Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:16]([NH2:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C)C=O>[CH2:16]([NH:22][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH2:8])[N:5]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCN
Reactant: Nc1nc(N)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCNc1nc(N)nc(N)n1

Procedure:
A mixture of 72.8 g. (0.500 mole) of 2,4-diamino-6-chloro-s-triazine, 63.6 g. (0.600 mole) of anhydrous sodium carbonate, and 200 ml. of N,N-dimethylformamide (DMF) was heated over 43 minutes of 124° C. To this was added, over a period of 2.35 hours, a solution of 60.7 g. (0.600 mole) of n-hexylamine in 100 ml. of DMF; temperature was controlled at 122°-127° C. during the addition. The reaction mixture was heated for an additional 19 hours at 124°-125° C., then was filtered hot. The filter cake was washed with 100 ml of hot DMF, and the combined filtrate was cooled and added with stirring to about 5 liters of ice-water. The precipitate was recovered by filtration, reslurried with 3 liters of water, filtered again, washed thoroughly with deionized water, and dried to constant weight in a vacuum oven at 60° C. The yield of n-hexylmelamine, m.p. 115°-117.5° C., was 91.4 g. (87.0%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C>ClCCl>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([NH:16][C:14](=[O:15])[NH:13][C:9]2[CH:8]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=[CH:11][CH:10]=2)=[CH:18][CH:19]=1
Reactant: Nc1cccc(NC(=O)Nc2ccnc3ccccc23)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(NC(=O)Nc2ccnc3ccccc23)c1
Reaction time: 16 h

Procedure:
Methanesulphonyl chloride (27 ul) was added to 1-(3-aminophenyl)-3-quinolin-4-ylurea (0.08 g) in dichloromethane (25 ml) containing triethylamine (48 ul) and stirred for 16 h. The precipitate that formed was separated by filtration, washed with tetrahydrofuran and diethyl ether and dried to give the title compound (0.081 g).
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])[O:10][C:6]=2[C:5]([O:16][CH3:17])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C]=[O:55].[O:56]1[CH2:60]CCC1.O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:13]1([C:11]([C:9]2[O:10][C:6]3[C:7](=[C:2]([C:60]([OH:56])=[O:55])[CH:3]=[CH:4][C:5]=3[O:16][CH3:17])[CH:8]=2)=[O:12])[CH2:15][CH2:14]1
Reactant: C1CCOC1
Reactant: [C]=O
Reactant: COc1ccc(Br)c2cc(C(=O)C3CC3)oc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)O)c2cc(C(=O)C3CC3)oc12
Temperature: 25 °C

Procedure:
To a solution of (4-bromo-7-methoxybenzofuran-2-yl)-cyclopropyl-methanone (1.0 g) in tetrahydrofuran/water (40 ml/20 ml) was added palladium acetate (76 mg), 1,3-bis(diphenylphosphino)propane (280 mg) and triethylamine (4.7 ml). The reaction mixture was heated at 90° C. under a 150 psi atmosphere of carbon monoxide for 3 days. The reaction mixture was allowed to cool to room temperature and the carbon monoxide pressure released. The tetrahydrofuran was removed in vacuo and the aqueous residue washed with ethyl acetate (2×75 ml) and acidified to pH3 with 2M hydrochloric acid. The latter was extracted with ethyl acetate (2×200 ml), the organic layer separated, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a pale yellow solid (0.76 g).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:58])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:45]2)[CH:7]([CH3:59])[CH2:6][CH2:5][C:4]1=[O:60])[CH3:2].C(N(CC)CC)C.[CH:68]1([C:71](Cl)=[O:72])[CH2:70][CH2:69]1>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:58])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:71]([CH:68]3[CH2:70][CH2:69]3)=[O:72])[CH:46]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:45]2)[CH:7]([CH3:59])[CH2:6][CH2:5][C:4]1=[O:60])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(Oc4ccccc4)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NC(=O)C4CC4)C(Oc4ccccc4)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 34 mg of 17-ethyl-1-hydroxy-12-[2'-(4"-amino-3"-phenoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in dry methylene chloride (0.4 ml) is cooled to 0° C. To this solution is added triethylamine (10 μl) followed by a solution of cyclopropane carbonyl chloride (5 mg) in methylene chloride (0.1 ml). The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is purified by preparative tlc on silica gel to give the title compound.
Reaction SMILES: CS(O[C@@H:6]1[C@@H:11]([CH3:12])[CH2:10][C@@H:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:8][C@H:7]1[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=O)=O.[N-:35]=[N+:36]=[N-:37].[Na+]>CN(C=O)C>[C:23]([O:22][C:20]([NH:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[C@H:9]1[CH2:8][C@@H:7]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@@H:6]([N:35]=[N+:36]=[N-:37])[C@@H:11]([CH3:12])[CH2:10]1)=[O:21])([CH3:26])([CH3:25])[CH3:24].[C:23]([O:22][C:20]([NH:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[C@@H:9]1[CH2:8][C@H:7]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@H:6]([N:35]=[N+:36]=[N-:37])[C@H:11]([CH3:12])[CH2:10]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H]1C[C@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1N=[N+]=[N-]
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %
Yield: 21 %

