Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([C@H:18]1[O:20][CH2:19]1)[Cl:17]>[Cl-].[Zn+2].[Cl-].CS(C)=O>[Cl:17][CH2:16][C@@H:18]([OH:20])[CH2:19][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClC[C@@H]1CO1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CS(C)=O
Product: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
Dibenzylamine (39.4 g, 0.20 mol) and zinc chloride (81.6 g, 0.6 mol) were added to 200 mL dimethyl sulfoxide. The mixture was stirred at 25° C. for 30 minutes. (S)-epichlorohydrin (37.2 g, 0.4 mol) was then added and reacted at 120° C. for 8 hours. The mixture was filtered and water was added to the filtrate. The filtrate was extracted with ethyl acetate for 3 times, and then the organic phases were combined, the solvent was evaporated to provide 53 g of colorless oil with 92% yield. HPLC: 99.0%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:21]([N+:22]([O-])=O)=[CH:20][NH:19][N:18]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.CN(C=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:21]([NH2:22])=[CH:20][NH:19][N:18]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2n[nH]cc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2n[nH]cc2N)CC1
Yield: 73.8 %

Procedure:
4-[(4-Nitro-1H-pyrazole-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (13.05 g) was dissolved in ethanol/DMF (300 ml/75 ml), treated with 10% palladium on carbon (500 mg) then hydrogenated at room temperature and pressure overnight. The catalyst was removed by filtration through Celite and the filtrate evaporated and re-evaporated with toluene. The crude material was purified by flash column chromatography eluting with EtOAc then 2% MeOH/EtOAc then 5% MeOH/EtOAc. Product containing fractions were combined and evaporated to give 8.78 g of 4-[(4-amino-1H-pyrazole-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a brown foam. (LC/MS: Rt 1.91, [M+H]+ 310).
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[CH3:8][C:9]([CH3:13])=[CH:10][CH2:11]O.CC(C)=CC(O)=O>>[CH3:6][C:5]([CH2:7][CH2:11][CH:10]=[C:9]([CH3:13])[CH3:8])=[CH:4][C:2](=[O:1])[CH3:3]
Reactant: CC(=O)C=C(C)C
Reactant: CC(C)=CCO
Agent: CC(C)=CC(=O)O
Product: CC(=O)C=C(C)CCC=C(C)C
Yield: 86 %

Procedure:
A mixture of 400 parts of mesityl oxide, 100 parts of prenol and 5 parts of 3,3-dimethylacrylic acid is heated for 4 hours at a pressure of 1.9 atmospheres and a temperature of 175°C in a still provided with means for removing water. The water formed is removed azeotropically. The reaction mixture is worked up. 85 parts of 4,8-dimethyl-3,7-nonadien-2-one is obtained. This is equivalent to a yield of 86% of theory at a conversion of 51% based on prenol.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-])=O)[CH3:2].[C:12]([Mg]Br)([CH3:14])=[CH2:13].[Na+].[Cl-]>C1COCC1>[CH3:14][C:12]1[NH:9][C:4]2[C:5]([CH:13]=1)=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2]
Reactant: C=C(C)[Mg]Br
Reactant: CCc1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cccc2cc(C)[nH]c12
Temperature: -20 °C
Reaction time: 2 h

Procedure:
A solution of 36.5 g of 2-ethylnitrobenzene in 250 ml of THF is added dropwise at −20° C. to 1.6 l of 0.5M isopropenylmagnesium bromide in THF. The reaction medium is maintained at −20° C. with stirring for 2 hours and then the medium is poured onto 800 ml of saturated NaCl solution. The mixture is allowed to separate by settling and then extraction is carried out with ether. The ether extract is dried and evaporated and then the residue is chromatographed on silica while eluting with an AcOEt/cyclohexane (1/9, v/v) mixture. 23.75 g of the expected compound are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)=S.[S].CC(O)C>[Hg]=O.C(#N)C>[N:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:11][C:9]2[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N:8]=2)=[CH:14][CH:15]=1
Reactant: Oc1ccccc1NC(=S)NCc1ccncc1
Agent: O=[Hg]
Agent: [S]
Solvent: CC(C)O
Solvent: CC#N
Product: c1ccc2oc(NCc3ccncc3)nc2c1
Yield: 56 %

