Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[N:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([NH:27][C:24]1[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Nc1ccncc1
Product: COc1ccc2c(Nc3ccncc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and pyridin-4-ylamine to give 6-methoxy-N3-(5-methyl-1H-pyrazol-3-yl)-N1-pyridin-4-yl-isoquinoline-1,3-diamine. LC-MS m/e 347(MH+).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:63])[C@@H:22]([NH:52]C(OCC1C=CC=CC=1)=O)[CH2:23][S:24][CH2:25][C@H:26]([O:40][C:41](=[O:51])[NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:27][O:28][C:29](=[O:39])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>C(Cl)Cl>[NH2:52][C@@H:22]([CH2:23][S:24][CH2:25][C@H:26]([O:40][C:41](=[O:51])[NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:27][O:28][C:29](=[O:39])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:21](=[O:63])[NH:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][P:4](=[O:3])([OH:5])[OH:8]
Reactant: CCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)NCCCCCCCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCCCCCCCNC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCOCCP(=O)(O)O)OC(=O)NCCCCCCCC
Temperature: 32 °C
Reaction time: 8 h

Procedure:
To a solution of (14R,18R)-14-(benzyloxycarbonylamino)-18-(octylcarbamoyloxy)-13,21-dioxo-3,6,9,20-tetraoxa-16-thia-12,22-diazatriacontylphosphonic acid diethyl ester (1 eq) in DCM (0.1 M) was added trimethylsilyl bromide (10 eq). The reaction mixture was stirred at 32° C. overnight then cooled to room temperature, diluted with DCM and concentrated. The crude material was dried under high vacuum for 2 hours then purified by reverse phase high performance liquid chromatography (HPLC) with a C4 column eluting with a gradient of 40-100% MeCN/10 mM NH4OAc (95:5) in 10 mM NH4OAc (pH 9) to afford (14R,18R)-14-amino-18-(octylcarbamoyloxy)-13,21-dioxo-3,6,9,20-tetraoxa-16-thia-12,22-diazatriacontyl phosphonic acid as a white solid. 1H NMR (DMSO-d6): δ 8.57 (t, 1H), 7.42 (m, 2H), 4.78 (m, 1H), 4.01 (m, 2H), 3.0-3.6 (m, 18H), 2.88 (m, 4H), 2.52-2.81 (m, 5H), 1.68 (m, 2H), 1.54 (m, 2H), 1.40 (m, 2H), 1.12-1.24 (m, 20H), 0.82 (t, 6H). LRMS [M+H]=745.4.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:23][CH3:24])=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1.[F-:25].[K+]>CC(N(C)C)=O>[F:25][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:23][CH3:24])=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(-c3ccc(C(C)C)cc3)c2cc1OC
Reactant: [F-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2nc(F)nc(-c3ccc(C(C)C)cc3)c2cc1OC
Yield: 33.3 %

Procedure:
A solution of 80 mg (0.23 mmol) 2-chloro-4-(4-isopropyl-phenyl)-6,7-dimethoxy-quinazoline and 100 mg (1.70 mmol) KF in 1 ml dimethylacetamide is stirred at 90° C. for 5 days. After extraction (ethyl acetate/brine) the organic layer is dried and evaporated. Flash-chromatography (hexane/ethyl acetate) yields 25 mg (33%) of the product as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16]C)=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH:11]([CH3:13])[CH3:12])[S:7][C:6]=2[C:14]=1[Cl:15].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH:11]([CH3:13])[CH3:12])[S:7][C:6]=2[C:14]=1[Cl:15]
Reactant: COc1cc2cc(CC(C)C)sc2c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)Cc1cc2cc(O)c(Cl)c(Cl)c2s1
Yield: 70.1 %

Procedure:
A mixture of 12 g of 6,7-dichloro-5-methoxy-2-isobutylbenzo[b]thiophene and 130 g of pyridine hydrochloride is heated at 190°-200° for 4 hrs. The cooled mixture is poured onto ice and extracted with ether. The ether extracts are washed with 10% hydrochloric acid, water, dried over anhydrous magnesium sulfate-charcoal and filtered. Evaporation of the filtrate affords an oil. Chromatography of the oil on silica gel gives 8.0 g of 6,7-dichloro-5-hydroxy-2-isobutylbenzo[b]thiophene, mp 58°-59°.
Reaction SMILES: BrCCCCC[OH:7].CCN(CC)CC.[CH3:15][C:16]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])[CH3:17].[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Si:19]([OH:7])([C:16]([CH3:18])([CH3:17])[CH3:15])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCCCCBr
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](O)(c1ccccc1)c1ccccc1
Yield: 155.3 %