Procedure:
To a solution of (+/−)-(1R,2R,4R,6S)-2-(tert-butoxycarbonylamino)-4-(3-(tert-butoxycarbonylamino)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate (1.0 equiv.) in DMF (0.13 M) was added NaN3 (1.0 equiv.). The solution was submerged in an 80° C. oil bath and left stirring under Ar for 16 hrs. The solution was cooled to rt and left stirring under Ar overnight. The solution was partitioned between EtOAc and H2O. The organic layer was washed with Na2CO3(sat), NaCl(sat), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography. Purification was completed via SFC (15% IPA, 100 mL/min, IA column) to yield tert-butyl ((1R,2S,3S,5R)-5-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-azido-3-methylcyclohexyl)carbamate (21% yield, 99% ee) and tert-butyl ((1S,2R,3R,5S)-5-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-azido-3-methylcyclohexyl)carbamate (22% yield, 99% ee). LC/MS (m/z)=447.3 (MH+), Rt=0.86 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12].Cl.Cl[CH2:15][CH2:16][CH2:17][NH2+:18][CH3:19].[C:20](=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O:12][CH2:15][CH2:16][CH2:17][N:18]([CH3:19])[CH3:20]
Reactant: COc1cc([N+](=O)[O-])ccc1O
Reactant: O=C([O-])[O-]
Reactant: C[NH2+]CCCCl
Agent: Cl
Agent: [K+]
Product: COc1cc([N+](=O)[O-])ccc1OCCCN(C)C
Temperature: 120 °C
Yield: 53.3 %

Procedure:
To a solution of 2-methoxy-4-nitrophenol (1.0 g, 5.9 mmol) and 3-chloro-N-methylpropan-1-aminium hydrochloride salt (1.03 g, 6.5 mmol) in N,N-dimethylformide (10 mL), was added potassium carbonate (2.03 g, 14.7 mmol). The resulting reaction mixture was heated at 120° C. for 18 hours. After this time, TLC analysis showed no starting material remaining so the mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried (Na2SO4) and concentrated. The crude residue was purified by silica gel chromatography using a 95:5 mixture of dichloromethane and methanol as eluent to afford the title product as yellow oil (0.8 g, 53% yield). 1H NMR (400 MHz, d6-DMSO) δ: 7.57 (1H, m), 7.44 (1H, m), 7.06 (1H, m), 4.07 (2H, m), 3.81 (3H, s), 3.812 (3H, s), 3.807 (2H, s), 2.33 (2H, m), 2.13 (6H, s), 1.86 (2H, m). MS m/z: 268.26 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19](=[O:21])[CH3:20]>CC(C)=O>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([O:10][CH2:18][C:19](=[O:21])[CH3:20])=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 82.1 %

Procedure:
Into acetone (300 ml ) were suspended 41.7 g (0.3 mol) of p-nitrophenol and 41.4 g (0.3 mol) of anhydrous potassium carbonate. Under stirring and reflux, 27.7 g (0.3 mol) of chloroacetone were added dropwise therein over five hours. After the resulting mixture was reacted for two hours as it was, it was cooled down, and the reaction liquid was dispersed into ice water (500 ml). After the extract obtained by extraction therefrom with ethyl acetate (500 ml) was washed with water and dried, the solvent was distilled off under reduced pressure. The thus-obtained light-yellow crystalline residue was recrystallized from ethyl acetate/n-hexane, whereby 48.1 g of the title compound were obtained. (Yield: 82.2%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([CH2:18][C:19]#[N:20])[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])=[C:4]([CH3:21])[N:3]=1.O=P(Cl)(Cl)[Cl:24]>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:24])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([CH2:18][C:19]#[N:20])[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])=[C:4]([CH3:21])[N:3]=1
Reactant: COc1ccc(CC#N)cc1Cc1c(C)nc(N)nc1O
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(CC#N)cc1Cc1c(C)nc(N)nc1Cl
Temperature: 90 °C