Procedure:
A mixture of 14 parts of N-(2-hydroxyphenyl)-N'-(4-pyridinylmethyl)-thiourea, 20 parts of mercury(II) oxide, 1 part of sulfur, 160 parts of 2-propanol and 160 parts of acetonitrile was stirred and refluxed for 14 hours. The reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated. The oily residue was crystallized from acetonitrile, yielding 6.8 parts (56%) of N-(4-pyridinylmethyl)-2-benzoxazolamine; mp. 147.9° C. (intermediate 74).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16])C1C=CC=CC=1.[H][H]>C1COCC1.CCO.[Pd]>[CH3:16][C:15]1[O:14][C:13]([C:17]2[CH:18]=[CH:19][C:20]([N:23]([CH3:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:22]=2)=[N:12][C:11]=1[CH2:10][CH2:9][OH:8]
Reactant: [H][H]
Reactant: Cc1oc(-c2ccc(N(C)c3ccccc3)cc2)nc1CCOCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccc(N(C)c3ccccc3)cc2)nc1CCO
Yield: 60.2 %

Procedure:
A solution of {4-[4-(2-benzyloxy-ethyl)-5-methyl-oxazol-2-yl]-phenyl}-methyl-phenyl-amine (195 mg, 0.490 mmol) in THF (2 mL) and EtOH (10 mL) was treated a slurry of Pd/C (200 mg) in EtOH (2 mL). The resulting mixture was treated with hydrogen under balloon pressure for 14 h and filtered through a pad of Celite. The filtrate was concentrated, and crude product was purified by silica gel chromatography column (50% EtOAc/hexanes) to yield the title compound (91 mg, 60%).
Reaction SMILES: [NH2:1][C:2]1[S:6][NH:5][C:4](=[O:7])[N:3]=1.C(O[CH:12]1[O:20][C@H:19]([CH2:21][O:22]C(=O)C)[C@@H:14]([O:15]C(=O)C)[CH2:13]1)(=O)C.C(=O)(O)[O-].[Na+].C[O-].[Na+]>ClC(Cl)C.CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[S:6][N:5]([C@H:12]2[O:20][C@H:19]([CH2:21][OH:22])[C@@H:14]([OH:15])[CH2:13]2)[C:4](=[O:7])[N:3]=1
Reactant: Nc1nc(=O)[nH]s1
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)C[C@@H]1OC(C)=O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1nc(=O)n([C@@H]2C[C@H](O)[C@@H](CO)O2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2 %

Procedure:
5-Amino-1,2,4-thiadiazol-3-one (1, 2.0 g, 0.017 mole) was silylated as described in example II, and dissolved in dry dichloroethane (100 ml). 1,3,5-Tri-O-acetyl-2-deoxy-D-ribofuranose [M. J. Robins and R. K. Robins, J. Amer. Chem. Soc., 87, 4934 (1965); 4.4 g, 0.017 mole] in dichloroethane (25 ml) was added followed by stannic chloride (2.1 ml). The reaction mixture was protected from moisture and stirred at ambient temperature overnight, before it was poured into 250 ml of cold, saturated aqueous sodium bicarbonate solution containing 200 ml of chloroform keeping the mixture basic at all times. The organic layer was separated and washed with water (2 × 100 ml) before it was dried over anhydrous sodium sulfate. The solvent was evaporated to dryness and the residual gum was chromatographed on silica gel column (4 × 70 ml) using chloroform:methanol (95:5, v/v) as the solvent. The band carrying the products was collected and evaporated to dryness, leaving 0.4 g of gummy blocked anomeric nucleosides (5) which was dissolved in anhydrous methanol (25 ml). The methanolic solution was treated with 1N sodium methoxide in methanol till the pH of the solution was 8.5 and stirred at ambient temperature for 2 hr. The sodium ions were removed by stirring the reaction mixture with Amberlite IRC-50 (H+) resin (5 g, dry weight) for 15 min before the neutral solution, free from resin, was evaporated to dryness. The residual gum was subjected to preparative tlc (silica gel) using ethyl acetate:water:n-propanol(4:2:1, v/v, upper phase) as the developer. The bands carrying the homogeneous products were eluted with the same solvent system and evaporated to dryness. The residue was crystallized from water to yield 80 mg of 5-amino-2-(2-deoxy-α-D-ribofuranosyl)-1,2,4-thiadiazol-3-one (11), m.p. > 150° (dec.) 1H nmr (Me2SO-d6) multiplet of four centered at δ6.1 and other protons.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C[O:29][C:30](=O)[C:31]([F:34])([F:33])[F:32].O>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH:15][C:30](=[O:29])[C:31]([F:34])([F:33])[F:32])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(F)(F)F
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)C(F)(F)F