Procedure:
A solution of 5-bromo-pentanol (0.9889 g, 5.9 mmol, 1 eq) in anhydrous CH2Cl2 (20 mL) under N2 at 25° C. was treated with anhydrous Et3N (1.0 mL, 7.2 mmol, 1.2 eq), TBDPSCl (1.7 mL, 6.5 mmol, 1.1 eq) and DMAP (0.23 g, 1.9 mmol, 0.3 eq). The reaction mixture was stirred for 2 h before an aqueous solution of saturated NH4Cl (100 mL) was added. The aqueous layer was extracted with EtOAc (3×100 mL) and the organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was chromatographed (Sio2, 5×20 cm, 0-20% EtOAc/hexanes, gradient elution) to afford TBDPSOH (2.35 g, 98%) as a clear oil; 1H NMR (CDCl3, 400 MHz) δ7.66-7.60 (m, 4H) 7.44-7.33 (m, 6H), 3.64 (t, 2H, J=6.1 Hz), 3.37 (t, 2H, J=6.9 Hz), 1.82 (p, 2H, J=7.3 Hz), 1.59-1.45 (m, 4H), 1.03 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ135.6, 129.6, 127.6, 127.5, 63.5, 33.9, 32.5, 31.6, 26.8, 24.5, 19.2; IR (film) υmax 3069, 2930, 2856, 2359, 1470, 1427, 1389, 1106, 822, 738, 700 cm−1; FABHRMS (NBA-CsI) m/z 537.0235 (C21H29OSiBr+Cs+ requires 537.0225).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:18])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:19]1(C)C(C)=CC=CC=1>C(OC(OCC)OCC)C>[Cl:18][C:3]1[C:2]2[N:1]=[CH:19][N:12]([CH2:13][C:14]([CH3:15])([CH3:17])[OH:16])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: CC(C)(O)CNc1c(N)c(Cl)nc2ccccc12
Reactant: Cc1ccccc1C
Solvent: CCOC(OCC)OCC
Product: CC(C)(O)Cn1cnc2c(Cl)nc3ccccc3c21
Temperature: 80 °C

Procedure:
A suspension of 1-[(3-amino-2-chloro-4-quinolinyl)amino]-2-methyl-2-propanol (5 g from EXAMPLE 13) in xylene (50 mL) and triethylorthoformate (5 mL) was heated at 80° C. until no starting material remained as determined by thin layer chromatography. The resulting solution was cooled, and the precipitated product was isolated by filtration and washed with xylene (3×10 mL).
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([S:16][CH3:17])[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:24]=[CH:25]\[C:26]#[N:27]>>[CH3:17][S:16][C:14]1[N:15]=[C:11]2[CH:10]=[C:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)[CH:25]=[C:26]([NH2:27])[N:12]2[N:13]=1
Reactant: CSc1nc(CS(=O)(=O)c2ccccc2)n[nH]1
Reactant: N#C/C=C\c1ccccn1
Product: CSc1nc2cc(-c3ccccn3)cc(N)n2n1

Procedure:
The title compound, MS m/e (%):258 (M+H+,100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-methylsulfanyl-1H-[1,2,4]triazole and (E)/(Z)-3-pyridin-2-yl-acrylonitrile.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][C:11]([N:13]([CH3:45])[CH2:14][CH2:15][CH:16]1[CH2:23][N:22]2[C:24]3[CH:25]=[C:26]([C:37]([O:39][CH3:40])=[O:38])[CH:27]=[CH:28][C:29]=3[C:30]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:21]2[C:20]2[CH:41]=[CH:42][CH:43]=[CH:44][C:19]=2[O:18][CH2:17]1)=[O:12])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCOC(C)=O>[CH:31]1([C:30]2[C:29]3[CH:28]=[CH:27][C:26]([C:37]([O:39][CH3:40])=[O:38])=[CH:25][C:24]=3[N:22]3[C:21]=2[C:20]2[CH:41]=[CH:42][CH:43]=[CH:44][C:19]=2[O:18][CH2:17][CH:16]([CH2:15][CH2:14][N:13]([CH3:45])[C:11](=[O:12])[CH2:10][CH2:9][NH:8][CH3:6])[CH2:23]3)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCN(C)C(=O)CCN(C)C(=O)OC(C)(C)C)COc1ccccc1-3
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCC(=O)N(C)CCC1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 7(R,S)-{2-[[N-(tert-butoxycarbonyl)-N-methyl-β-alanyl](methyl)amino]ethyl}-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.09 M) in DCM was treated with TFA (20 eq) and the resulting mixture was stirred overnight at RT. The reaction was diluted with EtOAc and the combined organic layers were washed with sat. aq. NaHCO3 then brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The product was used directly in the next step without further purification. (ES+) m/z 532 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:8]([C:11]1[CH:21]=[CH:20][C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[CH:12]=1)([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:6]([O:5][C:3]([CH2:2][N:15]1[C:14]2[CH:20]=[CH:21][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][C:13]=2[O:18][CH2:17][C:16]1=[O:19])=[O:4])[CH3:7]
Reactant: O=C1COc2cc([N+](=O)[O-])ccc2N1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN1C(=O)COc2cc([N+](=O)[O-])ccc21
Yield: 71.4 %

