Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](Br)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(CC)CC.[C:19]([C:23]1[CH:28]=[C:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:26]([CH3:37])=[CH:25][C:24]=1[SH:38])([CH3:22])([CH3:21])[CH3:20]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:19]([C:23]1[CH:28]=[C:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[C:26]([CH3:37])=[CH:25][C:24]=1[S:38][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1cc(S)c(C(C)(C)C)cc1O[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Sc2cc(C)c(O[Si](C)(C)C(C)(C)C)cc2C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 96 h

Procedure:
A mixture of tosyl bromide (1.82 g, 7.76 mmol), Et3N (1.08 mL, 7.76 mmol), and CCl4 (15 mL) was cooled to 0° C. and treated with a solution of 2-tert-butyl-4-(tert-butyl-dimethyl-silanyloxy)-5-methyl-benzenethiol (prepared in Example III; 1.94 mmol) in CCl4 (15 mL) via addition funnel over a period of 45 minutes. The mixture was then allowed to warm to room temperature where it was stirred for 4 days. The mixture was diluted with CH2Cl2 and quenched with saturated NH4Cl. The layers were separated, the organic layer dried (Na2SO4) and the solvent removed in vacuo. The residue was submitted to column chromatography (3:1 hexanes:CH2Cl2 to 1:1 hexanes:CH2Cl2) to provide the title compound. 1H NMR (CDCl3) δ 0.0 (s, 6 H), 0.78 (s, 9 H), 0.97 (s, 9 H), 1.84 (s, 3 H), 2.18 (s, 3 H), 6.60 (s, 1 H), 6.94-7.02 (m, 4 H), 7.25 (s, 1 H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.C(O)(C)C>[CH:21]1[C:22]2[C:17](=[CH:16][C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:24][CH:23]=2)[CH:18]=[CH:19][N:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc3cnccc3c2)CC1
Agent: Cl
Solvent: CC(C)O
Product: c1cc2cc(NC3CCNCC3)ccc2cn1
Yield: 114.7 %

Procedure:
258 mg (0.79 mmol) 4-(Isoquinolin-6-ylamino)-piperidine-1-carboxylic acid tert-butyl ester were stirred in 6N HCl in isopropanol for 2 h. After evaporation the residue was taken up in water and lyophilized. 206 mg of Isoquinolin-6-yl-piperidin-4-yl-amine as the hydrochloride could be obtained.
Reaction SMILES: CCC1C2N=C(C=C3C(C=C)=C(C)C(=CC4[C@@H](C)[C@H](CCC(O)=O)C(=C(CC(O)=O)C5NC(C=2)=C(C)C=5C(O)=O)N=4)N3)C=1C.[CH3:45][CH2:46][C:47]1[C:51]2=[CH:52][C:53]3[N-:57][C:56]4[C:58]([C@@H:100]([C:103]([O:105][CH3:106])=[O:104])[C:101](=[O:102])[C:55]=4[C:54]=3[CH3:107])=[C:59]3[N:63]=[C:62]([CH:64]=[C:65]4[N-:70][C:68](=[CH:69][C:49](=[N:50]2)[C:48]=1[CH3:108])[C:67]([CH:71]=[CH2:72])=[C:66]4[CH3:73])[C@@H:61]([CH3:74])[C@@H:60]3[CH2:75][CH2:76][C:77]([O:79][CH2:80]/[CH:81]=[C:82](/[CH2:84][CH2:85][CH2:86][C@@H:87]([CH2:89][CH2:90][CH2:91][C@@H:92]([CH2:94][CH2:95][CH2:96][CH:97]([CH3:99])[CH3:98])[CH3:93])[CH3:88])\[CH3:83])=[O:78].[Mg+2]>>[CH3:45][CH2:46][C:47]1[C:48]([CH3:108])=[C:49]2[NH:50][C:51]=1[CH:52]=[C:53]1[N:57]=[C:56]3[C:55]([C:101]([C@H:100]([C:103]([O:105][CH3:106])=[O:104])[C:58]3=[C:59]3[N:63]=[C:62]([CH:64]=[C:65]4[NH:70][C:68](=[CH:69]2)[C:67]([CH:71]=[CH2:72])=[C:66]4[CH3:73])[C@@H:61]([CH3:74])[C@@H:60]3[CH2:75][CH2:76][C:77]([O:79][CH2:80]/[CH:81]=[C:82](/[CH2:84][CH2:85][CH2:86][C@@H:87]([CH2:89][CH2:90][CH2:91][C@@H:92]([CH2:94][CH2:95][CH2:96][CH:97]([CH3:98])[CH3:99])[CH3:93])[CH3:88])\[CH3:83])=[O:78])=[O:102])=[C:54]1[CH3:107]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[n-]c(cc6nc(cc1[n-]2)C(C)=C6CC)c(C)c5C(=O)[C@@H]4C(=O)OC)[C@@H](CCC(=O)OC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@@H]3C
Agent: C=Cc1c(C)c2cc3nc(c(CC(=O)O)c4[nH]c(cc5nc(cc1[nH]2)C(C)=C5CC)c(C)c4C(=O)O)[C@@H](CCC(=O)O)[C@@H]3C
Agent: [Mg+2]
Product: C=Cc1c(C)c2cc3nc(c4c5nc(cc6[nH]c(cc1[nH]2)c(C)c6CC)C(C)=C5C(=O)[C@@H]4C(=O)OC)[C@@H](CCC(=O)OC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@@H]3C

