Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]Cl.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:27]=[CH:26][C:25]4[C:24]5[C:19](=[CH:20][C:21]([Si](C)(C)C)=[CH:22][CH:23]=5)[C:18]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:17]=4[CH:16]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>CO.ClCCl>[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:27]=[CH:26][C:25]4[C:24]5[C:19](=[CH:20][C:21]([I:1])=[CH:22][CH:23]=5)[C:18]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:17]=4[CH:16]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCCCCCCCC1(CCCCCCCC)c2cc(-c3ccccc3-c3ccncc3)ccc2-c2ccc([Si](C)(C)C)cc21
Reactant: ClI
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCC1(CCCCCCCC)c2cc(I)ccc2-c2ccc(-c3ccccc3-c3ccncc3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
1.5 ml of an 1.0 M ICl solution in MeOH was slowly added to a solution of 500 mg (0.813 mmol) of 2-(6-p-pyridyl-phenyl)-7-trimethylsilyl-9,9-dioctylfluorene in 5 mL of dichloromethane. The resulting darkred solution was stirred for 2 h at room temperature after which the reaction mixture was quenched with a large excess of a Na2S2O3 in water. The mixture was extracted with water, and the organic fraction was dried using MgSO4 and the solvents were removed under reduced pressure. The product was purified using flash column chromatography (dichloromethane: Rf: 0.36). 450 mg (85%) product was obtained as a highly blue fluorescent, colourless solid material. 1H NMR (250 MHz, CDCl3): δ=8.73 (d, 3J=4.7 Hz, 1H; CH—N), 8.12 (d, 3J=8.5 Hz, 2H; CH—C—C(CH)—N), 7.80-7.73 (mp, 4H, ArH), 7.68 (s, 2H, ArH), 7.65 (d, 3J=5.0 Hz, 2H; CH—CH—N), 7.60 (s, 2H; ArH), 7.48 (d, 1H; 3J=8.4 Hz; ArH), 2.05-1.94 (mp, 4H; CH2—C), 1.05-1.25 (mp, 20H, CH2), 0.81 (t, 3J=6.6 Hz, 6H; CH3), 0.70 (br m, 4H, CH2). 13C{1H} NMR (500 MHz, CDCl3): δ=157.0 (CN), 153.4, 150.9 (C—C—CH2), 149.8 (CH—N), 142.0, 140.4, 140.0, 139.6, 138.2 (ArC), 136.8 (CH—CH—CH—N), 135.9, 132.1 (C—CI), 127.5, 127.3, 126.1, 122.1, 121.5, 121.3, 120.4, 120.1 (CH), 92.6 (CI), 55.5 (C—CH2), 40.2 (C—CH2), 31.7, 29.9, 29.2, 29.1 (CH2), 23.7 (C—CH2—CH2), 22.6 (CH3—CH2), 14.1 (CH3). Exact Mass (IE) m/z: 669.2825 [M]+ (calcd. 669.2832) fractions: 543.6 (m; [M-I]+), 318.4 (m; [M-(C8H17)—I]+). C40H48IN: calcd. C, 71.74; H, 7.22; N, 2.09. found C, 72.34; H, 7.20; N, 2.12.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:23][C:24]([OH:26])=O)=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)[S:11][CH:12]=1.Cl.[N:28]1([C:33]([NH2:35])=[NH:34])[CH:32]=[CH:31][CH:30]=[N:29]1.C(N(C(C)C)CC)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:23][C:24]([NH:35][C:33](=[NH:34])[N:28]2[CH:32]=[CH:31][CH:30]=[N:29]2)=[O:26])=[C:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:17][CH:18]=2)[S:11][CH:12]=1
Reactant: CCCOc1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)O)cc1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)NC(=N)n2cccn2)cc1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
