Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2(O)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][C:10](=[O:22])[CH:9]2[CH2:23][C:24]([O:26]C)=[O:25])[CH:7]=1.Br>C1(C)C=CC=CC=1.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][C:10](=[O:22])[C:9]=2[CH2:23][C:24]([OH:26])=[O:25])[CH:7]=1
Reactant: COC(=O)CC1C(=O)Nc2ccc(C(F)(F)F)cc2C1(O)c1cc(Cl)ccc1OC
Agent: Br
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1-c1c(CC(=O)O)c(=O)[nH]c2ccc(C(F)(F)F)cc12
Yield: 78.3 %

Procedure:
A stirred suspension of crude 4-(5-chloro-2-methoxyphenyl)-4-hydroxy-1,2,3,4-tetrahydro-2-oxo-6-(trifluoromethyl)-3-quinolineacetic acid, methyl ester prepared in Step B (2 g, 4.5 mmol) in toluene (25 mL) was treated with a solution of 35% HBr in acetic acid (5 mL). The resultant mixture was heated at 85° C. overnight. The reaction mixture was evaporated to dryness and the residue was partitioned between water and EtOAc. The EtOAc extract was washed with brine and dried (MgSO4) and then evaporated to afford the title compound (1.45 g, 78%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:8]2[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=[C:7]2[N:6]=[C:5]([C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[CH:4]=1.[F:25][CH2:26][CH2:27][CH2:28]O>>[F:25][CH2:26][CH2:27][CH2:28][NH:20][C:19]1[CH:21]=[CH:22][C:16]([C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[N:8]3[C:9]4[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=4[N:11]=[C:7]3[N:6]=2)=[CH:17][CH:18]=1
Reactant: Nc1ccc(-c2cc(C(F)(F)F)n3c(n2)nc2ccccc23)cc1
Reactant: OCCCF
Product: FCCCNc1ccc(-c2cc(C(F)(F)F)n3c(n2)nc2ccccc23)cc1

Procedure:
The title compound was prepared using General Procedure S from 4-(4-(trifluoromethyl)benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)aniline and 3-fluoropropan-1-ol on a 0.03 mmol scale. N-(3-Fluoropropyl)-4-(4-(trifluoromethyl)benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)aniline (T693) was obtained as a orange solid (3.9 mg, 33%). 1H NMR (400 MHz, DMSO-d6): δ 8.25 (d, J=8.8, 2H), 8.07 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 6.81 (t, J=5.2 Hz, 1H), 6.76 (d, J=8.8 Hz, 2H), 4.64 (t, J=5.6 Hz, 1H), 4.53 (t, J=5.6 Hz, 1H), 3.28 (m, 2H), 1.97 (m, 2H); MS (ESI) m/z [M+H]+389.
Reaction SMILES: C[O-].[Na+].[N+](C(C)C)([O-])=[O:5].Br[CH2:11][C:12]1[C:13]([Cl:24])=[C:14]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:15]([O:17][CH3:18])=[O:16].Cl>CO>[Cl:24][C:13]1[C:12]([CH:11]=[O:5])=[C:21]([O:22][CH3:23])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: CC(C)[N+](=O)[O-]
Reactant: COC(=O)c1ccc(OC)c(CBr)c1Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(OC)c(C=O)c1Cl
Yield: 54 %