Procedure:
According to a preferred embodiment, the chlorin e6-protocol B comprises the steps of: (a) treating chlorophyll-a obtained by the above method with the acid to eliminate Mg2+ from chlorophyll-a, thereby obtaining the precipitate of pheophytin a; (b-1) adding the acetone solvent to the precipitate of pheophytin a to obtain a solution of pheophytin a; and (b-2) treating the pheophytin a solution with the base to obtain chlorin e6.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([N:25]5[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]5)[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[N:13][N:14]=[C:8]2[CH:7]=1.Cl.[OH-].[Na+]>C1COCC1.CO.O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[N:13][N:14]=[C:8]2[CH:7]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(N5CCN(C(=O)OC(C)(C)C)CC5)c4n3)nnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: COCCOc1ccn2c(-c3ccc4cccc(N5CCNCC5)c4n3)nnc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.7 %

Procedure:
To a solution of tert-butyl 4-(2-(7-(2-methoxyethoxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yl)piperazine-1-carboxylate (0.022 g, 0.0436 mmol) in THF/MeOH (1 mL) was added 4 M HCl (0.109 mL, 0.436 mmol) in dioxane. The reaction mixture was stirred at ambient temperature for 16 hours then neutralized with 1 M NaOH and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified via flash column chromatography (40:1 DCM/MeOH followed by 10:1 DCM/MeOH) to provide 4 mg (23%) of desired product as a yellow solid. MS APCI (+) m/z 405.4 (M+1) detected.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[N:9][N:10]=[C:6]2[C:5]([N+:11]([O-])=O)=[C:4]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:3]=1[CH3:27]>[Pd].C(#N)C>[NH2:11][C:5]1[C:6]2[N:7]([N:8]=[N:9][N:10]=2)[C:2]([CH3:1])=[C:3]([CH3:27])[C:4]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25]
Reactant: Cc1c(NCCCCNC(=O)OC(C)(C)C)c([N+](=O)[O-])c2nnnn2c1C
Agent: [Pd]
Solvent: CC#N
Product: Cc1c(NCCCCNC(=O)OC(C)(C)C)c(N)c2nnnn2c1C
Reaction time: 5 h
Yield: 80.9 %