[4-(2-Chlorophenyl)-2-(4-propoxyphenyl)thien-3-yl]acetic acid (0.630 g, 1.62 mmol) was dissolved in CH2CL2 (5 mL) and carbonyldiimidizole (1.31 g, 8.1 mmol) was added. The solution was stirred under argon at room temperature for thirty minutes. 1-H-Pyrazole-1-carboxamidine hydrochloride (2.37 g, 16.2 mmol) and diisopropyl ethylamine (4.23 mL, 3.14 g, 24.3 mmol) were added the solution was stirred overnight. The solvent was removed and the mixture was absorbed onto silica gel and purified by flash chromatography (20:1 CHCl3:MeOH to yield 2-[4-(2-chlorophenyl)-2-(4-propoxyphenyl)thien-3-yl]-N-[imino(1H-pyrazol-1-yl)methyl]acetamide (0.421 g) as a white solid. mp 119-120 ° C.; 1H NMR (500 MHz, DMSO-d6) δ: 0.98 (t, 3H, J=7.3 Hz), 1.73 (m, 2H), 3.55 (s, 2H), 3.96 (t, 2H, J=6.4 Hz), 6.53 (m, 1H), 7.02 (d, 2H, J=8.7 Hz), 7.30 (m, 4H), 7.40 (s, 1H), 7.49 (d, 2H, J=8.5 Hz), 7.89 (s, 1H), 8.08 (s, 1H). MS (ES) m/z 479.1 ([M+H]+). MS (ES) m/z 957.2 ([2M+H]+). MS (ES) m/z 979.2 ([2M+NA]+). Anal. Calcd for C25H23ClN4O2S: C, 62.69; H, 4.84; N, 11.70. Found: C, 62.35; H, 4.86; N, 11.58.
Reaction SMILES: CC([Si](C(C)C)(C(C)C)[O:5][C:6]1[C:11]2[C:12]([CH3:16])([CH3:15])[CH2:13][O:14][C:10]=2[C:9]([CH3:17])=[CH:8][CH:7]=1)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:15][C:12]1([CH3:16])[C:11]2=[C:6]([OH:5])[CH:7]=[CH:8][C:9]([CH3:17])=[C:10]2[O:14][CH2:13]1
Reactant: Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)c2c1OCC2(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(O)c2c1OCC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
Tris(1-methylethyl)[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]silane (Intermediate 26, 3.6 g, 10.84 mmol) was dissolved in THF (36 mL) to obtain a dark yellow solution. TBAF (8.5 g, 32.5 mmol) was added and the reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with aqueous HCl, then aqueous NaHCO3 and finally brine. The organic solution was dried over Na2SO4 and evaporated to dryness and the residue was purified by flash chromatography on silica gel using cyclohexane to cyclohexane/ethyl acetate 95:5 as eluents affording the title compound (1.69 g) as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].FC1C(C)=C(C2C=CC(C(O)=O)=CC=2COC)C=CC=1.[OH-].[Na+]>CCO>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14]
Reactant: COCc1cc(C(=O)OC)ccc1Br
Agent: COCc1cc(C(=O)O)ccc1-c1cccc(F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCc1cc(C(=O)O)ccc1Br
Temperature: 60 °C
Yield: 87.8 %

Procedure:
To a solution of methyl 4-bromo-3-(methoxymethyl)benzoate (Intermediate 1, Step 2, 7.0 g, 27.0 mmol) in EtOH (210 mL) was added a 5 N aqueous solution of NaOH (16 mL, 80.0 mmol). The resulting mixture was heated at 60° C. for 1 hour. The reaction mixture was cooled to RT and concentrated under vacuum. The residue was taken up with water and washed with EtOAc. The aqueous layer was then acidified with a 1N aqueous solution of HCl and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated under vacuum to give the title compound as a yellow solid (5.81 g, 87%). 1H NMR (DMSO-d6, 300 MHz) 13.19 (br s, 1H), 8.00 (m, 1H), 7.77 (m, 2H), 4.49 (s, 2H), 3.40 (s, 3H). LC/MS (Method B): 245.0 (M−H)−. HPLC (Method A) Rt 3.63 min (purity: 97.4%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].[C:12]12[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:17]C(=O)O[C:13]2=[O:14]>>[NH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=1[C:13]([NH:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4])=[O:14]
