Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:16])[CH2:11][CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([CH3:17])[CH:3]=1.[F-].[Cs+].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][C:4]1[CH:3]=[C:2]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]1[C:10](=[O:16])[CH2:11][CH2:12][C:13]=1[O:14][CH3:15]
Reactant: COC1=C(c2c(C)cc(Br)cc2C)C(=O)CC1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Product: COC1=C(c2c(C)cc(-c3ccccc3)cc2C)C(=O)CC1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 70.4 %

Procedure:
To a mixture of 2-(4-bromo-2,6-dimethylphenyl)-3-methoxy-cyclopent-2-enone (1 g, 3.4 mmol), cesium fluoride (1.5 g, 9.87 mmol), phenylboronic acid (0.5 g, 4.1 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (0.44 g, 0.54 mmol) is added degassed dimethoxyethane (10 ml) and the resulting suspension is stirred under nitrogen for 45 minutes then heated at 80° C. for 4 hrs. After cooling to room temperature the reaction mixture is acidified with 1N aqueous hydrochloric acid. The aqueous phase is further extracted with ethyl acetate (3×100 ml) and then all organic fractions are combined, dried over anhydrous sodium sulphate and concentrated in vacuo. The resulting material is purified by column chromatography on silica gel to afford 2-(3,5-dimethylbiphenyl-4-yl)-3-methoxy cyclopent-2-enone (0.7 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[N:14][O:15][CH3:16])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+]>>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][NH:14][O:15][CH3:16])=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CON=Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
Reduction of 4-(methoxyimino-methyl)-benzoic acid tert-butyl ester with sodium cyanoborohydride as described in the preparation of compound 3-B gave the title hydroxylamine as a clear oil after chromatography on silica gel (elution hexane-ethyl acetate 8:2) (56% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.59 (9H, s, t-Bu), 3.49 (3H, s, OCH3), 4.09 (2H, s, NCH2), 7.41 (2H, d, J=8.6 Hz, aromatics), 7.96 (2H, d, J=8.6 Hz, aromatics). The hydrochloride salt was obtained as a white solid: mp 130-132° C. Anal. calcd for C13H19NO3—HCl: C, 57.04; H, 7.36; N, 5.12. Found: C, 56.90; H, 7.27; N, 5.00.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([C:12]([O:14]CC)=[O:13])[S:10][CH:11]=2)=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([C:12]([OH:14])=[O:13])[S:10][CH:11]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1nc(-c2ccncc2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nc(-c2ccncc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To the obtained ethyl 4-(4-pyridyl)-2-thiazolecarboxylate (1.5 g) in ethanol (10 ml) solution was added 1 N sodium hydroxide solution (10 ml), and the solution was stirred at room temperature for 2 hours. The reaction solution was concentrated and the residue was dissolved in water, to which was added 1 N hydrochloric acid (10 ml). The precipitate was filtered, washed with water and dried to give the title compound (1.105 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:29])[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:11]=2[N:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)c1ccc2oc(-c3ccncc3Cl)nc2c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc(-c2nc3cc(C(F)(F)F)ccc3o2)c(Cl)c1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 52.7 %

Procedure:
To a mixture of 0.45 g of 2-(3-chloropyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 5 ml of chloroform, 0.53 g of 65% m-chloroperbenzoic acid was added while ice-cooling. The reaction mixture was stirred at room temperature for 5.5 hours, and was then diluted with chloroform, and washed with 5% aqueous solution of sodium hydroxide and a saturated sodium chloride solution, sequentially. Organic layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 3-chloro-4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide (hereinafter, referred to as “active compound 19”).