Procedure:
The product from step (ii) (2.8 g) was added to POCl3 (25 ml) and heated at 90° C. for 15 h and then evaporated under reduced pressure. The residue was diluted with ice/water (20 mL) and the mixture adjusted to pH ˜7 with sodium bicarbonate. The mixture was heated at 50° C. for 1 h and the precipitate collected by filtration. The solid was dried under vacuum to give the subtitle compound as a brown solid, 2.88 g.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.C([O-])([O-])=O.[K+].[K+].[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>C(#N)C.O>[CH2:25]([N:27]([CH2:28][CH3:29])[CH2:2][CH2:3][CH2:4][N:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:26]
Reactant: ClCCCN1c2ccccc2Oc2ccccc21
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN(CC)CCCN1c2ccccc2Oc2ccccc21

Procedure:
1 g (4.31 mmol) of the product of Example 1 was dissolved in 150 mL of anhydrous acetonitrile, and 1.5 g KI, 2.13 g K2CO3 and 1.6 mL (15.4 mmol) of N,N-diethylamine were added. The mixture was refluxed overnight until a substantial amount of product was formed (TLC, System B, Rf =0.40). The reaction mixture was diluted with water and extracted with ether three times. The ether layer was washed with water and dried over anhydrous Na2SO4 and evaporated. The crude oil was subjected to column chromatography for purification. Ethylacetate-petroleum ether (50 mL+50 mL) eluted the title compound as the free base as a colorless oil, which was dried and used for NMR studies. An ethereal solution of the free base was treated with an excess of tartaric acid to separate the hygroscopic tartrate salt (1.2 g). UV-λmax (MeOH) 215, 238 and 320 nm; IR (CHCl3) 3378, 2974, 2838, 1453, 1375, 1155, 973 and 722 cm-1 ; 1H-NMR (`δ`) 6.51-6.80 (m, 8H, ArH, H1 -H4 and H6 -H9), 1.16 (t, 6H, Hc and Hd), 1.70 (m, 2H, H1), 2.50 (q, 4H, Ha and Hb, J=7 Hz), 3.42-3.63 (m, 4H, Hk and Hm); 13C-NMR 111.54 (C1 and C9), 115.49 (C4 and C6), 121.21 (C3 and C7), 123.85 (C2 and C8), 132.72 (C1' and C9'), 144.95 (C4' and C6'), 8.21 (Cc and Cd), 19.90 (C1), 40.72 (Ca and Cb), 45.87 (Cm), and 48.50 (Ck); EIMS (m/z) 296 (M+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]23[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]4)[CH2:11]2)[CH2:17]3)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]#[C:29][CH3:30].CN(C=O)C>C1C=CC=CC=1>[CH2:27]([N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]23[CH2:11][CH:12]4[CH2:18][CH:16]([CH2:15][CH:14]([CH2:13]4)[CH2:19]2)[CH2:17]3)=[CH:7][CH:8]=1)[C:28]#[C:29][CH3:30]
Reactant: CC#CCBr
Reactant: CNc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC#CCN(C)c1ccc(OC23CC4CC(CC(C4)C2)C3)cc1

Procedure:
A mixture of 2.0 g. (0.0079 mole) of N-methyl-p-(1-adamantyloxyl)aniline, 1.07 g. K2CO3 and 1.03 g. of 1-bromo-2-butyne in 10 ml. DMF and 40 ml. C6H6 was heated at reflux for 17 hours. The mixture was allowed to cool and washed well with H2O and brine. The gum which remained when the organic layer was taken to dryness was dissolved in Et2O. The solid which precipitated on addition of HCl in Et2O was recrystallized from CH2Cl2 :EtOAc. There was obtained 2.09 g. (77%) of N-(2-butynyl)-N-methyl-p-(1-adamontyloxy)aniline, m.p. 180°-181°.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH:14]=1)[C:9](O)=[O:10].[CH2:28]([O:30][C:31](=[O:40])[CH2:32][S:33][C:34]1[S:38][C:37]([NH2:39])=[N:36][CH:35]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:40])[CH2:32][S:33][C:34]1[S:38][C:37]([NH:39][C:9](=[O:10])[C:8]2[CH:12]=[C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[C:6]([O:5][CH2:4][C:3]3[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=3[Cl:1])[CH:7]=2)=[N:36][CH:35]=1)[CH3:29]
Reactant: O=C(O)c1cc(OCc2ccccc2Cl)cc(OCc2ccccc2Cl)c1
Reactant: CCOC(=O)CSc1cnc(N)s1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(OCc3ccccc3Cl)cc(OCc3ccccc3Cl)c2)s1