Procedure:
A mixture of tert-butyl 4-[(5,6-dimethyl-8-nitrotetraazolo[1,5-a]pyridin-7-yl)amino]butylcarbamate (9.00 g, 23.7 mmol), 10% palladium on carbon (900 mg), and acetonitrile (100 mL) was hydrogenated on a Parr apparatus for 5 hours. The mixture was filtered through CELITE filter agent, which was rinsed afterwards with methanol. The filtrate was concentrated under reduced pressure to yield 6.70 g of tert-butyl 4-[(8-amino-5,6-dimethyltetraazolo[1,5-a]pyridin-7-yl)amino]butylcarbamate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]3[O:14][C@@H:8]3[C:7]=2[CH:15]=1)#[N:2].[CH3:16][N:17]1[N:21]=[N:20][C:19]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:18]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@H:9]([OH:14])[C@@H:8]([N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][C:19]3[N:20]=[N:21][N:17]([CH3:16])[N:18]=3)[C:7]=2[CH:15]=1)#[N:2]
Reactant: Cn1nnc(CNc2ccccc2)n1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@H]2O[C@H]21
Product: Cn1nnc(CN(c2ccccc2)[C@H]2c3cc(C#N)ccc3OC(C)(C)[C@@H]2O)n1
Yield: 77.4 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using (3R,4R)-6-cyano-2,2-dimethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (200 mg, 0.99 mmol) and N-(2-methyl-2H-tetrazol-5-ylmethyl)phenylamine (188 mg, 0.99 mmol). The crude product was purified, to give desired compound (299 mg, yield: 77%).
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25]([C:26]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]([CH2:45][CH2:46][CH3:47])=[N:5][C:4]=1C=O.C([O:53][CH2:54][CH3:55])(=O)C>C1COCC1>[OH:53][CH2:54][C:55]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25]([C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:24]=[N:23][N:22]=3)=[CH:13][CH:14]=2)[C:6]([CH2:45][CH2:46][CH3:47])=[N:5][C:4]=1[CH:3]=[CH2:2]
Reactant: CCCc1nc(C=O)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1nc(CCC)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
The suspension became a dark yellow solution. Afterwards, a solution of 5-hydroxymethyl-2-n-propyl-1-[(2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl-4-yl)methyl]imidazole-4-carboxaldehyde (1.31 g, 2.0 mmol, 1.0 eq) in THF (minimum to dissolve) was added thereto and the resultant light milky yellow solution was stirred overnight at room temperature. The solution was diluted with ethyl acetate and washed with water (3×). The organic layer was dried (MgSO4), the solvent removed in vacuo, and the residue flash chromatographed over silica gel in 1:1 hexane/ethyl acetate to yield 620 mg (48%) of a white glass: NMR (DMSO-d6) δ 7.79 (d,1H,J=7Hz); 7.62 (t,1H,J=7Hz); 7.55 (t,1H,J=7Hz); 7.45 (d,1H,J=7Hz); 7.41-7.18 (m,9H); 7.06 (d,2H,J=9Hz); 6.95-6.80 (m,8H); 6.80-6.55 (m,1H); 5.73 (d of d,1H,J=17,3 Hz); 5.17 (s,2H); 5.10 (t,1H,J=7Hz); 5.05 (d of d,1H,J=12,3Hz); 4.28 (d,2H,J=7Hz); 2.37 (t,2H,J=7Hz); 1.50 (t of q,2H,J=7,7Hz); 0.78 (t,3H,J=7Hz). IR (neat) 1029; 1006; 909; 733; 698 cm-1. Anal. calcd. for C42H38N6O.H2O: C, 76.34; H, 6.10; N, 12.72. Found: C, 76.49; H, 5.88; N, 12.52. ##STR80##
Reaction SMILES: Cl.[Si]([O:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[N:19][C:20]=1[CH:21](OC)[O:22]C)[N:17]([C:26]([NH:28][C:29]1[CH:34]=[C:33]([NH:35][CH2:36][C:37]([OH:40])([CH3:39])[CH3:38])[C:32]([C:41]#[N:42])=[CH:31][N:30]=1)=[O:27])[CH2:16][CH2:15][CH2:14]2)(C(C)(C)C)(C)C.C([O-])(O)=O.[Na+]>C1COCC1.O>[C:41]([C:32]1[C:33]([NH:35][CH2:36][C:37]([OH:40])([CH3:38])[CH3:39])=[CH:34][C:29]([NH:28][C:26]([N:17]2[C:18]3[C:13](=[CH:12][C:11]([CH2:10][OH:9])=[C:20]([CH:21]=[O:22])[N:19]=3)[CH2:14][CH2:15][CH2:16]2)=[O:27])=[N:30][CH:31]=1)#[N:42]
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Nc1cc(NCC(C)(C)O)c(C#N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)CNc1cc(NC(=O)N2CCCc3cc(CO)c(C=O)nc32)ncc1C#N
Reaction time: 4.5 h