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: Nc1ccccc1C(=O)N[C@H](CO)Cc1ccccc1

Procedure:
The product was prepared by the method of procedure 1a from 5 g (S)-(-)-2-amino-3-phenyl-1-propanol and isatoic anhydride. 3.6 g of the product were obtained.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:16]([NH:17][CH2:18][CH3:19])=[C:15]([C:20]([OH:22])=[O:21])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([F:23])[CH:13]=3)[N:8]=2)=[CH:3][CH:2]=1.O.[C:31](OC(=O)C)(=[O:33])[CH3:32]>S(=O)(=O)(O)O>[C:31]([CH2:19][CH2:18][NH:17][C:16]1[C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:6][CH:5]=2)=[N:8][C:9]2[C:14]([C:15]=1[C:20]([OH:22])=[O:21])=[CH:13][C:12]([F:23])=[CH:11][CH:10]=2)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CCNc1c(-c2ccc(-c3ccccc3)cc2)nc2ccc(F)cc2c1C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)CCNc1c(-c2ccc(-c3ccccc3)cc2)nc2ccc(F)cc2c1C(=O)O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A 2.8 g portion of 2-[1,1'-biphenyl]-4-yl-3-(ethylamino)-6-fluoro-4-quinolinecarboxylic acid was suspended in 25 ml of acetic anhydride. To this suspension was added 5 drops of concentrated sulfuric acid, then the mixture was heated at 80° C. for 2 hours. The solution was cooled, added to 200 ml of water and stirred for 30 minutes. The resulting solid was collected, washed with water, then dichloromethane and dried at 110° C. in vacuo, giving 2.0 g of the desired product as a pale yellow solid, mp 260°-262° C.
Reaction SMILES: C(O)C.[BH4-].[Na+].Cl.[CH2:7]([O:14][C:15]1[C:16]([CH:30]=[O:31])=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[CH:20]([NH:26][CH:27]([CH3:29])[CH3:28])[CH2:19][CH2:18]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl-].[Na+]>C(OCC)(=O)C>[CH2:7]([O:14][C:15]1[C:16]([CH2:30][OH:31])=[C:17]2[C:22](=[CH:23][CH:24]=1)[C@@H:21]([OH:25])[C@H:20]([NH:26][CH:27]([CH3:29])[CH3:28])[CH2:19][CH2:18]2)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)NC1CCc2c(ccc(OCc3ccccc3)c2C=O)C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)N[C@@H]1CCc2c(ccc(OCc3ccccc3)c2CO)[C@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 10 ml. of ethanol is suspended 100 mg. of sodium borohydride and, under stirring, is added 200 mg. of 6-benzyloxy-5-formyl-2-isopropylamino-3,4-dihydro-1(2H)-naphthalenone hydrochloride. The mixture is agitated at room temperature for 2 hours, after which time a saturated solution of sodium chloride and ethyl acetate was added. The ethyl acetate layer is taken, washed with a saturated aqueous solution or sodium chloride and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is recrystallized from ethyl acetate-ethanol. The above procedure provides trans-6-benzyloxy-1-hydroxy-5-hydroxymethyl-2-isopropylamino-1,2,3,4-tetrahydronaphthalene as white crystals. Yield 128 mg.; melting point: 138°-139° C.
