOP(=O)(CN(CC(=O)OCCCC)C(=O)C(F)(F)F)ONCC=C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a solution of butyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (7.9 g, 0.022 mole) in 200 ml. of ether was added slowly with good stirring allylamine (5.02 g, 0.088 mole) in 50 ml. of ether. The reaction was stirred overnight at room temperature, then was filtered, and the filtrate concentrated in vacuo. The residue was dissolved in ether, washed with water, dried over MgSO4, and concentrated in vacuo to yield butyl N-trifluoroacetyl-N-(bis(allylamino)phosphonomethyl)glycinate (6.8 g), ND =1.4624.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH3:13][C@@H:14]1[CH2:18][O:17][C:16](=[O:19])[NH:15]1>>[CH3:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[N:15]1[C@H:14]([CH3:13])[CH2:18][O:17][C:16]1=[O:19])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C[C@@H]1COC(=O)N1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Product: COC(=O)c1ccc(N2C(=O)OC[C@H]2C)c(C)c1
Yield: 100.3 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 12 and using methyl 4-bromo-3-methylbenzoate (1.1 g) and (R)-4-methyloxazolidin-2-one (607 mg) described in Preparation Example 25, the title compound (1.2 g) was obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].[BH4-].[Na+].II>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH2:5][OH:6]
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(CO)cc1I
Reaction time: 0.5 h

Procedure:
A mixture of 1.0 mmol of 3-iodo-4-methylbenzoic acid and 1.2 mmol of NaBH4 in 4 mL of anhydrous THF was stirred for 30 min and then 0.5 mmol of iodine in 2.0 mL of THF at 5° C. was added. After stirring for 2 h the mixture was processed by extraction to provide 3-iodo-4-methylbenzyl alcohol.