Procedure:
To 40 ml methanol, was added 28% methanol solution of sodium methylate in an amount of 5.4 g and the resulting mixture was then fed dropwise with 2-nitropropane in an amount of 2.5 g at an ambient temperature. Then, the mixture was further added with methyl 3-bromomethyl-2-chloro-4-methoxybenzoate in an amount of 7.5 g and stirred for an hour under reflux and heating. After cooling the mixture, the reacted-mixture was added with 100 ml 1N-hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate layer obtained was washed with saturated saline solution and dried with anhydrous magnesium sulfate. The solvent remained in the layer was condensed under reduced pressure to obtain crystals. The crystals obtained were then washed with ethyl ether to obtain methyl 2-chloro-3-formyl-4-methoxybenzoate in an amount of 3.1 g in crystalline form. The yield was 54%.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([O:36]CC)=[O:35])[CH:28]=[CH:27]4)=[C:20]([CH3:39])[CH:19]=2)=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1.Cl.O>O1CCCC1.CO>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([OH:36])=[O:35])[CH:28]=[CH:27]4)=[C:20]([CH3:39])[CH:19]=2)=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3C)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)ccc1-c1ccc2nc(C(=O)O)ccc2c1
Temperature: 90 °C
Yield: 98.2 %

Procedure:
A 1 N solution of sodium hydroxide (187.7 μL, 187.7 μmol) was added to ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-methylphenyl]-2-quinolinecarboxylate (54.0 mg, 93.8 μmol) in tetrahydrofuran and methanol (1:1, 1.9 mL) and the mixture was heated in the microwave at 90° C. for 10 minutes. After cooling, the mixture was neutralized with 1 N hydrochloric acid (187.7 μL), water was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, then dried over anhydrous magnesium sulfate, filtered and concentrated to give 50.4 mg (98%) of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-methylphenyl]-2-quinolinecarboxylic acid as a solid. 1H NMR (400 MHz, d6-DMSO): δ 13.41 (br s, 1H), 8.54 (d, J=9 Hz, 1H), 8.14 (d, J=9 Hz, 1H), 8.12 (d, J=9 Hz, 1H), 7.96 (s, 1H), 7.79 (dd, J=9.2 Hz, 1H), 7.66-7.60 (m, 2H), 7.56 (dd, J=9, 7 Hz, 1H), 7.19 (d, J=9 Hz, 1H), 6.78 (d, J=2 Hz, 1H), 6.73 (dd, J=8, 2 Hz, 1H), 4.86 (s, 2H), 3.47 (septet, J=7 Hz, 1H), 2.21 (s, 3H), 1.35 (d, J=7 Hz, 6H). HRMS C30H24Cl2N2O4 m/z 547.1191 (M+H)+Cal; 547.1188 (M+H)+Obs.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:6][C:5]2=[O:15].[N+]([O-])([O-])=O.[Na+].[ClH:21]>O.[Cu]Cl>[Cl:21][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:6][C:5]2=[O:15]
Reactant: Nc1ccc2c(c1)C(=O)CC21CCCC1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CC2(CCCC2)c2ccc(Cl)cc21
Temperature: 100 °C

Procedure:
A mixture of 5'-amino-spiro(cyclopentane-1,1'-indan)-3'-one (20.1 g; 0.1 mole), 23% hydrochloric acid (35 ml), water (76 ml) and ice (3 g) is diazotised at about +5° C. with a solution of sodium nitrate (11 g) in water (25 ml). The clear solution is added to an ice cooled solution of copper(I)chloride(15 g) in 23% hydrochloric acid (150 ml) and water (60 ml). After agitation for 2.5 hours the mixture is heated to 100° C. for a short while and is then allowed to cool. The brown precipitate is sucked off and thoroughly washed with water. Crude yield 20 g (90%). The crude product is purified by distillation in vacuum, bp. 135°-136° C./1,5 mm Hg. A sample is crystallized from n-hexane and then melts at 54° C. The oxime melts at 140° C.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]#[N:8])=[CH:5][N:6]=1.[NH2:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[NH2:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[O:16][C:2]1[S:3][C:4]([C:7]#[N:8])=[CH:5][N:6]=1
Reactant: N#Cc1cnc(Cl)s1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cnc(Oc2cccc(N)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
2-chloro-thiazole-5-carbonitrile (1.09 g, 7.5 mmol; prepared as described in WO 01/17995, p. 103) and 3-amino phenol (820 mg, 7.5 mmol) were combined in N,N-dimethyl formamide (5 mL). To this solution, K2CO3 (3.1 g, 22.5 mmol) was added and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into water and extracted with ethyl acetate (2×). The combined organics were dried (Na2SO4), filtered and concentrated by rotary evaporation. The residue was purified by flash column chromatography (ethyl acetate:hexanes; 5%-75% ethyl acetate gradient) to give the title compound (1.63 g, 7.5 mmol, 100%) as a white solid. MS (ESI APCI) m/z 217.9 (M+H+), 1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H) 7.14 (t, J=7.91 Hz, 2H) 6.40-6.64 (m, 2H) 5.54 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]([CH2:21][OH:22])=[C:19]([Cl:23])[N:18]=[C:17]2[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:11][CH:10]=1)#[N:2].[CH3:28][Sn:29]([N:32]=[N+:33]=[N-:34])([CH3:31])[CH3:30]>>[CH3:28][Sn:29]([N:32]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[CH:10]=[CH:11][C:12]([CH2:15][N:16]3[C:20]([CH2:21][OH:22])=[C:19]([Cl:23])[N:18]=[C:17]3[CH2:24][CH2:25][CH2:26][CH3:27])=[CH:13][CH:14]=2)=[N:2][N:34]=[N:33]1)([CH3:31])[CH3:30]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C#N)cc1
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2[Sn](C)(C)C)cc1
Temperature: 115 °C
Reaction time: 41 h