Procedure:
The title compound was prepared from 3,5-bis-(2-chloro-benzyloxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].[C:13]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: CS(=O)(=O)c1ccc(O)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(S(C)(=O)=O)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 2-bromo-4-(methylsulfonyl)phenol (3.2 g, 12.7 mmol) in DMF (35 mL) at 0° C. was added K2CO3 (5.3 g, 38.1 mmol). The reaction was stirred at 0° C. for 0.5 h and to this cold solution was slowly added CH3I (2.7 g, 19.1 mmol) drop wise. The reaction was stirred at r.t. overnight. After the reaction was completed, 80 mL of ice-water was added. The mixture was extracted with EA (60 mL×3). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and evaporation of the solvent, the obtained residue was purified on column chromatography (silica gel, ethyl acetate/petroleum ether=1:4) to give 2-bromo-1-methoxy-4-(methylsulfonyl)benzene (2.12 g, 63.0%) as yellow solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([N:13]([CH2:21]N(OC)C)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:26]1([Mg]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1C[O:37]CC1>>[Si:1]([O:8][CH2:9][CH:10]([N:13]([CH:21]=[O:37])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:11][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)CN(C(=O)OC(C)(C)C)C(C=O)CO[Si](C)(C)C(C)(C)C
Reactant: C1CCOC1
Product: CC(C)(C)OC(=O)N(C=O)C(CO[Si](C)(C)C(C)(C)C)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2.25 h
Yield: 65 %

Procedure:
tert-butyl 3-(tert-butyldimethylsilyloxy)-1 (methoxy(methyl)amino)-1-oxopropan-2-ylmethylcarbamate (35) (2.2 g, 5.7 mmol, 1.0 equiv.) was added to a 250 mL RBF followed by THF (60 mL). The mixture was cooled to 0° C. via an ice bath and a 1.0 M solution of PhMgBr in THF (11.5 mL, 11.5 mmol, 2.0 equiv.) was added over 5 min. The reaction stirred for 2.25 h at 0° C. and was quenched by addition of 0.5 M HCl (60 mL). The solution was transferred to a separatory funnel with additional 0.5 M HCl (20 mL) and extracted with EtOAc (3×60 mL). The organic layers were combined, washed with sat. NaCl (1×50 mL), and dried over Na2SO4. The solution was concentrated on a rotary evaporator and dried under vacuum to give 2.8 g of crude material. The residue was purified by flash column chromatography (5% EtOAc/Hexanes) to give 1.5 g (65%) of 36 as an oil. Rf=0.23 (5% EtOAc/Hexanes); IR (film) 2954, 2928, 2855, 1687, 1390, 1148, 1120 cm−1; 1H NMR (500 MHz, CDCl3) δ Major rotamer: 8.01 (d, J=7.5 Hz, 1H, Ph-H), 7.91 (d, J=7.5 Hz, 1H, Ph-H), 7.55 (t, J=7.0 Hz, 1H, Ph-H), 7.47 (m, 2H, Ph-H), 5.60 (m, 1H, Boc-N—CH), 4.14 (m, 1H, CH—CH2), 4.04 (m, 1H, CH—CH2), 2.75 (s, 3H, Boc-N—CH3), 1.41 (s, 9H, Boc-t-butyl-CH3), 0.90 (s, 9H, Si-t-butyl-CH3), 0.06 (s, 3H, Si—CH3), 0.04 (s, 3H, Si—CH3). Minor rotamer: 5.13 (m, 1H, Boc-N—CH), 2.91 (s, 3H, Boc-N—CH3), 1.43 (s, 9H, Boc-t-butyl-CH3), 0.87 (s, 9H, Si-t-butyl-CH3), 0.08 (s, 3H, Si—CH3), 0.06 (s, 3H, Si—CH3); 13C NMR (125 MHz, CDCl3) δ 198.9, 198.1, 155.9, 155.0, 136.1, 133.3, 128.7, 128.6, 128.5, 128.3, 80.9, 80.2, 63.2, 61.1, 60.8, 60.3, 32.7, 31.1, 28.5, 26.0, 25.9, 18.4, 18.3, −5.3, −5.4, −5.5; LRMS (ESI-MS m/z): Mass calcd for C20H33NO4Si [M]+, 393.59. Found 394.
Reaction SMILES: [CH2:1]([O:13][CH2:14][CH:15]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:16][O:17]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>C(Cl)(Cl)Cl>[CH2:1]([O:13][CH2:14][CH:15]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:16][OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCCCCCCCCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCCCCCOCC(CO)OCCCCCCCCCC
Yield: 63 %