Reaction SMILES: [CH2:1]([N:3]([CH3:15])[C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([CH3:14])[N:13]=1)[C:7]([NH:9][OH:10])=[NH:8])[CH3:2].[CH:16](N(C)C1C=C(C=C(C)N=1)C(O)=O)(C)C>>[OH:10][NH:9][C:7](=[NH:8])[C:6]1[CH:11]=[C:12]([CH3:14])[N:13]=[C:4]([N:3]([CH:1]([CH3:16])[CH3:2])[CH3:15])[CH:5]=1
Reactant: Cc1cc(C(=O)O)cc(N(C)C(C)C)n1
Reactant: CCN(C)c1cc(C(=N)NO)cc(C)n1
Product: Cc1cc(C(=N)NO)cc(N(C)C(C)C)n1

Procedure:
The title compound is prepared in analogy to 2-(ethyl-methyl-amino)-N-hydroxy-6-methyl-isonicotinamidine from 2-(isopropyl-methyl-amino)-6-methyl-isonicotinic acid; LC-MS: tR=0.50 min, [M+1]+=223.13.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4](=[C:13]1[CH2:16][N:15]([CH:17]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14]1)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1.[BH4-].[Na+].CCOCC>CO.C(Cl)Cl>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([CH:17]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[N:15]2[CH2:14][CH:13]([CH:4]([C:5]3[CH:6]=[C:7]([F:12])[CH:8]=[C:9]([F:11])[CH:10]=3)[C:3]([O:2][CH3:1])=[O:32])[CH2:16]2)=[CH:30][CH:29]=1
Reactant: COC(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 5.0 g (10.54 mmol) of methyl{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(3,5-difluorophenyl)acetate in 60 mL of MeOH and 15 mL of CH2Cl2 was slowly added 798 mg (21.08 mmol) of NaBH4. The solution was stirred for 5 h at 0° C., then poured into 250 mL of ether and washed with 50 mL of aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound; 1H-NMR(CDCl3) δ 2.68 (m, 1H), 2.92 (m, 1H), 3.10-3.15 (m, 2H), 3.44 (m, 1H), 3.69 (s, 3H), 3.86 (d, J=11 Hz, 1H), 4.30 (s, 1H), 6.74 (m, 1H), 6.85 (m, 2H), 7.24-7.34 (m, 8H); Mass Spectrum: m/e=476 (M+1 35Cl, 35Cl) and 478 (M+1 35Cl, 37Cl).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][Cl:20].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[ClH:20].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][S:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: ClCc1ccccn1
Reactant: Sc1cnc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: c1ccc(CSc2cnc3ccccc3n2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
In 50 ml of acetone was dissolved 2.0 g of 2-mercaptoquinoxaline. To the solution were added 2.02 g of 2-picolyl chloride hydrochloride, 4.0 g of potassium carbonate and 5 ml of water. The resulting mixture was stirred at room temperature for 0.5 hr., and the solvent was removed under reduced pressure. The residue was extracted with chloroform after addition of chloroform and water. The organic layer was separated and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was placed under reduced pressure to remove the solvent. To the residue were added 20 ml of ethanol and 1.03 ml of conc. hydrchloric acid and then added ether. Thus precipitated crystals were washed with ethanol-ether (1:1) and dried under reduced pressure to give 2.09 g of 2-(2-pyridylmethylthio)quinoxaline hydrochloride as a yellow crystalline powder.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][N:17]1[C:22]2=[C:23]3[N:28]([C:29]([C:30]4[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=4)=[C:21]2[C:20](=[O:38])[N:19]([CH3:39])[C:18]1=[O:40])[CH2:27][CH2:26][CH2:25][C:24]3=O.N1C(C)=CC=CC=1C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:24]1[C:23]2[N:28]([C:29]([C:30]3[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=3)=[C:21]3[C:20](=[O:38])[N:19]([CH3:39])[C:18](=[O:40])[N:17]([CH3:16])[C:22]3=2)[CH2:27][CH2:26][CH:25]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCCC3=O)c1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCC=C3OS(=O)(=O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Trifluoromethanesulfonic anhydride (253 μL, 1.50 mmol) was added to an ice-cooled solution of 1,3-dimethyl-5-m-tolyl-8,9-dihydropyrimido[4,5-a]indolizine-2,4,10(1H,3H,7H)-trione (step 3) (388 mg, 1.15 mmol) and 2,6-lutidine (201 μL, 1.73 mmol) in DCM (7 mL). The solution was allowed to reach room temperature slowly and was stirred for 16 hours. A further portion of trifluoromethanesulfonic anhydride (39 μL, 0.23 mmol) was added and the solution was stirred for a further 30 minutes. The reaction mixture was diluted with dichloromethane (15 mL) and washed with water (2×8 mL) and sat brine (1×8 mL). The organic phase was dried with magnesium sulfate and the solvent was removed under vacuum, keeping the rotary evaporator water bath at 20° C. to give the title compound.