Procedure:
112.5 g (0.41 mmol) of O-benzyltyrosine is suspended in 1 liter of dry methanol and mixed at room temperature with 58.9 ml (0.42 mol) of triethylamine. After addition of 67 ml (0.53 mol) of trifluoroacetic acid methyl ester, it is stirred for 130 hours at room temperature with exclusion of water. The unreacted initial material is separated and the leaving components are removed by shaking with ethyl acetate/aqueous hydrochloric acid. The ethyl acetate phase is decolored with activated carbon. After evaporation of the solvent, 120.7 g (80% of theory) of colorless crystals is obtained.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[C:1]1([S:7]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:23](=[O:25])[CH3:24])=[CH:14][CH:15]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cl
Reactant: O=S(=O)(c1ccccc1)c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(S(=O)(=O)c2ccccc2)cc1

Procedure:
In 150 ml of CH2Cl2 were dissolved 23 g of the compound obtained in step 2; and, 12.9 ml of pyridine and 7.8 ml of acetyl chloride was slowly added at room temperature thereto. The reaction solution was washed with 0.2N HCl and with saturated NaHCO3 aqueous solution, dried over Na2SO4 and concentrated under reduced pressure to obtain residue, which was used for subsequent reaction without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.[CH3:23][O:24][C:25]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=[C:27]([NH2:40])[N:26]=1>>[CH3:23][O:24][C:25]1[C:30]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[CH:5]=[C:4]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:3]=2)=[CH:29][N:28]=[C:27]([NH2:40])[N:26]=1
Reactant: COc1ccc(Nc2cc(N3CCOCC3)nc(Cl)n2)cn1
Reactant: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Product: COc1ccc(Nc2cc(N3CCOCC3)nc(-c3cnc(N)nc3OC)n2)cn1

Procedure:
According to Example 1, the reaction of 2-chloro-N-(6-methoxypyridin-3-yl)-6-morpholinopyrimidin-4-amine (40 mg, 0.124 mmol) with 4-methoxy-5-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))pyrimidine-2-ylamine (94 mg, 0.372 mmol) gave 4′-methoxy-N4-(6-methoxypyridin-3-yl)-6-morpholino-2,5′-bipyrimidine-2′,4-diamine. A mixture of crude 4′-methoxy-N4-(6-methoxypyridin-3-yl)-6-morpholino-2,5′-bipyrimidine-2′,4-diamine and morpholine (0.108 mL, 1.24 mmol) in N-methylpyrrolidinone (2 mL) was heated under microwave irradiation (high absorption, fixed hold time) for 20 minutes at 200° C. Additional morpholine (0.108 mL, 1.24 mmol) was added and the solution heated at 200° C. under microwave irradiation for another 50 minutes. Another portion of morpholine (0.108 mL, 1.24 mmol) was added and the mixture heated at 200° C. under microwave irradiation for 90 minutes. Upon cooling the material was directly purified by reverse-phase HPLC. After lyophilization, the bis-TFA salt of 2-amino-5-(4-(6-methoxypyridin-3-ylamino)-6-morpholinopyrimidin-2-yl)pyrimidin-4(3H)-one was isolated as an off white solid (24.6 mg, 50%): LCMS (m/z): 397.1 (MH+). Rt: 1.92 min.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][NH:6][CH2:5]2)[CH2:3][O:2]1.[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22](O)=[O:23])=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>>[CH2:1]1[C:4]2([CH2:7][N:6]([C:22]([C:21]3[CH:25]=[CH:26][N:27]=[CH:28][C:20]=3[NH:19][C:17]([C:15]3[C:14]([NH:29][C:30]4[CH:31]=[N:32][CH:33]=[N:34][CH:35]=4)=[CH:13][CH:12]=[C:11]([CH:8]4[CH2:10][CH2:9]4)[N:16]=3)=[O:18])=[O:23])[CH2:5]2)[CH2:3][O:2]1
Reactant: C1NCC12COC2
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: O=C(Nc1cnccc1C(=O)N1CC2(COC2)C1)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 9 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 2-oxa-6-aza-spiro[3.3]heptane with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (9%) as amorphous off-white solid.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=13)=[O:10])[NH:2]2.[F:20][C:21]1[CH:22]=[C:23]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[O:19][CH:18]=[CH:17][C:16]=34)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:34])[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2occc12
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4occc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 5-(3-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.38 min; [M+H]+=476.1.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:12][C:13](=[O:33])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][C:25]3[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=3[F:32])[CH:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Li+]>O1CCOCC1>[F:32][C:26]1[CH:27]=[CH:28][C:29]([CH3:31])=[CH:30][C:25]=1[CH2:24][CH2:23][O:22][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[O:20][CH3:21])[C:13]([NH:12][C:5]1([C:3]([OH:4])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:33]
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cc(C)ccc3F)c2)CCCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)NC2(C(=O)O)CCCCCC2)cc1OCCc1cc(C)ccc1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
The compound of step 3 (160 mg, 0.35 mmol) was dissolved in dioxane (1.8 ml). 1 M aqueous lithium hydroxide (1.8 ml) was added, the mixture was stirred at 60° C. for 30 min, cooled, and partitioned between 2 N hydrochloric acid and EA. The aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness. The residue was stirred in ether and the solid material which formed was filtered and dried in vacuo to yield the title compound (126 mg).
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[O:10]>>[C:15]1([CH3:18])[CH:16]=[CH:17][C:12]([O:11][C:9]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:10])=[CH:13][CH:14]=1
Reactant: Cc1ccc(OC(=O)Cl)cc1
Reactant: COP(OC)OC
Product: COP(=O)(OC)C(=O)Oc1ccc(C)cc1
Yield: 93 %