Procedure:
1-[(2'-Cyanobiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole (766 g), trimethyl tin azide (766 g) and xylenes (7.90 L) were charged to a 12 liter round-bottomed flask equipped with mechanical stirrer, condenser with N2 inlet and thermometer contained in a heating mantle. The slurry was heated to 115° C., giving a clear solution, and held for 41 hours. The resulting slurry was cooled to room temperature and the crude product isolated by vacuum filtration, washed with toluene (800 ml) and dried in vacuo at ~50° C. overnight. The crude product (1202 g) was charged to a 12 liter round-bottomed flask and slurried at 105° C. with toluene (70 L). The slurry was cooled to 50° C. and the product isolated by vacuum filtration, washed with one liter of toluene and dried in vacuo at 50° C. overnight. Yield: 1071 g, 94%. M.P.: 211°-214° C.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(N(CC)CC)C.Cl[S:13]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]1[C:27]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[N:28][C:29]3[C:34]([N:35]=1)=[CH:33][C:32]([C:36]([O:38][CH3:39])=[O:37])=[CH:31][CH:30]=3)[CH2:21][CH2:20][CH2:19]2)(=[O:15])=[O:14].C(OCC)(=O)C>ClCCl>[CH3:2][N:3]([CH3:4])[S:13]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]1[C:27]([C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)=[N:28][C:29]3[C:34]([N:35]=1)=[CH:33][C:32]([C:36]([O:38][CH3:39])=[O:37])=[CH:31][CH:30]=3)[CH2:21][CH2:20][CH2:19]2)(=[O:14])=[O:15]
Reactant: CNC
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(S(=O)(=O)Cl)ccc43)nc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(S(=O)(=O)N(C)C)ccc43)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
To a solution of dimethylamine hydrochloride (49.66 mg, 0.61 mmol) in dichloromethane (50 mL) was added and triethylamine (102 mg, 1.01 mmol) and stirred for 10 min. Then methyl 3-[6-(chlorosulfonyl)-1,2,3,4-tetrahydroquinolin-1-yl]-2-(4-fluorophenyl)quinoxaline-6-carboxylate (260 mg, 0.51 mmol) in dichloromethane (20 mL) was added dropwise with stirring for 30 min at room temperature. The reaction mixture was concentrated under vacuum to give the residue, which was applied onto a silica gel column with 2%-5% ethyl acetate in petroleum ether to afford methyl 3-[6-(dimethylsulfamoyl)-1,2,3,4-tetrahydroquinolin-1-yl]-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (240 mg, 91%).
Reaction SMILES: [CH2:1]([C@:3]([OH:18])([C@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].S(=O)(=O)(O)O.C([O-])(=O)C.[Na+]>[Pd].C(O)(=O)C>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:9][C@@:3]([OH:18])([CH2:1][CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)[C@](O)(CC)[C@@H](O)c1ccccc1F
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)[C@](O)(CC)Cc1ccccc1F
Reaction time: 48 h

