Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[N:17][C:12]=2[CH:11]=1.Br[C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:32]([CH3:40])[CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)(=[O:31])=[O:30])=[CH:25][CH:24]=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>O1CCOCC1.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]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH:18][C:23]3[CH:28]=[CH:27][C:26]([S:29]([N:32]([CH3:40])[CH2:33][CH2:34][N:35]4[CH2:36][CH2:37][CH2:38][CH2:39]4)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: CN(CCN1CCCC1)S(=O)(=O)c1ccc(Br)cc1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(N)nnc3c2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(S(=O)(=O)N(C)CCN5CCCC5)cc4)nnc3c2)c1
Temperature: 100 °C

Procedure:
7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.33 mmol, 1.0 equiv), 4-bromo-N-methyl-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide (0.5 mmol, 1.5 equiv), Cs2CO3 (0.99 mmol, 3.0 equiv), Pd2(dba)3 (0.033 mmol, 0.10 equiv.), and Xantphos (0.066 mmol, 0.2 equiv) were dissolved in 10 mL dioxane and refluxed at 100° C. under an argon atmosphere for 18 h. The reaction was cooled to room temperature and filtered. The filtrate was dissolved in EtOAc and washed with saturated NaHCO3 and brine, and the organic phase was dried (Na2SO4). The organics were concentrated under reduced pressure to afford residue that was purified by reverse phase HPLC using a 10-50-75 gradient over 30 minutes, and again concentrated under reduced pressure to afford 4-[7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-N-methyl-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide, as a tan residue (168 mg, 90% yield). Rf=0.50 (9:1 DCM/MeOH) MS (ES+) m/z=567. LC retention time 2.82 min.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[CH:23]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:28]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:29])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Reactant: O=C(O)C1CCCC1
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3C(=O)C3CCCC3)c21
Yield: 25 %

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and cyclopentyl carboxylic acid in 25% yield. H NMR (DMSO-d6, 400 MHz, 80° C.): 1.40 (m, 1H), 1.53 (m, 2H), 1.63 (m, 8H), 1.77 (m, 4H), 3.00 (m, 1H), 3.97 (br m, 1H), 4.20 (m, 1H), 4.50 (t, J=8.0 Hz, 1H), 5.06 (br s, 1H), 6.67 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.80 (br s, 2H), 10.6 (br s, 1H). MS=407 (MH+).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.[OH-].[Na+].C1(CBr)CCCCC1.Cl>C(OC)CCC.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:10]([NH2:9])[CH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NCc1ccccn1
Reactant: O=Cc1ccccc1
Agent: BrCC1CCCCC1
Agent: CCCCOC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Product: NC(CC1CCCCC1)c1ccccn1
Yield: 43.4 %

Procedure:
Under a nitrogen atmosphere, 1.365 kg (12.86 moles) of benzaldehyde was added with stirring and cooling to 1.39 kg (12.86 moles) of 2-(aminomethyl)pyridine maintaining the temperature <50° C. After stirring for 2-4 hours, the mixture was diluted with 13 L oft-butylmethyl ether (MTBE). To the clear solution was added 1.05 kg (27.72 moles) sodium hydroxide (flakes) and 2.375 kg (6.43 moles) of tetrabutylammonium iodide. The suspension was stirred for 2 hrs., then 2.3 kg (12.86 moles) of cyclohexylmethyl bromide was added. The reaction mixture was refluxed for 36-48 hrs. After cooling the mixture, it was diluted with 3 L of water followed by 12 L of 3N hydrochloric acid and stirred for 2-6 hours. The organic phase was separated and discarded. The aqueous phase was washed four times with 3 L of methylene chloride, then basified with 2.5 L of 0.5N ammonium hydroxide solution. The racemic amine was extracted three times with 4 L of methylene chloride, dried over sodium sulfate and concentrated to dryness. The oil product was stirred with 2 L of hexane, filtered and concentrated to yield 1.14 kg (43.5%) of 1-(R,S)-(2-pyridyl)-2-cyclohexylethylamine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].[NH:10]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[C:13]=2[CH:12]=[CH:11]1.C([O-])(=O)C.[K+].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.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]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[CH:12]=[CH:11][NH:10]3)=[CH:4][C:3]=1[F:9]
Reactant: Fc1cc(I)ccc1Br
Reactant: OB(O)c1cccc2[nH]ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: Fc1cc(-c2cccc3[nH]ccc23)ccc1Br
Yield: 80.8 %