Procedure:
Detritylation of 3-dodecyloxy-2-decyloxy-1-triphenylmethoxypropane was accomplished using p-toluenesulfonic acid (0.9 g) in CHCl3 :MeOH (72 mL:36 mL) (stirred at room temperature for 48 h, added 10% sodium bicarbonate, extracted with CHCl3, dried over magnesium sulfate, and concentrated). The residue was purified by column chromatography using a gradient of hexanes:ethyl acetate (20:1 to 5:1) to give 3.5 g (63%) of pure 3-dodecyloxy-2-decyloxy-1-propanol.
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[CH:12]=[CH:11][C:10]=1[C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:25][C:24]=2[CH:34]=1.[CH3:35][CH:36](O)[CH2:37][CH3:38]>CN(C=O)C>[F:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[CH:12]=[CH:11][C:10]=1[C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH:28]3[CH2:29][CH2:30][N:31]([C:3]([O:5][CH:36]([CH2:37][CH3:38])[CH3:35])=[O:4])[CH2:32][CH2:33]3)=[N:25][C:24]=2[CH:34]=1
Reactant: CCC(C)O
Reactant: Fc1cc(-n2cnnn2)ccc1-c1ccc2oc(C3CCNCC3)nc2c1
Reactant: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCC(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(-n5cnnn5)cc4F)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.8 %

Procedure:
Tert-butyl 4-{5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate (250 mg, 0.54 mmol) dissolved in DCM (15 ml) and added Trifluoroacetic acid (1 ml). This mixture was stirred at rt for 2 h. DCM removed from the reaction mixture to obtain 5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoro acetate (260 mg). 5-[2-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (150 mg, 0.31 mmol) was dissolved in DMF (2.6 ml) and added N,N-Carbonyl diimidazole (101 mg, 0.63 mmol) and stirred at rt for 1 h. To this mixture added 2-butanol (46 mg, 0.63 mmol) and TEA (0.13 ml, 0.94 mmol) and stirred at 60° C. for overnight. Work up (EtOAc/H2O) and purification of the crude by combiflash with gradient mixture of ethyl acetate and petether (1:1) as eluent afforded the titled compound (30 mg) as an off-white solid. M.P.: 118-122° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 9.03 (s, 1H), 7.88 (s, 1H), 7.72-7.58 (m, 4H), 7.55-7.50 (m, 1H), 4.82-4.73 (m, 1H), 4.21 (d, J 12.7, 2H), 3.24-3.13 (m, 1H), 3.06 (t, J 11.6, 2H), 2.19 (d, J 10.9, 2H), 2.00-1.88 (m, 2H), 1.69-1.50 (m, 2H), 1.24 (d, J 6.2, 3H), 0.92 (t, J 7.4, 3H).
Reaction SMILES: [Cl-].[Li+].C(N(C(C)C)CC)(C)C.[CH:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=O.[N+:27]([C:30]1[CH:46]=[CH:45][C:33]([C:34]([CH2:36]P(=O)(OCC)OCC)=[O:35])=[CH:32][CH:31]=1)([O-:29])=[O:28]>C(#N)C.O>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][CH:14]([CH:12]=[CH:36][C:34]([C:33]2[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:46][CH:45]=2)=[O:35])[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CCOP(=O)(CC(=O)c1ccc([N+](=O)[O-])cc1)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C=CC(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.6 %

Procedure:
0.28 g of lithium chloride, 0.85 g of diisopropylethylamine and 2.13 g of 4-formyl-l-t-butoxycarbonylpiperidine were added to 2.0 g of diethyl (4-nitrobenzoylmethyl)phosphonate dissolved in 20 ml of acetonitrile, and the mixture was stirred at room temperature for about 3 days. Then, water was added to the reaction mixture, and the mixture was extracted with toluene. The extract was dried over anhydrous sodium sulfate and condensed. The obtained residue was applied to silica gel column chromatography to obtain 1.76 g of the title compound as pale yellow crystal.