Procedure:
Ethyl (2S, 3S)-2-ethyl-3-(2-fluorophenyl)-2,3-dihydroxypropanoate (5.2 g, 20 mmol), 10% palladium on carbon (2.5 g) and concentrated sulfuric acid (0. 53 mL, 10 mmol) were mixed in acetic acid (100 mL). The reaction mixture was hydrogenated at 45 psi for 48 hrs. Sodium acetate (1.7 g, 20 mmol) was added and the reaction mixture was stirred for 10 min before it was filtered through silica gel. Concentration of the filtrate gave essentially pure ethyl (2S)-2-(2-Fluoro-benzyl)-2-hydroxy-butyrate, which was hydrolyzed with KOH (2 N, 25 mL) in methanol (150 mL) to give the title compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][N:13]=1)#[N:11].[NH:20]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@@H:21]([C:29]([N:31]1[CH2:38][CH2:37][CH2:36][C@H:32]1[C:33](O)=[O:34])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:10]([C:12]1[N:13]=[CH:14][C:15]([CH2:18][NH:19][C:33](=[O:34])[C@@H:32]2[CH2:36][CH2:37][CH2:38][N:31]2[C:29](=[O:30])[C@@H:21]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:20][C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])=[CH:16][CH:17]=1)#[N:11]
Reactant: N#Cc1ccc(CN)cn1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc(C#N)nc1
Reaction time: 2 h

Procedure:
8.12 g of diisopropylethylamine, and subsequently 11 ml (15 mmol) of propanephosphonic anhydride (50% strength solution in ethyl acetate), were added dropwise to a solution of 2.11 g (12.5 mmol) of 2-cyano-5-(aminomethyl)pyridine and 4.5 g (12.5 mmol) of Boc-D-Phe-Pro-OH in 70 ml of CH2Cl2 at -5° C. The mixture was then stirred for 2 h, allowing the temperature to rise from -5° to 20° C. The organic phase was washed with water, 5% strength sodium bicarbonate and 5% strength citric acid solutions, dried over Na2SO4 and evaporated to dryness, a pale yellowish crystalline residue was obtained, melting point 167-170° C., which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]2)=[CH:5][CH:4]=1.[Br-].C[S+](C)[CH:20]=[C:21]=[CH2:22].[O-]CC.[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][C:11](=[O:16])[C:12]3[C:21]([CH3:22])=[CH:20][O:15][C:13]=3[CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2CC(=O)CC(=O)C2)cc1
Reactant: C=C=C[S+](C)C
Agent: CC[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C2CC(=O)c3c(C)coc3C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.5 %

Procedure:
A mixture of 5-(4-methoxyphenyl)cyclohexane-1,3-dione (0.95 g), dimethyl-1,2-propadien-1-yl sulfonium bromide (1.5 g), sodium ethoxide (0.31 g) and ethanol (10 ml) was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in toluene (20 ml), and to the solution was added p-toluenesulfonic acid(0.85 g). The mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate, and the mixture was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane) to give colorless crystals of 6-(4-methoxyphenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.14 g).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][O:7][CH2:8][C:9]1[N:10]=[C:11]([CH2:31][CH2:32][CH3:33])[N:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[C:13](=[O:15])[CH:14]=1.[Br:34]Br>C(O)(=O)C>[Br:34][C:14]1[C:13](=[O:15])[N:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[C:11]([CH2:31][CH2:32][CH3:33])=[N:10][C:9]=1[CH2:8][O:7][CH3:6]
Reactant: BrBr
Reactant: CCCc1nc(COC)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1nc(COC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 4 h
Yield: 39 %