Procedure:
4-Bromo-3-fluoroiodobenzene (250 mg, 0.8 mmol, 1.2 eq.), indole-4-boronic acid (110 mg, 0.7 mmol), potassium acetate (70 mg, 1 eq.), Pd(dppf)Cl2 (70 mg, 0.1 eq.), and Cs2CO3 (700 mg, 3 eq.) in DMSO (5 mL) were heated under argon at 80° C. during 1 h. The reaction mixture was extracted from water into ether, dried Na2SO4, concentrated, and chromatographed on silica gel (5→15% EtOAc/hexanes) to give 4-(4-bromo-3-fluorophenyl)indole (164 mg, 83%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([O:9][CH2:10][CH3:11])[CH:3]=1.[Li]CCCC.[B:17](OC)([O:20]C)[O:18]C>C1COCC1>[CH2:10]([O:9][C:4]1[CH:3]=[C:2]([B:17]([OH:20])[OH:18])[CH:7]=[CH:6][C:5]=1[F:8])[CH3:11]
Reactant: COB(OC)OC
Reactant: CCOc1cc(Br)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(B(O)O)ccc1F
Reaction time: 4 h
Yield: 67.9 %

Procedure:
To a solution of 32A (3.86 g, 17.6 mmol) in THF (60 mL) at −78° C. was added n-BuLi (1.6 M in hexanes, 14.3 mL, 22.8 mmol). The mixture was stirred at −78° C. for 40 min before trimethyl borate (3.63 mL, 33 mmol) was added. The reaction was left stirring from −78° C. to rt over 4 h. It was quenched with 1.0 N HCl (40 mL), extracted with EtOAc, washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude solid product was triturated with EtOAc/hexanes (1:4). After filtration, 32B (2.2 g, 69% yield) was collected as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.42 (t, J=7.03 Hz, 3H) 4.11 (q, J=7.03 Hz, 2H) 7.03 (dd, J=11.42, 8.35 Hz, 1H) 7.18-7.29 (m, 2H) 7.35 (d, J=7.91 Hz, 1H).
Reaction SMILES: OS(O)(=O)=O.[I:6][C:7]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([I:17])[C:8]=1N.NC1C=CC=CC=1.N([O-])=O.[Na+]>CCO>[I:6][C:7]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([I:17])[CH:8]=1
Reactant: Nc1c(I)cc([N+](=O)[O-])cc1I
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: Nc1ccccc1
Product: O=[N+]([O-])c1cc(I)cc(I)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To an iced-cooled solution of concentrated H2SO4 (95-98%, 100 mL) was added in small portions 2,6-diiodo-4-nitroaniline (25 g, 64.1 mmol). After complete dissolution of the aniline, NaNO2 (9.7 g, 141 mmol) was added at 0° C. and stirred for 2 h at this temperature. Then, the viscous black solution was poured into ice (500 g) and any solid material was filtered off. The brown filtrate obtained was carefully poured into a refluxed solution of CuSO4.5H2O (1.0 g, 6.4 mmol) in EtOH (300 mL) and stirred at reflux for 2 h to reduce the diazonium salt. After cooling to room temperature, 3,5-diiodonitrobenzene precipitated from the reaction mixture. After filtration, the product was then recrystallized with hot EtOH to give 15.92 g (67%) of fine brown needles. HR-MS-EI(+): calculated for C6H3I2NO2 [M] 374.8253, found 374.8354.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([NH:13][C@H:14]([C:42]([OH:44])=O)[CH2:15][C:16](=[O:41])[NH:17][C@@H:18]2[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]2[O:20][C:21](=[O:23])[CH3:22])(=[O:12])=[O:11])=[C:5]([CH3:45])[C:4]=1[CH3:46].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[ClH:72].[C:73]([C:76]1[CH:92]=[CH:91][C:79]([CH2:80][C@H:81]([C:83]([N:85]2[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]2)=[O:84])[NH2:82])=[CH:78][CH:77]=1)(=[NH:75])[NH2:74]>CN(C=O)C>[ClH:72].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([NH:13][C@H:14]([C:42]([NH:82][C@@H:81]([C:83]([N:85]2[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]2)=[O:84])[CH2:80][C:79]2[CH:91]=[CH:92][C:76]([C:73](=[NH:74])[NH2:75])=[CH:77][CH:78]=2)=[O:44])[CH2:15][C:16](=[O:41])[NH:17][C@@H:18]2[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]2[O:20][C:21](=[O:23])[CH3:22])(=[O:12])=[O:11])=[C:5]([CH3:45])[C:4]=1[CH3:46]
Reactant: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)N[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)C(=O)O)c(C)c1C
Reactant: N=C(N)c1ccc(C[C@@H](N)C(=O)N2CCCCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)N[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)C(=O)N[C@H](Cc2ccc(C(=N)N)cc2)C(=O)N2CCCCC2)c(C)c1C
Reaction time: 24 h