Reaction SMILES: CN(C)C=CC(C1C=COC=1)=[O:6].[O:13]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]3[CH:24]=[N:25][C:26]([C:27]#[N:28])=[C:22]3[N:21]=[CH:20][CH:19]=2)=[CH:14]1>>[O:13]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]3[CH:24]=[N:25][C:26]([C:27]([NH2:28])=[O:6])=[C:22]3[N:21]=[CH:20][CH:19]=2)=[CH:14]1
Reactant: CN(C)C=CC(=O)c1ccoc1
Reactant: N#Cc1ncn2c(-c3ccoc3)ccnc12
Product: NC(=O)c1ncn2c(-c3ccoc3)ccnc12

Procedure:
3-Dimethylamino-1-(3-furyl)-2-propen-1-one (prepared as described in Example 4) can be substituted for 3-dimethylamino-1-(2-thienyl)-2-propen-1-one (prepared as described in Example 4) in the procedure of Example 6, to produce 4-(3-furyl)imidazo[1,5-a]pyrimidine-8-carboxamide.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[ClH:9].[F:10][C:11]1[CH:12]=[C:13]([CH:35]=[CH:36][CH:37]=1)[CH2:14][N:15]1[C:19]2=[C:20]([N:24]3[CH2:33][CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25]3)[N:21]=[CH:22][CH:23]=[C:18]2[CH:17]=[C:16]1[CH3:34]>ClCCl>[ClH:9].[Br:1][C:17]1[C:18]2[C:19](=[C:20]([N:24]3[CH2:33][CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25]3)[N:21]=[CH:22][CH:23]=2)[N:15]([CH2:14][C:13]2[CH:35]=[CH:36][CH:37]=[C:11]([F:10])[CH:12]=2)[C:16]=1[CH3:34]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2ccnc(N3CCc4ccccc4C3)c2n1Cc1cccc(F)c1
Agent: Cl
Solvent: ClCCl
Product: Cc1c(Br)c2ccnc(N3CCc4ccccc4C3)c2n1Cc1cccc(F)c1
Reaction time: 1 h
Yield: 8.9 %

Procedure:
N-Bromosuccinimide (41 mg, 0.23 mmol) and silica gel (100 mg) were added to a solution of 2-[1-(3-fluorobenzyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl]-1,2,3,4-tetrahydroisoquinoline hydrochloride (88 mg, 0.23 mmol) prepared in Example 613 in dichloromethane (2 ml). The reaction mixture was stirred for 1 hour and then filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 10 mg of the titled compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.C(OCC)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][N:23]3[C:19](=[O:29])[C:20]4[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:22]3=[O:24])=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(=O)c1cccc(-c2ccc(CO)cc2)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 139.3 %

Procedure:
To a stirred mixture of 1.4 g (5.8 mmol.) 4′-hydroxymethyl-biphenyl-3-carboxylic acid methyl ester, 1.0 g (6.9 mmol.) phthalimide, and 1.8 g (6.9 mmol.) triphenylphosphine in 25 mL tetrahydrofuran at 0° C. was added 1.2 ml (7.5 mmol.) diethylazodicarboxylate. The mixture was warmed to ambient temperature and stirred for 18 hours. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were combined then washed successively with 1N NaOH, 1N HCl, water, brine then dried (MgSO4) and concentrated in vacuo to give a solid. Trituration with diethyl ether gave 3.0 g 4′-[1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl]-biphenyl-3-carboxylic acid methyl ester as a solid.