Procedure:
To a solution of sodium acetate (3.4 g) and 4′-{[4-(methoxymethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (15 g) in acetic acid (150 mL) was added bromine (2.1 mL), and the mixture was stirred for 4 hr. Acetic acid was removed in vacuo, and the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow solid (7 g, 39%).
Reaction SMILES: [Se](=O)=O.[Cl:4][C:5]1[C:6]([CH2:15][O:16][CH3:17])=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2.[O:18]1CCOC[CH2:19]1>>[Cl:4][C:5]1[C:6]([CH2:15][O:16][CH3:17])=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([CH:19]=[O:18])[CH:11]=[CH:10]2
Reactant: COCc1ccc2cccnc2c1Cl
Reactant: C1COCCO1
Agent: O=[Se]=O
Product: COCc1ccc2ccc(C=O)nc2c1Cl
Temperature: 85 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
Referring to FIG. 20, under a nitrogen atmosphere, selenium dioxide (0.0604 g, 0.544 mmol) was added to a solution of 8c (0.1232 g, 0.5184 mmol) in p-dioxane (3 mL), and the resulting orange solution was stirred in a sealed flask for 2 h at 85° C. The black precipitate was removed by vacuum filtration and the filtrand was evaporated, leaving a residue, which was purified by column chromatography (2:8 EtOAc/hexane) to afford 9c (0.0724 g, 0.288 mmol, 56%) as a pale yellow solid (mp 118-121° C.): 1H NMR (CDCl3) δ 10.30 (1H, s), 8.30 (1H, d, J=8.0 Hz), 7.99, (1H, d, J=8.0 Hz), 7.81 (1H, d, J=9.6 Hz), 7.70 (1H, d, J=8.8 Hz), 5.45 (2H, s), 3.60 (3H, s); 13C NMR (CDCl3) δ 193.9, 154.7, 153.4, 145.6, 138.0, 127.2, 127.0, 121.3, 120.2, 116.5, 95.7, 57.0; FTIR (neat) 2931, 2835, 1713, 1615, 1303, 1159, 1043, 920, 775 cm−1; MS (ESI) m/z calculated for (C12H10ClNO3+H)+ 252 (35Cl) and 254 (37Cl), found 252 (35Cl) and 254 (37Cl); HRMS (ESI) m/z calculated for (C12H10ClNO3+H)+ 252.0427 (35Cl) and 254.0398 (37Cl), found 252.0418 (35Cl) and 254.0390 (37Cl).
Reaction SMILES: [BH4-].[Li+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[I:21])[C:14](OC)=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1.[Cl-].[NH4+]>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH2:14][OH:15])[CH:18]=[CH:19][C:20]=1[I:21])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(I)c(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(I)c(OCc2ccccc2)c1
Temperature: 60 °C
Yield: 106.3 %

Procedure:
1.18 g (54 mmol, 3 eq) of lithium borohydride are added to a solution of 6.9 g crude (17.98 mmol, 1 eq) of methyl 3-benzyloxy-4-iodobenzoate in 30 ml of THF. The reaction mixture is heated at 60° C. for 12 hours and then hydrolyzed in saturated ammonium chloride solution NH4Cl and extracted with ethyl acetate. 6.5 g of (3-benzyloxy-4-iodophenyl)methanol are obtained in oil form and are used in the following reaction without further purification.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[S:22][CH2:23][C:24]([OH:26])=O.[NH2:27][C@@H:28]1[C:35](=[O:36])[N:34]2[C@@H:29]1[S:30][CH2:31][C:32](/[CH:40]=[C:41]1/[C:42](=[O:50])[N:43]([CH2:46][CH:47]3[CH2:49][CH2:48]3)[CH2:44][CH2:45]/1)=[C:33]2[C:37]([OH:39])=[O:38]>CN(C)C=O>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[S:22][CH2:23][C:24]([NH:27][C@@H:28]1[C:35](=[O:36])[N:34]2[C@@H:29]1[S:30][CH2:31][C:32](/[CH:40]=[C:41]1/[C:42](=[O:50])[N:43]([CH2:46][CH:47]3[CH2:49][CH2:48]3)[CH2:44][CH2:45]/1)=[C:33]2[C:37]([OH:39])=[O:38])=[O:26]
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC4CC4)C3=O)CS[C@H]12
Reactant: O=C(O)CSc1nc2ccccc2s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(CSc1nc2ccccc2s1)N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC4CC4)C3=O)CS[C@H]12