Procedure:
Compound 20 (2.50 g), HOBt (0.65 g) and DCCI (1.15 g) were dissolved in DMF (100 mL) and after 1 h 4-amidino-D-phenylalanine-piperidide hydrochloride (1.50 g) was mixed in. The mixture was stirred for a further 24 h and concentrated by evaporation in vacuo. The residue was dissolved in chloroform and washed with water. The organic phase was concentrated in vacuo. The crude product obtained was purified by column chromatography on silica gel with chloroform and methanol 3:1.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[CH:22][C:21](N)=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].N([O-])=O.[Na+].[C:29](=O)(O)[O-:30].[Na+]>S(=O)(=O)(O)O.CO>[NH2:1][C:2]1[N:23]=[C:22]([O:30][CH3:29])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: Nc1cnc(N)c(C(=O)NCc2ccc(Oc3ccccc3)s2)c1
Reactant: O=C([O-])O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)c(N)n1
Reaction time: 0.5 h

Procedure:
2,5-Diamino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Preparation Example A+-10 (27 mg, 59 μmol), sodium nitrite (4.1 mg, 59 μmol) and sulfuric acid (several drops) were dissolved in methanol (5 mL), and the solution was stirred for 30 minutes under reflux. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, and the organic layer was washed with brine. The solvent was evaporated in vacuo, the residue was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), then, further by NH silica gel column chromatography (hexane:ethyl acetate=5:1), and the title compound (0.7 mg) was obtained as a white solid.
Reaction SMILES: [CH2:1]([NH:5][C@H:6]([C:22]([OH:24])=[O:23])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH:2]([CH3:4])[CH3:3].[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.Cl>[CH2:1]([N:5]([C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:6]([C:22]([OH:24])=[O:23])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CN(C(=O)c1ccccc1)[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of Nα-isobutyl-Nε-benzyloxycarbonyl-L-lysine (213 mg, 0.50 mmol) in CH2Cl2 (5 mL) was added benzoyl chloride (140 mg, 1.00 mmol) and DIEA (130 mg, 1.00 mmol). The reaction mixture was stirred at room temperature for 1 h and then diluted with 1N HCl. The mixture was extracted with EtOAc, dried over MgSO4 and evaporated to dryness. The residue was purified by flash chromatography. Elution with 70% EtOAc in hexane provided Nα-isobutyl-Nα-benzoyl-Nε-benzyloxycarbonyl-L-lysine that was further hydrogenolyzed using 10% Pd/C and then treated with 9-fluorenylmethyl chloroformate instead of N-(9-fluorenylmethoxycarbonyloxy) succinimide as outlined in step D of example 38 to provide the title compound (90% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[CH:7][C:8]=1[Cl:9])[CH3:2].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)Cl>>[Cl:9][C:8]1[CH:7]=[CH:6][C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:3]=1[CH2:1][CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCc1cc(O)ccc1Cl
Solvent: ClCCl
Product: CCc1cc(Oc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-ethyl-4-chlorophenol (2.0 g, 0.013 mol), phenylboronic acid (4.7 g, 0.038 mol), TEA (11 mL, 0.077 mol), cupric acetate (4.2 g, 0.023 mol) and DCM (60 mL, 0.9 mol) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 24 h. The solvent was then removed under reduced pressure and the resulting residue was purified by flash chromatography (5% EtOAc in Hexane).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([O:19][CH3:20])[CH:3]=1.[H-].[Na+].[CH3:23]I>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:23])[C:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: COc1cc(Br)ccc1NC(=O)CCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1N(C)C(=O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A solution of N1-(4-bromo-2-methoxyphenyl)-3-phenylpropanamide (1.0 g, 3 mmol) in dimethylformamide (20 mL) at 0° C. was treated with pre-washed (3 times with heptane) sodium hydride (0.158 g, 6.6 mmol). The reaction mixture was stirred for 1 h at 0° C. Methyl iodide (0.511 g, 3.6 mmol) was added drop-wise, and the solution stirred for 15 min at 0° C. The ice bath was removed and the reaction mixture was stirred overnight at room temperature. The reaction did not go to completion over night; additional methyl iodide (0.511 g, 3.6 mmol) was added and the reaction mixture stirred over night. The reaction mixture was quenched with water (30 mL). Ethyl acetate was added, and the layers were partitioned. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting 3:1 heptane:ethyl acetate, and afforded 0.729 g (70%) of N1-(4-bromo-2-methoxyphenyl)-N1-methyl-3-phenylpropanamide. 1H NMR (DMSO-d6, 400 MHz) δ 7.330-7.326 (s, 1H), 7.235-7.178 (m, 2H), 7.161-7.116 (m, 3H), 7.058-7.040 (m, 2H), 3.811 (s, 3H), 3.002 (s, 3H), 2.753-2.708 (m, 2H), 2.282-2.204 (m, 1H), 2.138-2.061 (m, 1H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 7.366 min (96%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([F:13])[C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH3:14][O:15][C:16]([C@@H:18]1[O:20][CH2:19]1)=[O:17].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C>[F:13][C:11]1[C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=[C:2]([NH:1][CH2:19][C@@H:18]([OH:20])[C:16]([O:15][CH3:14])=[O:17])[CH:12]=1
Reactant: COC(=O)[C@H]1CO1
Reactant: Cn1c(=O)oc2cc(N)cc(F)c21
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: COC(=O)[C@H](O)CNc1cc(F)c2c(c1)oc(=O)n2C
Temperature: 90 °C
Yield: 99.6 %