Reaction SMILES: CN(C)C=O.[CH3:6][CH:7]([OH:9])[CH3:8].[H-].[Na+].[Br:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH2:21]Cl)=[CH:15][C:14]=1[O:23][CH3:24]>O>[Br:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH2:21][O:9][CH:7]([CH3:8])[CH3:6])=[CH:15][C:14]=1[O:23][CH3:24]
Reactant: COc1cc(CCl)cc(OC)c1Br
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COC(C)C)cc(OC)c1Br
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To an N,N-dimethylformamide (15 ml) solution of 2-propanol (7.81 ml, 102 mmol) was added sodium hydride (4.08 g, 102 mmol) at room temperature, and the mixture was stirred for 30 minutes. To the mixture was added an N,N-dimethylformamide (15 ml) solution of 2-bromo-5-(chloromethyl)-1,3-dimethoxybenzene (2.70 g, 10.2 mmol) and the mixture was stirred for one hour. After the reaction was completed, water was added to the reaction mixture while cooling on ice, which was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane/ethyl acetate: 3/1) to obtain the title compound (1.85 g, 6.40 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=O)=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([C:28]([NH2:31])([CH3:30])[CH3:29])=[N:9]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][CH2:41][CH2:42]Br>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([C:28]([CH3:29])([N:31]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[CH3:30])=[N:9]1
Reactant: BrCCCCBr
Reactant: CC(C)(N)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CS(=O)c1cccc(-c2ccc(-c3cc(C(C)(C)N4CCCC4)nn3-c3ccccc3Cl)s2)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of the 2-[1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-1H-pyrazol-3-yl]propan-2-amine (142 mg, 0.3 mmol), K2CO3 (83 mg, 0.6 mmol), 1,4-dibromobutane (0.1 mL, 0.7 mmol) and anhydrous EtOH was stirred at 100° C. in a sealed vial for 18 h. The solvent was removed in vacuo, and the residue was purified by flash chromatography (0-40% 20% MeOH/DCM) to give the title compound as a pale-yellow solid. 1HNMR (CDCl3): Et 8.03 (m, 1H), 7.86-7.83 (m, 1H), 7.74-7.71 (m, 1H), 7.61-7.47 (m, 5H), 7.23 (d, 1H), 6.93 (s, 1H), 6.83 (d, 1H), 3.68 (m, 2H), 3.08 (s, 3H), 2.17 (m, 2H), 2.04 (s, 6H), 1.83 (m, 2H). MS(ES): 526 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21](=O)[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[CH3:26][C:27]1[C:28]([NH2:32])=[N:29][O:30][CH:31]=1.[B][B][B][B][B][B][B][B][B][B]>CO.C(O)(=O)C.C(OCC)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([N:13]4[CH2:14][CH2:15][CH:16]([O:19][CH2:20][CH:21]([NH:32][C:28]5[C:27]([CH3:26])=[CH:31][O:30][N:29]=5)[CH3:22])[CH2:17][CH2:18]4)[O:12][C:8]=3[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1conc1N
Reactant: CC(=O)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1conc1NC(C)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of 1-({1-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)propan-2-one (50 mg) and 4-methylisoxazol-3-amine (21.4 mg) in methanol (1 mL) and acetic acid (50 μL) was added decaborane (26.6 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with distilled water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (NH, hexane/ethyl acetate). 1M Hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (42.1 mg).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([CH:24]=[O:25])[CH2:22][CH2:21][C:20]([C:26]([O:28]C)=[O:27])=[CH:19][C:18]=3[CH:30]=2)=[CH:10][CH:9]=1)[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([CH:24]=[O:25])[CH2:22][CH2:21][C:20]([C:26]([OH:28])=[O:27])=[CH:19][C:18]=3[CH:30]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-(3-ethoxypropoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.31 g). To the solution was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at 50° C. for 1.5 hours and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-(3-ethoxypropoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.3 g) as colorless crystals.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=O)OCC)C.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O>>[F:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reactant: O=Cc1cccc(F)c1