Procedure:
Ethyl bromoacetate (18.4 g) was added dropwise at a temperature of 30° C. to 40° C. to a mixture of 7-nitro-2H-1,4-benzoxazin-3(4H)-one (19.4 g), potassium carbonate (15.2 g) and acetonitrile (100 ml), the mixture was refluxed under heating for 3 hours. When the reaction was completed, the liquor was filtered, the filtrate was distilled. Recrystallization of the resulting solid from toluene-hexane gave the desired 4-ethoxycarbonylmethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (20 g). mp. 120.5°-121.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:12][N:5]2[C:6](=[O:11])[C:7]=1[N+:8]([O-])=O.[Sn].Cl>O1CCOCC1>[NH2:8][C:7]1[C:6](=[O:11])[N:5]2[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:14][C:4]2=[N:3][C:2]=1[NH2:1]
Reactant: Nc1nc2sc(-c3ccccc3)cn2c(=O)c1[N+](=O)[O-]
Agent: Cl
Agent: [Sn]
Solvent: C1COCCO1
Product: Nc1nc2sc(-c3ccccc3)cn2c(=O)c1N
Reaction time: 0.5 h

Procedure:
2.0 g of 7-amino-6-nitro-2-phenyl-5H-thiazolo[3,2-a]pyrimidin-5-one was suspended in 50 ml of 90% dioxane, and 3.0 g of tin powder and 5 ml of concentrated hydrochloric acid were added thereto, followed by stirring the mixture at 80° to 90° C. for 30 minutes. Any insoluble material was removed by filtration, and the filtrate was concentrated. After cooling, the precipitate formed was separated by filtration and added to concentrated aqueous ammonia. The precipitate was separated by filtration and recrystallized from dimethylformamide to obtain 6,7-diamino-2-phenyl-5H-thiazolo[3,2-a]pyrimidin-5-one as yellow needles having a melting point higher than 300° C.
Reaction SMILES: Cl[C:2]([F:7])([F:6])[C:3]([O-])=O.[Na+].[CH:9]1([CH:14]([C:35]2[CH:40]=[CH:39][C:38](C=O)=[CH:37][CH:36]=2)[C:15]([NH:17][C:18]2[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=2)[CH2:21][C:22]2([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]2)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C(OCC)(=O)C>[CH:9]1([CH:14]([C:35]2[CH:40]=[CH:39][C:38]([CH:3]=[C:2]([F:7])[F:6])=[CH:37][CH:36]=2)[C:15]([NH:17][C:18]2[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=2)[CH2:21][C:22]2([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:23][CH2:24]2)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(NC(=O)C(c3ccc(C=O)cc3)C3CCCC3)c2)CC1
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)C1(Cc2cccc(NC(=O)C(c3ccc(C=C(F)F)cc3)C3CCCC3)c2)CC1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
At 60° C., 475.6 mg (3.12 mmol) of sodium chloro(difluoro)acetate were added to a mixture of 800.0 mg (1.73 mmol) of (+/−)-tert-butyl 1-(3-{[cyclopentyl(4-formylphenyl)acetyl]-amino}benzyl)cyclopropanecarboxylate and 681.9 mg (2.60 mmol) of triphenylphosphine. The mixture was heated to 110° C. and stirred at this temperature for 30 min. After cooling, the mixture was poured into water. Ethyl acetate was added, and the organic phase was separated off, washed with saturated sodium chloride solution, dried with magnesium sulphate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (mobile phase acetonitrile/water). This gave 319.2 mg (37.2% of theory) of the target compound.
Reaction SMILES: C(N1CCOCC1)C.C1CCC(N=C=NC2CCCCC2)CC1.[NH:24]([C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[C@@H:25]([C:33]([OH:35])=O)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:57][C@H:58]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:59][O:60][C:61]([CH3:64])([CH3:63])[CH3:62]>CN(C)C=O>[NH:24]([C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[C@@H:25]([C:33]([NH:57][C@H:58]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:59][O:60][C:61]([CH3:64])([CH3:62])[CH3:63])=[O:35])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC[C@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9.07 ml of N-ethylmorpholine and 16.05 g of DCC are added at 0° C. to a solution of 21.2 g of Z-D-Phe-OH, 9.6 g of HOBt and 17.9 g of HCl.H-Ser(tBu)-OtBu in 150 ml of dimethylformamide. The mixture is left to stir at 0° C. for one hour and to stand at room temperature overnight. The precipitate is filtered off with suction, and the filtrate is concentrated. The residue is partitioned between ethyl acetate and water. The ethyl acetate phase is extracted by shaking successively with saturated NaHCO3 solution, KHSO4 /K2SO4 solution and water, dried over Na2SO4 and concentrated. The substance crystallizes after trituration with petroleum ether.
Reaction SMILES: [CH2:1]([P:12](=[O:21])([O:17][CH2:18][CH:19]=[CH2:20])[O:13][CH2:14][CH:15]=[CH2:16])[P:2](=[O:11])([O:7][CH2:8][CH:9]=[CH2:10])[O:3][CH2:4][CH:5]=[CH2:6].[H-].[Na+].[N+:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1)([O-:26])=[O:25].[NH4+].[Cl-]>CN(C=O)C.C1COCC1.O>[N+:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31][CH:1]([P:2](=[O:11])([O:7][CH2:8][CH:9]=[CH2:10])[O:3][CH2:4][CH:5]=[CH2:6])[P:12](=[O:21])([O:13][CH2:14][CH:15]=[CH2:16])[O:17][CH2:18][CH:19]=[CH2:20])=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: C=CCOP(=O)(CP(=O)(OCC=C)OCC=C)OCC=C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: C=CCOP(=O)(OCC=C)C(Cc1ccc([N+](=O)[O-])cc1)P(=O)(OCC=C)OCC=C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.2 %