Procedure:
With 220.0 mg (1.35 mmol) 1,1′-carbonyldiimidazole, 304.1 mg (1.35 mmol) (benzothiazol-2-ylsulfanyl)-acetic acid and 394.8 mg (1.13 mmol) (E)-(6R,7R)-7-amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 7 ml N,N-dimethylformamide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:11][CH:12]=1)(=[O:6])=[O:5].[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>ClCCl.CN(C)C1C=CN=CC=1>[Si:16]([O:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:11][CH:12]=1)(=[O:6])=[O:5])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)CCO)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of 955 mg (4.13 mmol) of 3-[(2-hydroxyethyl)sulfonyl]-nitrobenzene in 30 mL of dichloromethane were added 747 mg (4.96 mmol) of tert-butyldimethylsilyl chloride and 10 mg of 4-dimethylaminopyridine, and the mixture was stirred for over night at room temperature. Then, the reaction mixture was diluted with dichloromethane and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1 to 2/1) to give 1.27 g (89%) of the title compound.
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Cl.C(=O)([O-])[O-].[K+].[K+].CC#N.O>CN(C=O)C>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][N:11]1[CH2:12][CH2:13][N:8]([CH2:14][C:15]2[N:16]=[N:17][C:18]3[C:19](=[C:21]([NH2:26])[N:22]=[C:23]([NH2:25])[N:24]=3)[N:20]=2)[CH2:9][CH2:10]1
Reactant: COc1cccc(CCl)c1
Reactant: Nc1nc(N)c2nc(CN3CCNCC3)nnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(CN2CCN(Cc3nnc4nc(N)nc(N)c4n3)CC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.3 %

Procedure:
To a stirred solution of 3-Piperazin-1-ylmethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine TFA salt 5 (50 mg; 0.08 mmol; prepared in EXAMPLE 4) in dry DMF (1.0 mL) was added m-methoxybenzyl chloride (19 mg; 0.12 mmol) followed by potassium carbonate (55 mg; 0.40 mmol). The mixture was allowed to stir for 24 h at room temperature then taken up into CH3CN/H2O/0.1% TFA. The mixture was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 50% CH3CN gradient, CH3CN/H20, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 30 mg of yellow colored 3-[4-(3-Methoxy-benzyl)-piperazin-1-ylmethyl]-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine as the trifluoroacetate salt.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[C:28]([F:31])([F:30])[F:29]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:9]([C:3]1[C:2]([NH:1][S:24]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([C:28]([F:31])([F:29])[F:30])[CH:20]=2)(=[O:26])=[O:25])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cc(Cl)cnc1C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
A solution of (3-amino-5-chloro-pyridin-2-yl)-phenyl-methanone (40 mg, 0.17 mmol), 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (72 mg, 0.26 mmol), and DMAP (11 mg, 0.09 mmol) in anhydrous pyridine (0.5 mL) was heated at 60° C. for 4 days. The product was separated by preparative HPLC and pure product fractions were lyophilized to provide pure product as a solid. 1H NMR (400 MHz, CDCl3) δ10.56 (s, 1H), 8.39 (s, 1H), 8.17 (s, 1H), 8.07 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.54 (d, J=7.6 Hz, 2H), 7.61-7.58 (m, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.45-7.42 (m, 2H); MS m/z: 475.0 (M+H).