Procedure:
Concentrated hydrochloric acid (0.17 ml) was added to a solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-((2-hydroxy-2-methylpropyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 78C, 30 mg, 0.051 mmol) in THF (1 ml) and water (0.5 ml) at room temperature. After stirring for 1 h at room temperature additional concentrated hydrochloric acid (0.17 ml) was added and stirring continued for a further 4.5 h. Saturated aqueous NaHCO3 was then added, the mixture extracted with DCM (2×), the organic layers dried over Na2SO4 and evaporated. The residue was purified by reversed phase preparative chromatography (RP 2) to give the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=1>>[O:14]=[C:6]1[C:5]2[CH:15]=[CH:16][C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=3)=[CH:3][C:4]=2[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: CC(=O)Nc1ccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Yield: 13.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (50 mg, 0.22 mmol) and N-(4-Amino-phenyl)-acetamide (38 mg, 0.33 mmol) to provide 234 (10 mg, 17% yield) as a brown solid. LC-MS (M+H=345, obsd.=345).
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[S:17])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C([N:23](CC)CC)C.N>ClCCl.O>[CH:5]1([C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:23])=[S:17])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: OC(=S)c1ccc(C2CCCCCC2)cc1
Reactant: CCN(CC)CC
Agent: N
Solvent: ClCCl
Solvent: O
Solvent: O=S(Cl)Cl
Product: NC(=S)c1ccc(C2CCCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.4 %

Procedure:
Add thionyl chloride (1.35 mL, 18.4 mmol) to a mixture of 4-cycloheptylthio-benzoic acid (984 mg, 3.93 mmol) in dichloromethane (15 mL) at 0° C. Heat the mixture to reflux for 1 h. Cool the mixture to room temperature and concentrate in vacuo. Dissolve the residue in dichloromethane (20 mL) and cool to 0° C. Add triethylamine (1.1 mL, 7.86 mmol) and bubble ammonia gas through the solution Warm the mixture to room temperature and stir for 1 h. Dilute with water (20 mL) and extract the aqueous phase with dichloromethane (3×20 mL). Wash the combined organic extracts with saturated aqueous NaHCO3 (20 mL). Dry the organic solution over Na2SO4, filter and concentrate in vacuo to provide the desired intermediate as an off-white solid (976 mg, 99%). MS (APCI) m/z: 250 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26](O)=[O:27])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:19]=[CH:20][C:21]([CH:24]=[CH:25][C:26]([NH:38][S:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:37])=[O:36])=[O:27])=[CH:22][CH:23]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Product: O=C(C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1)NS(=O)(=O)c1ccccc1

Procedure:
Prepared from the coupling of 2e and benzene sulfonamide by the method described in Procedure 1, Method A. Yield (70%); 1H NMR (d6-DMSO) δ 12.25 (s, 1H), 7.94 (d, J=7.3 Hz, 2H), 7.66 (m, 3H), 7.42 (d, J=15.7 Hz, 1H), 7.34-7.14 (m, 10H), 6.88 (d, J=8.1 Hz, 2H), 6.72 (d, J=7.3 Hz, 1H), 6.48 (d, J=15.7 Hz, 1H), 2.79 (m, 2H), 2.28 (m, 2H), 2.09 (m, 2H); ESI m/z: 504 (M−H−, 100%).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Na+].[I-].[H-].[Na+].[CH3:18][O:19][C:20]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[C:25]([OH:32])[CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21]>CN(C=O)C.C(Cl)Cl>[CH3:18][O:19][C:20]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[C:25]([O:32][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21]
Reactant: CCCCCCCCCCCCBr
Reactant: COC(=O)c1ccc2cccc(O)c2n1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1cccc2ccc(C(=O)OC)nc12
Reaction time: 8 h
Yield: 14 %