Procedure:
To a solution of bisphosphonate 23 (8.02 g, 23.9 mmol) in DMF (24 mL) was added NaH (60% dispersion in mineral oil, 954 mg, 23.9 mmol) portionwise and the solution was stirred for 1.5 h at room temperature. A solution of p-nitrobenzyl bromide (7.75 g, 35.9 mmol) in THF (32 mL) was added and the mixture was stirred for 3 h at room temperature. It was then poured into a mixture of saturated aqueous NH4Cl solution and water and extracted with CH2Cl2 (3×). The combined organic layers were washed with saturated brine once, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using a gradient of 0-50% EtOAc in CH2Cl2 as eluant to provide nitrobenzyl bisphosphonate 26 as a clear yellow oil (4.42 g, 9.38 mmol, 39%). 1H NMR (400 MHz, CDCl3) δ 2.73 (tt, J=23.8, 6.5 Hz, 1H), 3.37 (dt, J=16.4, 6.5 Hz, 2H), 4.51-4.61 (m, 8H), 5.21-5.25 (m, 4H), 5.29-5.35 (m, 4H), 5.83-5.93 (m, 4H), 7.44 (d, J=8.8 Hz, 2H), 8.14 (d, J=8.8 Hz, 2H).
Reaction SMILES: C[O:2][C:3](=[O:51])[CH2:4][N:5]([CH2:46][C:47]([O:49]C)=[O:48])[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]=[C:8]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][CH:37]=2)[CH:7]=1.[OH-].[Na+]>CO>[C:3]([CH2:4][N:5]([C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:9]=[C:8]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:43])=[O:44])=[CH:38][CH:37]=2)[CH:7]=1)[CH2:46][C:47]([OH:49])=[O:48])([OH:51])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(S(C)(=O)=O)cc2)cc(N(CC(=O)OC)CC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(S(C)(=O)=O)cc2)cc(N(CC(=O)O)CC(=O)O)c1
Yield: 86.3 %

Procedure:
A solution of 1.01 g (1.37 mmol) of N-(2-methoxy-2-oxoethyl)-N-[3-[3-[4-(methylsulfonyl) phenoxy]propoxy]-5-(octadecyloxy)-phenyl]glycine methyl ester and 0.92 ml (5.5 mmol) of 6N NaOH in 30 ml of methanol was stirred at reflux for 4 hours under argon. The methanol was removed at reduced pressure, the residue was acidified and the product was extracted with ethyl acetate. The dried extract was concentrated to a solid which was recrystallized from methylene chloride-ether to give 0.835 g (86% yield, mp 118°-120°) of N-(carboxymethyl)-N-[3-[3-[4-(methylsulfonyl)phenoxy]propoxy]-5-(octadecyloxy)phenyl]glycine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[NH:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: NCCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 97.2 %