Procedure:
From 10.3 g (85 mmole) of trimethylphosphite and 10.3 g (60 mmole) of p-tolyl chloroformate (prepared according to M. J. Zabik and R. D. Schuetz, J. Org. Chem. 32 (1967) 300). (100° C., 2 hours). Yield 93%. Bp0.2 131° C., nD20 1.4972.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[C:20]([C:22]3[O:23][C:24]([CH3:27])=[N:25][N:26]=3)[CH:19]=[CH:18][C:17]=2[CH3:28])=[CH:12][CH:11]=1)=[O:9].I[CH3:33]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]([CH3:33])[C:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[C:20]([C:22]3[O:23][C:24]([CH3:27])=[N:25][N:26]=3)[CH:19]=[CH:18][C:17]=2[CH3:28])=[CH:14][CH:15]=1)=[O:9]
Reactant: COc1cccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)c1
Reactant: CI
Product: COc1cccc(CN(C)C(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)c1

Procedure:
N-(3-Methoxybenzyl)-N-methyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from N-(3-methoxybenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.76,(1H, b), 7.58-7.45,(5H, m), 7.30,(1H, t), 6.93-6.72,(3H, m), 4.67-4.51,(2H, m), 3.76,(3H, s), 2.92-2.89,(3H, m), 2.55,(3H, s), 2.32,(3H, s). LCMS; retention time 3.39 min, MH+ 428.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2C3SC=CC=3ON=2)C=CC=1.[NH2:39][CH2:40][CH:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[OH:42].C(=O)([O-])[O-].[K+].[K+]>>[C:43]1([CH:41]([OH:42])[CH2:40][NH:39][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[C:16]4[S:17][CH:18]=[CH:19][C:15]=4[O:14][N:13]=3)[CH:7]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: NCC(O)c1ccccc1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Agent: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OC(CNCCCOc1cccc(-c2noc3ccsc23)c1)c1ccccc1
Yield: 100 %