Procedure:
In a first step, dodecyl bromide (767 μL, 3.2 mmol), NaI (478 mg, 3.2 mmol) and NaH (76 mg, 3.2 mmol) were added to a solution of 8-hydroxyl-quinoline-2-carboxylic acid methyl ester (2.11 mmol) stirring in DMF (dry, 10 mL), and the red reaction was allowed to stir overnight. The crude material resulting from removal of solvents by rotary evaporation was taken into DCM, washed with water, dried over Na2SO4, and filtered. The resulting solution was evaporated to dryness and the desired intermediate, 8-dodecyloxy-quinoline-2-carboxylic acid methyl ester, was obtained by HPLC (isocratic, 75% acetonitrile, 25% water) yielding 169 mg (about 14% yield). This intermediate was in turn deprotected using LiOH in THF/H2O as described in the method of Example 336 to yield the title compound, which was utilized further without additional purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH:14][C:15](=O)[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[OH:17].[OH-].[Na+]>C1(C)C=CC=CC=1>[OH:17][CH:16]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH2:15][NH:14][CH2:13][CH2:12][C:3]1[CH:4]=[CH:5][C:6]([O:10][CH3:11])=[C:7]([O:8][CH3:9])[C:2]=1[Cl:1]
Reactant: COc1ccc(C(O)C(=O)NCCc2ccc(OC)c(OC)c2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc(C(O)CNCCc2ccc(OC)c(OC)c2Cl)cc1
Reaction time: 4 h
Yield: 77.2 %

Procedure:
10.58 g of N-(2-chloro-3,4-dimethoxyphenylethyl)-4-methoxymandelamide was dissolved in 105.8 ml of toluene. A solution of 16.5 ml of Vitrite in 16.5 ml of toluene was added dropwise to the solution at room temperature. Then the reaction was conducted at 50° C. for 4 hours. After cooling, 100 ml of a 10% NaOH solution was added dropwise thereto and the mixture was left to stand overnight. Crystals thus formed were separated by filtration, washed with water and dried to obtain 7.87 g (yield: 77.2%) of N-[2-hydroxy-2-(4-methoxyphenyl)ethyl]-2-(2-chloro-3,4-dimethoxyphenyl)ethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:17](O)(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccncc1
Reactant: COc1ccc(N)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2ccncc2)cc1
Temperature: 23 °C
Reaction time: 4 h
Yield: 87.6 %