Product: O=[N+]([O-])c1ccc(C=Cc2cccc(F)c2)cc1
Yield: 82 %

Procedure:
Prepared in analogy to example 56b) from (4-nitro-benzyl)-phosphonic acid diethyl ester and 3-fluoro-benzaldehyde. Yellow solid. Yield=82%. MS: m/e=243.0 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[C:11]1[N:16]=[C:15](Cl)[C:14]([F:18])=[CH:13][N:12]=1>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:11]2[N:16]=[C:15]([NH:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[C:14]([F:18])=[CH:13][N:12]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: N#Cc1ccc(Nc2ncc(F)c(Nc3ccc(C#N)cc3)n2)cc1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-4-pyrimidineamine, 4-aminobenzonitrile and 2,4-dichloro-5-fluoropyrimidine gave N2,N4-bis(4-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 7.26 (d, J=8.7 Hz, 2H), 7.36 (d, J=9.0 Hz, 2H), 7.43 (d, J=8.7 Hz, 2H), 7.60 (d, J=8.7 Hz, 2H), 7.86 (d, J=3.6 Hz, 1H), 9.49 (br, 1H, NH), 9.51 (br, 1H, NH); 19F NMR (282 MHz, DMSO-d6): δ−161.48; LC: 27.15 min.; 100%; MS (m/e): 331.00 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12]O)[CH3:2].S(Cl)([Cl:16])=O>ClCCl>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][Cl:16])[CH3:2]
Reactant: CCn1c(CO)nc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCn1c(CCl)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
20 mg (0.11 mmol) 1-ethyl-2-hydroxymethylbenzimidazole was dissolved in 2 ml dichloromethane. Thionyl chloride (24 μl, 0.33 mmol) was diluted 20 times with dichloromethane and the solution was added to the reaction mixture. Reaction mixture was stirred at room temperature for two hours, evaporated to dryness and washed with water to yield 1-ethyl-2-chloromethylbenzimidazole as pale yellow crystals, 36 mg (95%).
Reaction SMILES: S(O)(O)(=O)=O.N[C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][N:11]=1.[BrH:18].N([O-])=O.[Na+]>C(Cl)Cl.O>[Br:18][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][N:11]=1
Reactant: Br
Reactant: Nc1nnc(-c2ccccc2)s1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Brc1nnc(-c2ccccc2)s1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
A mixture of 2-amino-5-phenyl-1,3,4-thiadiazole sulfate (Aldrich, 2.5 g, 9.08 mmol) and 48% aqueous HBr (10 mL) was cooled to 5° C. and a solution of NaNO2 (0.69 g, 9.99 mmol) H2O (10 mL) was added dropwise at a rate so the internal temperature is maintained at approximately 5° C. The mixture was stirred for 15 min after the addition, then CuBr (0.69 g, 4.8 mmol) was added portion-wise so as to maintain the temperature at approximately 5° C. After the addition was complete, the mixture was allowed to warm to ambient temperature and stirred for 16 h. The mixture was diluted with 20 mL CH2Cl2 and 10 mL H2O. The organic layer was separated and concentrated under reduced pressure to provide the title compound (1.63 g, 6.76 mmol, 74% yield). MS (DCl/NH3) m/z 241, 243 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:16]2[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 73.7 %

Procedure:
4-chloro-2-(methyloxy)-1-nitrobenzene (10 g, 53.2 mmol, Aldrich), 1,1-dimethylethyl 1-piperazinecarboxylate (20 g, 107.5 mmol), cesium carbonate (35.0 g, 107.5 mmol), Pd2dba3 (5 g, 5.5 mmol), and XANTPHOS (4.62 g, 8.0 mmol) were added to degassed dioxane (100 mL) and heated to 100° C. under a water cooled reflux condenser for 12 hours. The dioxane was removed under reduced pressure and the solids were partitioned between methylene chloride (500 mL) and water (500 mL). The organic layer was dried over sodium sulfate, taken to a residue under reduced pressure, and triturated with a methylene choride/hexanes mixture (15:85) to precipitate out analytically pure 1-dimethylethyl 4-[3-(methyloxy)-4-nitrophenyl]-1-piperazinecarboxylate as a yellow solid (13.2 g, 39.2 mmol, 73% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.49 (s, 9 H), 3.33-3.42 (m, 4 H), 3.62-3.64 (m, 4 H), 3.96 (s, 3 H), 6.39 (s, 1 H), 6.44 (dd, J=9.16, 2.56 Hz, 1 H), 8.01 (d, J=9.16 Hz, 1 H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:48]([C:50]1[CH:51]=[C:52]([N:56]2[CH2:60][CH2:59][CH:58]([C:61](O)=[O:62])[C:57]2=[O:64])[CH:53]=[CH:54][CH:55]=1)[CH3:49]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:61]([CH:58]1[CH2:59][CH2:60][N:56]([C:52]2[CH:53]=[CH:54][CH:55]=[C:50]([CH2:48][CH3:49])[CH:51]=2)[C:57]1=[O:64])=[O:62]
Reactant: CCc1cccc(N2CCC(C(=O)O)C2=O)c1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: CCc1cccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)c1
Yield: 33.6 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.099 g; 0.428 mmol), PyBOP (0.335 g; 0.643 mmol), N,N-diisoprpylethylamine (0.222 mL; 1.29 mmol) and 1-(3-ethylphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.428 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.059 g (33%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:22]([O-])=O)=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH4+].[Cl-]>CO.O.C(Cl)(Cl)Cl.[Zn]>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[N:9]=[CH:8][N:7]=[C:6]([NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:5]=2[C:4]=1[NH2:22]
Reactant: COc1cc2ncnc(Nc3ccccc3)c2c([N+](=O)[O-])c1OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2ncnc(Nc3ccccc3)c2c(N)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (6,7-dimethoxy-5-nitro-quinazolin-4-yl)-phenyl-amine (1.0 g, 3.14 mmol) (from Example 1, Step B, supra), NH4Cl (1.7 g, 31.4 mmol) in MeOH, H2O and CHCl3 (40 mL, 2:1:1) was added Zn powder (2.0 g, 31.4 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 1 hour. The mixture was then filtered, the filtrate was concentrated and then extracted with chloroform (100 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2 (1:1) as eluent to give the desired 6,7-dimethoxy-N 4-phenyl-quinazoline-4,5-diamine as a yellow gum. (Yield 0.5 g, 54%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[C:9](=O)[CH3:10].O.[NH2:13][NH2:14]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:9]([CH3:10])=[N:13][NH:14]2
Reactant: CC(=O)c1c(F)cccc1F
Reactant: NN
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1n[nH]c2cccc(F)c12
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 85 %

Procedure:
2′,6′-Difluoroacetophenone (0.468 g, 3 mmol) was dissolved in anhydrous hydrazine (2 ml), followed by irradiating microwaves thereon with stirring at 150° C. for 5 min. The addition of water (0.5 ml) at 0° C. terminated the reaction. Afterwards, the reaction solution was diluted with ethyl acetate (10 ml) and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated using vacuum evaporation. The residue was re-crystallized in dichloromethane to give the title compound (Yield 85%).