Procedure:
60 g (0.27 mol) of 2-chloro-1-nitro-5-trifluoromethylbenzene, 50 g (0.56 mol) of β-alanine and 41 g (0.3 mol) of potassium carbonate were refluxed in a mixture of 300 ml of dimethylformamide and 50 ml of water for 6 h. The mixture was then poured into ice-water, the aqueous phase was acidified with hydrochloric acid, and the precipitate was filtered off with suction to yield 73 g (99%) of the product.
Reaction SMILES: CCCCCCC.C(OCC)(=O)C.C(OC(=O)NCC(CC(=O)NCCC#N)CC(C)C)(C)(C)C.[Br-].[Li+].C[O:39][C:40](=[O:54])[CH:41]([CH2:50][CH:51]([CH3:53])[CH3:52])[CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>CC(C)=O>[C:46]([O:45][C:43](=[O:44])[CH2:42][CH:41]([CH2:50][CH:51]([CH3:52])[CH3:53])[C:40]([OH:54])=[O:39])([CH3:49])([CH3:48])[CH3:47]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)CC(C)C
Agent: CC(C)CC(CNC(=O)OC(C)(C)C)CC(=O)NCCC#N
Agent: [Br-]
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Yield: 95.4 %

Procedure:
Synthesis of Compound 1 Lithium aluminum hydride (69.4 mL of a 1 M solution in ether, 69.4 mmol) was added dropwise to a stirring solution of cis-cyclobutane-1,2-dicarboxylic acid (5 g, 34.7 mmol) in THF (60 mL) at 0° C. under argon. The mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was cooled to 0° C. and quenched by careful addition of water (2.7 mL), sodium hydroxide solution (2.7 mL of a 15% w/v solution), and water (8.1 mL). The mixture was stirred for 15 minutes, and the precipitate was removed by filtration. The solvent was evaporated under reduced pressure to give the alcohol 1 as a colorless oil (4.0 g, 98%); δH (400 MHz; CDCl3): 3.85 (2H, m), 3.6 (2H, m), 3.2 (2H, s), 2.7 (2H, m), 2 (2H, m); 1.55 (2H, m); δC (400 MHz; CDCl3): 63.15, 37.83, 20.40. Synthesis of Compound 2 Mesyl chloride (6.2 mL, 79.1 mmol) was added dropwise to a stirring solution of 1 (4.0 g, 34.4 mmol) in dichloromethane (150 mL) at −40° C. under argon. Triethylamine (12.0 mL, 86.0 mmol) was then added dropwise, and the mixture was allowed to warm slowly to room temperature. After stirring for 16 hours, the mixture was quenched by addition of dilute hydrochloric acid (50 mL). The organic layer was separated, and the aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ethyl acetate, 6:4) to give the mesylate 2 (6.1 g, 73%) as a white solid; Rf(heptane/ethyl acetate, 1:1) 0.18. δH (400 MHz; CDCl3): 4.3 (4H, m), 3.05 (6H, s), 2.9 (2H, m), 2.2 (2H, m), 1.8 (2H, m); δc(400 MHz; CDCl3): 69.51, 37.45, 35.28, 21.09. Synthesis of Compound 3 Anhydrous lithium bromide (10.6 g, 121.8 mmol) was added to a stirring mixture of 2 (5.95 g, 24.4 mmol) in acetone (50 mL) under argon, and the mixture was refluxed for 2 hours. After cooling, the acetone was evaporated under reduced pressure, and the residue was taken up in ether (50 mL), washed with water (50 mL), brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ethyl acetate, 95:5) to give the dibromide 3 (5.36 g, 86%) as an orange liquid; Rf (heptane-ethyl acetate,
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][O:19][CH3:20].Cl>O.CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:18][O:19][CH3:20])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: COCCl
Reactant: O=Cc1cc(Br)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COCOc1ccc(Br)cc1C=O
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To 600 ml of acetone solution containing 30.0 g (0.15 mol) of 5-bromo-2-hydroxybenzaldehyde was added 20.6 g (0.15 mol) of potassium carbonate, and then, 12.5 ml (0.17 mol) of chloromethylmethyl ether was added dropwise to the mixture over 30 minutes under ice-cooling. After stirring the mixture at the same temperature for 30 minutes, the mixture was further stirred at room temperature for 5 hours. After completion of the reaction, 600 ml of water was added to the reaction mixture. A pH of the mixture was adjusted to 7.6 with conc. hydrochloric acid, and extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 28.4 g of the title compound as a pale yellowish oil. (Yield: 77%)