Procedure:
A solution of p-anisidine (2.46 g, 20 mmol) and triethylamine (13.9 mL, 100 mmol) in ethyl acetate (200 mL) was treated with isonicotinic acid (2.46 g, 20 mmol) followed by 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 15.1 mL, 24 mmol). After stirring at 23° C. for 4 h, the reaction mixture was diluted with ethyl acetate, was washed with water and with brine, and the organic layer was dried (MgSO4), was filtered, and was concentrated in vacuo. Purification by silica gel chromatography with chloroform-methanol (40:1) gave 4 g (88% yield) of the title compound; diagnostic 13C NMR signals (100 MHz, CD3OD/CDCl3) δ 164.825, 157.213, 149.758, 143.349, 130.989, 123.085, 122.068, 55.285; MS (AP/Cl) 229.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([CH3:14])[C:5](=[O:13])[N:6]([CH2:9][CH2:10][CH2:11][CH3:12])[C:7]=1[CH3:8].[N:16]([O-])=O.[Na+].[OH-].[Na+]>O.Cl>[CH2:9]([N:6]1[C:7]2[CH:8]=[N:16][NH:1][C:2]=2[C:3](=[O:15])[N:4]([CH3:14])[C:5]1=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: O=N[O-]
Reactant: CCCCn1c(C)c(N)c(=O)n(C)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCn1c(=O)n(C)c(=O)c2[nH]ncc21
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To 1.03 g (4.88 mmol) of 5-amino-1-butyl-3,6-dimethyl-1H-pyrimidine-2,4-dione in 20 mL H2O and 5 mL conc HCl at 0° C. was added a solution of 320 mg (4.64 mmol) of NaNO2 and 3 mL H2O in drops such that the internal reaction temperature does not exceed 5° C. (10 min). After stirring for an additional 10 min, the resulting slurry was added in drops to a 0° C. solution of 20% aq. NaOH. After addition is complete, the resulting solution is stirred at 23° C. for 20 min, neutralized to pH ~7 with dilute aq. HCl, poured into 200 mL of pH 7 buffer, and extracted with 2×150 mL EtOAc. The combined organics were dried over Na2SO4, filtered and evaporated to an orange solid. Flash chromatography on silica gel, eluting with CH2Cl2 /EtOAc (20/1 to 4/1), gave 617 mg (2.78 mmol, a 57% yield) of the title compound as an off-white solid. mp: 160-162° C.; 1H NMR (300 MHz, CDCl3): δ 0.98 (t, J=7.4 Hz, 3H), 1.44 (hex, J=7.3 Hz, 2H), 1.71-1.80 (m, 2H), 3.47 (s, 3H), 3.95 (t, J=7.4 Hz, 2H), 7.56 (s, 1H); IR (KBr, cm-1): 3142w, 2953w, 2932w, 1708s, 1649s, 1610s, 1296w; MS (ES) m/z (relative intensity): 223 (M+ +H, 100). Anal. Calcd for C10H14N4O2 : C, 54.04; H, 6.35; N, 25.21. Found: C, 52.50; H, 6.23; N, 22.64.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:41][CH2:42][F:43]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:41][CH2:42][F:43])=[CH:22][CH:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C[C@@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C[C@@H](Cc1ccc(OCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
To 93 mg (0.2 mmol) of di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-(4-hydroxybenzyl)-D-glutamate in 4 mL N,N-dimethylformamide were added 56 mg (0.4 mmol) of powdered potassium carbonate and 69.6 mg (0.40 mmol) of 1-iodo-2-fluoroethane and the resulting suspension was heated for 1 h at 100° C. in a microwave oven. The reaction mixture was then filtered, the solvent evaporated and the residue was taken up in ethyl acetate and water. The organic phase was separated off, washed with water until neutral, dried over sodium sulfate and filtered, and the filtrate was concentrated in vacuo. Di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-[4-(2-fluoroethoxy)benzyl]-D-glutamate was obtained as crude product (40 mg, 39.1%) and deprotected without further purification: 2 mL of trifluoro acetic acid were added to the oily residue and the solution was stirred for 2 d at room temperature. The excess of trifluoro acetic acid was evaporated and the residue was taken up three times in tetrahydrofuran and then evaporated. The resulting oil was chromatographed on C-18 reversed phase silica gel using a water/acetonitrile gradient, the appropriate fractions were combined and concentrated.
Reaction SMILES: C([C@@H]1COC(=O)N1C(=O)[C@H]([CH2:19][S:20]([Cl:23])(=[O:22])=[O:21])C(C)C)C1C=CC=CC=1.[CH3:25][O:26][C:27]([C:29]1(SC(=O)C)[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1C)=[O:28]>>[CH3:25][O:26][C:27]([C:29]1([CH2:19][S:20]([Cl:23])(=[O:22])=[O:21])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)=[O:28]
Reactant: COC(=O)C1(SC(C)=O)CCCCC1C
Reactant: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Product: COC(=O)C1(CS(=O)(=O)Cl)CCCCC1
Yield: 96 %

Procedure:
Prepared according to the method for the preparation of 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methyl butyryl)oxazolidin-2-one, from 1-acetylsulfanyl-methylcyclohexanecarboxylic acid methyl ester (20 g), to provide the title compound as a red oil (14 g, 96%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]([CH3:11])=[CH2:10].[Br:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[OH:20]>CN(C=O)C>[Br:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[O:20][CH2:8][C:9]([CH3:11])=[CH2:10]
Reactant: C=C(C)CCl
Reactant: Oc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1ccc(F)cc1Br
Temperature: 60 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Potassium carbonate (829 mg, 6.00 mmol) and 3-chloro-2-methyl-1-propene (0.591 mL, 6.00 mmol) were added to a solution (25 mL) of 2-bromo-4-fluorophenol (955 mg, 5.00 mmol) in DMF, and stirred at 60° C. overnight. The solvent was distilled away under reduced pressure, and after diluted with ethyl acetate, the resultant was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away, and the resulting residue was purified by silica gel chromatography (hexane/ethyl acetate) to thus obtain the title compound.