Procedure:
A mixture of 6-amino-4-fluoro-3-methyl-1,3-benzoxazol-2(3H)-one (Step 7, 0.630 g, 3.46 mmol), methyl (2R)-glycidate (0.353 g, 3.46 mmol) and lithium trifluoromethanesulfonate (0.540 g, 3.46 mmol) in acetonitrile (10 ml) is stirred and heated at 90° C. overnight. The reaction mixture is diluted with ethyl actetate, washed with water and saline, dried (MgSO4), and evaporated under reduced pressure. Final purification by flash column chromatography (50% ethyl acetate/hexane) gives pure product as a white solid (0.98 g, 60%); MS for C12H13FN2O5 m/z 285 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH2:15][CH2:16][CH3:17])=[N:13][C:12]([SH:18])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:19]([O-:22])(O)=[O:20]>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([CH2:15][CH2:16][CH3:17])=[N:13][C:12]([S:18][S:18][C:12]3[N:13]=[C:14]([CH2:15][CH2:16][CH3:17])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:19]([O-:22])=[O:20])=[CH:5][CH:6]=4)[N:11]=3)=[N:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCCc1nc(S)nn1-c1ccc([N+](=O)[O-])cc1
Solvent: O
Product: CCCc1nc(SSc2nc(CCC)n(-c3ccc([N+](=O)[O-])cc3)n2)nn1-c1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 35 parts of 1-(4-nitrophenyl)-5-propyl-1H-1,2,4-triazole-3-thiol, 83 parts of concentrated nitric acid solution and 150 parts of water is stirred and warmed to 60° C. While stirring, the mixture is allowed to cool to room temperature and the whole is further stirred overnight at room temperature. The precipitated product is filtered off, washed with water and added to a hot solution of 20 parts of potassium carbonate in 200 parts of water at 100° C. The reaction mixture is allowed to cool to room temperature while stirring. The precipitated product is filtered off, dried and crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and recrystallized from 4-methyl-2-pentanone, yielding 19.8 parts of 3,3'-dithiobis[1-(4-nitrophenyl)-5-propyl-1H-1,2,4-triazole]; mp. 171.5° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([F:14])([F:13])[CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=1.[F:16][C:17]([F:26])([F:25])[C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.N.CO>C(O)C>[F:13][C:11]([C:9]1[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=[C:2]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([C:17]([F:16])([F:25])[F:26])=[CH:19][CH:20]=3)[N:7]2[N:8]=1)([F:14])[CH3:12]
Reactant: Cc1cc(Cl)n2nc(C(C)(F)F)nc2n1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: N
Solvent: CCO
Solvent: CO