Reaction SMILES: [OH:1][C:2]1[C:5](=[O:6])[C:4](=[O:7])[CH:3]=1.O>C(O)CCC.C1C=CC=CC=1>[CH2:5]([O:1][C:2]1[C:5](=[O:6])[C:4](=[O:7])[CH:3]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=c1cc(O)c1=O
Solvent: CCCCO
Solvent: O
Solvent: c1ccccc1
Product: CCCCOc1cc(=O)c1=O
Yield: 162.8 %

Procedure:
A suspension of 1.25 g of 1-hydroxycyclobutene-3,4-dione (A) in 10 ml of absolute n-butanol and 15 ml of benzene is heated to reflux in a Soxhlet apparatus. A passes slowly into solution. The water of reaction is bound to the molecular sieve 4A which is present in the apparatus. The reaction mixture is concentrated after 2 hours. The distillation of the residue at 105°-115° C/0.01 Torr yielded 1.6 g (=82% of theory) of 1-n-butoxycyclobutene-3,4-dione as a yellowish oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[O:34][C:33]([CH3:35])=[N:32][CH:31]=4)=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.FC(F)(F)C(O)=O.N>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[O:34][C:33]([CH3:35])=[N:32][CH:31]=4)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2
Reactant: Cc1ncc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)o1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncc(-c2c[nH]c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)o1
Yield: 96.5 %

Procedure:
(S)-5-Methyl-2-(1-((5-(2-methyloxazol-5-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (31 mg, 0.05 mmol) was treated with trifluoroacetic acid (1 ml, 13 mmol) and a solution of ammonia (7N in methanol, 2 ml, 14 mmol) according to the method described in Example 27 to give 22.5 mg (87% yield) of the title compound. Purity 94%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][CH3:29])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]CC)=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:13](=[O:14])[CH:12]([NH:11][S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[CH2:28][CH3:29])=[CH:21][CH:20]=1)([OH:25])=[O:24]
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(CC)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)Nc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
A mixture of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)butanamide (114.2 mg), ethanol (8 ml), and 2N NaOH (650 ml) was stirred at room temperature overnight under argon. The reaction mixture was concentrated under reduced pressure. It was repeated 3 times in order to remove ethanol completely that a small amount of purified water was added to the residue, and then the product was concentrated under reduced pressure. The residue was dissolved in purified water and washed with ethyl acetate. The aqueous layer was acidified with 1N HCl and then extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution and dried over Na2SO4. Then, the solvent was evaporated under reduced pressure to obtain (RS)-N-(4-(carboxymethyl) phenyl)-2-(4-chlorobenzenesulfonylamino) butanamide (91.1 mg).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([NH:9][C:10]([C:12]3[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=3)=[O:11])[S:7][CH:8]=2)[CH2:3][CH2:2]1.Br[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1>>[CH:1]1([C:4]2[N:5]=[C:6]([NH:9][C:10]([C:12]3[C:17]([NH:18][C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=4)=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=3)=[O:11])[S:7][CH:8]=2)[CH2:2][CH2:3]1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: Cc1ccc(N)c(C(=O)Nc2nc(C3CC3)cs2)n1
Product: Cc1ccc(Nc2cc(F)cc(F)c2)c(C(=O)Nc2nc(C3CC3)cs2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-cyclopropyl-thiazol-2-yl)-amide in accordance with the general method of example 20 using 1-Bromo-3,5-difluorobenzene instead of 3-bromopyridine to yield the final compound as a yellow solid, MS (ISP): m/e=387.4 (M+H+).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([Cl:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:16].Cl.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.Cl>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[ClH:15].[ClH:16].[CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[CH2:23][CH2:24]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Reactant: NC1CCN(c2ccncc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Cc2ccccc2)nc(NC2CCN(c3ccncc3)CC2)n1

Procedure:
To a suspension of 4-benzyl-2-chloro-6-methyl-pyrimidine (WO2009103652; 70 mg, 0.32 mmol) and 4-(4-aminopiperidino)pyridine dihydrochloride (ABCR; 80 mg, 0.32 mmol) in dioxane (2 mL) was added potassium carbonate (885 mg, 6.4 mmol), palladium(II) acetate (3 mg, 0.013 mmol) and 2-(dicyclohexylphosphino)biphenyl (11 mg, 0.031 mmol). The reaction mixture was refluxed overnight, concentrated, hydrolyzed and extracted with ethyl acetate. Chromatography on Si-Amine (Silicycle, 10 g) using cyclohexane/ethyl acetate as eluent gave a gummy solid which was dissolved in dioxane and treated with a few drops of dioxane saturated with HCl gas to yield the title compound as a slightly yellow solid (70 mg, 51%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([O:8][O:9][C:10]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[P:11]([OH:14])([OH:13])=[O:12])[CH2:6][OH:7])=[N+:2]=[N-:3].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>C(Cl)Cl>[N:1]([CH2:4][C@@H:5]([O:8][O:9][C:10]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:16])[CH3:17])[P:11]([OH:13])([OH:14])=[O:12])[CH2:6][O:7][S:29]([CH3:28])(=[O:31])=[O:30])=[N+:2]=[N-:3]
Reactant: CC(C)C(OO[C@@H](CO)CN=[N+]=[N-])(C(C)C)P(=O)(O)O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)C(OO[C@H](CN=[N+]=[N-])COS(C)(=O)=O)(C(C)C)P(=O)(O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of (R)-3-azido-2-O-(diisopropyl phosphonomethoxyl)-1,2-propanediol (6.4 g, 21.67 mmol) and triethylamine (4.39 g, 43.4 mmol) in methylene chloride (100 mL), methanesulfonylchloride (2.98 g, 26 mmol) was slowly added at 0° C. under nitrogen atmosphere. The resulting solution was stirred at 0° C. for 1 hour and then slowly warmed to room temperature during an hour. Water (100 mL) was added to the solution. The aqueous was separated and extrated with methylene chloride (150 mL×2). The combined methylene chloride extracts were dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by flash chromatography on silica gel (methylene chloride:acetone=10:1 to 3:1) to provide 7.21 g (87% yield) of the title compound as an oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([CH3:10])=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(O)=O.[Br:18]N1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.CCCCCCC.CC(OC)(C)C>[Br:18][C:8]1[CH:7]=[CH:6][C:5]([OH:9])=[C:4]([CH3:10])[C:3]=1[CH2:2][OH:1]
Reactant: Cc1c(O)cccc1CO
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1c(O)ccc(Br)c1CO
Temperature: -33 °C
Reaction time: 0.25 h

Procedure:
3-Hydroxymethyl-2-methyl phenol (113.9 g, 824.0 mmol) was dissolved in a mixture of acetonitrile (850 mL) and trifluoroacetic acid (750.0 mL, 9,735 mmol) in a 3-neck 5-L flask under nitrogen. The reaction mixture was cooled to −33° C. N-bromosuccinimide (141 g, 791 mmol) was added over 15 minutes, with the temperature during addition in the range of −35 to −33° C. The reaction mixture was allowed to stir for an additional 15 minutes during which time the temperature decreased to −40° C. The cooling bath was removed, and potassium carbonate (741.0 g, 5,358 mmol) diluted with water to a total of 1.0 L was added. Off-gassing was observed, and the temperature increased to 25° C. MTBE (1.5 L) was added, and the reaction mixture was transferred to a separatory funnel. The layers were separated. The aqueous layer was diluted with water (500 mL) and extracted with MTBE (1 L)+EtOAc (500 mL), and then MTBE (500 mL)+EtOAc (250 mL). The combined organic layers were washed with water (240 mL) and dried over sodium sulfate. The sodium sulfate was removed by filtration, washed with additional MTBE and concentrated under reduced pressure. MTBE (684 mL, 2 volumes) was added, and the suspension was heated to 40° C. to produce a homogeneous solution. The solution was allowed to cool to room temperature. Six volumes of heptane were added, and the suspension was stirred overnight. The suspension was filtered, and the crystals were washed with 4:1 heptane: MTBE (500 mL), followed by heptane (500 mL). The solid was dried under vacuum, providing 4-bromo-3-hydroxymethyl-2-methyl phenol.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([N:12]=[CH:13][C:4]2=[C:3]([C:14]([O:16]CC)=O)[N:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:19](=[N:22]O)([NH2:21])[CH3:20]>>[CH3:20][C:19]1[N:22]=[C:14]([C:3]2[N:2]=[CH:1][N:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:12]=[CH:13][C:4]=23)[O:16][N:21]=1
Reactant: CCOC(=O)c1ncn2c1cnc1ccccc12
Reactant: CC(N)=NO
Product: Cc1noc(-c2ncn3c2cnc2ccccc23)n1

Procedure:
M.p. 269°-270° C., from ethyl imidazo[1,5-a]quinoxaline-3-carboxylate and acetamide oxime. (Compound 11)