Procedure:
The title compound is prepared from a mixture of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 2-amino-1-phenylethanol and potassium carbonate essentially as described above in example 4 except that the column is eluted with a mixture of dichloromethane:methanol (95:5). Combine the appropriate fractions and concentrate to give the title compound (0.62 g, 100% Yield) as a solid. Purity by LC/MS (APCI)=100% area, [M+H]+=395 m/e.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([N:12]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)[CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]([OH:26])=O)[CH:22]=2)[NH:17][C:16]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH:78]1[CH2:83][CH2:82][O:81][CH2:80][CH2:79]1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:11])[N:12]([CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]([N:78]3[CH2:83][CH2:82][O:81][CH2:80][CH2:79]3)=[O:26])[CH:22]=2)[NH:17][C:16]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)[CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C1COCCN1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)O)cc3c2CCN(CCCCc2ccncc2)C(=O)OCc2ccccc2)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N4CCOCC4)cc3c2CCN(CCCCc2ccncc2)C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 100 mg (0.163 mmol) of 3-[2-[benzyloxycarbonyl-[4-(pyridin-4-yl)butyl]amino]ethyl]-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid hydrochloride 101.7 mg (0.196 mmol) of PyBOP reagent, 0.085 mL (85.2 mg, 0.978 mmol) of morpholine, and 1 mL of dry methylene chloride was stirred under nitrogen at room temperature in a stoppered flask. After 5 days, the solution was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the crude product by flash chromatography on silica gel (gradient elution with 1-4% MeOH in CH2Cl2) afforded a quantitative yield of the title compound as a yellow gum; homogeneous by TLC in 95:5 CH2Cl2-MeOH. 500 MHz 1H NMR (CDCl3) was complex, owing to rotamers, but was consistent with the assigned structure. Mass spectrum (ESI): m/e=645.6 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]3[C:33]([Cl:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=3[Cl:36])=[CH:20][CH:19]=2)[C:15]#[N:16])=[C:10]([CH3:37])[CH:9]=1.[BH4-].[Na+]>CO.C1COCC1.[OH-].[Na+].CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]3[C:29]([Cl:36])=[CH:30][C:31]([CH3:35])=[CH:32][C:33]=3[Cl:34])=[CH:22][CH:23]=2)[CH2:15][NH2:16])=[C:10]([CH3:37])[CH:9]=1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(C#N)c3ccc(-c4ccccc4Cl)cc3C)cc2)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CN)c3ccc(-c4ccccc4Cl)cc3C)cc2)c(Cl)c1
Reaction time: 12 h

Procedure:
To a solution of 2-(2′-chloro-3-methylbiphenyl-4-yl)-3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}propanenitrile from step 4 (1 eq.) in MeOH/THF (4:1; 0.08M) at room temperature was added cobaltous chloride hexahydrate (CoCl2.6H2O; 2 eq.) and then portionwise sodium borohydride (10 eq.). The final black mixture was stiffed for 12 h at room temperature, poured in aqueous NaOH (1N) and diluted with EtOAc. The precipitate was filtered-off on celite and the organic extract was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated. Purification by column chromatography on silica gel, eluting with CH2Cl2/MeOH(NH3 2M) 4%, afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.52-7.48 (m, 1H); 7.40-7.25 (m, 6H); 7.11 (s, 2H); 6.98 (d, 2 H); 6.80 (d, 2H); 4.39-4.32 (m, 4H); 3.35 (m, 1H); 3.10 (m, 2H); 3.0-2.75 (m, 4H); 2.30 (s, 3 H); 2.20 (s, 3H).
Reaction SMILES: [P:1]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].N1C=CC=CC=1.Cl[C:39]([O:41][CH:42]([Cl:44])[CH3:43])=[O:40]>C(Cl)Cl>[Cl:44][CH:42]([O:41][C:39](=[O:40])[O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][P:1]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH3:43]
Reactant: O=P(OCCOCCOCCOCCO)(OCc1ccccc1)OCc1ccccc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)OCCOCCOCCOCCOP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of dibenzyl 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl phosphate (500 mg, 1.1 mmol) and pyridine (200 mg, 205 μl, 2.53 mmol) in methylene chloride (6 mL) at −78° C. was added slowly 1-chloroethyl chloroformate (178 mg, 134 μl, 1.24 mmol) in methylene chloride (2 mL). After addition, the reaction mixture was allowed to stir at −78° C. for 1.5 h. Then the cold bath was removed and the reaction mixture was warmed up to room temperature. 1H-NMR showed the completion of the reaction. The reaction mixture was concentrated in vacuo. The residue was reconstituted with diethyl ether. The solids in the ethereal solution were filtered off and washed thoroughly with diethyl ether. The filtrate and washing solutions were combined and concentrated to give carbonic acid 2-(2-{2-[2-(bis-benzyloxy-phosphoryloxy)-ethoxy]-ethoxy}-ethoxy)-ethyl ester 1-chloro-ethyl ester as clear light-yellow thick oil. The crude product was used without further purification.