Product: Cc1cc(Nc2ccc(C(F)(F)F)cc2)n2nc(C(C)(F)F)nc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of Intermediate 3 (10 g, 43 mmol) in ethanol (150 mL), 4-(trifluoromethyl)aniline (ALDRICH, 6.93 g, 43 mmol) was added and the mixture was stirred at room temperature for 1 h. 7M Ammonia in MeOH (6.14 mL, 43 mmol) was added to neutralize the hydrochloride salt and solvent was removed in vacuo. The crude mixture was purified by flash chromatography (Si, eluting with Hexane/EtOAc mixtures from 95:5 to 40:60%) to yield the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1
Reactant: C1=COCCC1
Reactant: COc1cc(Br)c2cn[nH]c2c1
Solvent: C1CCOC1
Product: COc1cc(Br)c2cnn(C3CCCCO3)c2c1
Yield: 111.7 %

Procedure:
A round-bottom flask was charged with 4-bromo-6-methoxy-1H-indazole (1.00 g, 4.40 mmol), TsOH monohydrate (39 mg, 0.22 mmol), 3,4-dihydro-2H-pyran (1.48 g, 17.6 mmol), and THF (40 mL). The reaction mixture was degassed with nitrogen and refluxed for 18 h, and the solvent was then removed in vacuo. The residue was purified by SiO2 chromatography to afford 4-bromo-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.53 g, quantitative) as a yellow solid. MS (ESI) m/z: 311.2 [M+1]+.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][N:6]([C:8](=[O:19])[CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:11])[CH3:7])C.[OH-].[Na+]>CO>[C:15]([O:14][C:12]([N:10]([CH3:11])[CH2:9][C:8]([N:6]([CH2:5][C:4]([OH:20])=[O:3])[CH3:7])=[O:19])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)CN(C)C(=O)CN(C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CC(=O)O)C(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 65 °C

Procedure:
The ester was taken up in 49 mL of methanol, and to this was added a 1 M NaOH solution (25.1 mL, 25 mmol). The reaction mixture was heated at 65° C. for 3 h. The reaction mixture was cooled, and methanol was removed under reduced pressure. The residue was diluted with 50 mL of water and acidified with glacial acetic acid until the pH was 5. This solution was extracted with EtOAc (50 mL), and the organic layer was separated and dried over Na2SO4, and the solvent was removed under reduced pressure to give {[2-(tert-Butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid as an oil.
Reaction SMILES: O[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].OC1C=C(O)C=CC=1C(C1C=CC=CC=1)=O.OC1C=C(O)C=CC=1C(C1C=CC=CC=1O)=O.OC1C=C(OC)C=CC=1C(C1C=CC=CC=1O)=O>>[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:2]=1
Reactant: O=C(c1ccccc1)c1ccccc1O
Agent: COc1ccc(C(=O)c2ccccc2O)c(O)c1
Agent: O=C(c1ccccc1)c1ccc(O)cc1O
Agent: O=C(c1ccccc1O)c1ccc(O)cc1O
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
2-Hydroxybenzophenone, 2,4-dihydroxybenzophenone, 2,2′,4-trihydroxybenzophenone, 2,2′,4,4′-tetrahydroxybenzophonone, 2,2′-dihydroxy-4-methoxybenzophenone, and the like.