Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:27][CH2:28]C#N)[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[O:40]=C1COC2N=C(C3C=CC(C4(NC(=O)OC(C)(C)C)CCC4)=CC=3)C(C3C=CC=CC=3)=CC=2N1.BrCCO>>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:27][CH2:28][OH:40])[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCC#N)C(=O)CO4)cc2)CCC1
Agent: OCCBr
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCO)C(=O)CO4)cc2)CCC1

Procedure:
Following the procedure for tert-butyl(1-(4-(1-(2-cyanoethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate, tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (100 mg, 0.212 mmol) was reacted with 2-bromoethanol (80 mg, 0.636 mmol) to afford the title compound (75 mg. 1H NMR (500 MHz, CDCl3): 7.47 (s, 1H), 7.23-7.29 (m, 7H), 7.16-7.19 (m, 2H), 5.04 (br, 1H), 4.89 (s, 2H), 4.12 (m, 2H), 3.94 (m, 2H), 2.37-2.48 (m, 4H), 2.37 (t, 1H), 2.05 (m, 1H), 1.81 (m, 1H), 1.2-1.43 (br, 9H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[NH:9][C:10](=[O:21])[C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[F:20].O.[C:23]1(C)[CH:28]=[CH:27][C:26](S(O)(=O)=O)=[CH:25][CH:24]=1>>[N+:17]([C:15]1[CH:16]=[C:11]([C:10]2[O:21][C:2]3[CH:7]=[CH:6][C:5]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:4][C:3]=3[N:9]=2)[C:12]([F:20])=[CH:13][CH:14]=1)([O-:19])=[O:18]
Reactant: O=C(Nc1cc(Br)ccc1O)c1cc([N+](=O)[O-])ccc1F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1

Procedure:
Prepared by the method of Example 15c), from N-(2-hydroxy-5-bromophenyl)-2-fluoro-5-nitrobenzamide (11.0 g, 0.03 mol) and p-toluenesulfonic acid monohydrate (11.88 g, 0.06 mol) the subtitle compound was obtained (6 g, 58%). 1H NMR (DMSO) δ 8.98(dd, 1H), 8.54(m, 1H), 8.19(d, 1H), 7.97(d, 1H), 7.81(m, 4H), 7.52(t, 2H), 7.42(d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:15])[CH2:9][CH2:10]C(OC)=O)=[CH:4][CH:3]=1.[CH3:16][Mg]I.S(=O)(=O)(O)O.C([O:26][CH2:27][CH3:28])C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:9][CH2:10][C:27]([OH:26])([CH3:28])[CH3:16])=[CH2:15])=[CH:4][CH:3]=1
Reactant: C=C(CCC(=O)OC)c1ccc(Cl)cc1
Reactant: CCOCC
Reactant: C[Mg]I
Agent: O=S(=O)(O)O
Product: C=C(CCC(C)(C)O)c1ccc(Cl)cc1

Procedure:
A solution of methyl 4-(4-chlorophenyl)pent-4-enoate (5.8 g, prepared as described in Example 1) in dry diethyl ether (25 ml) was added to a stirred solution of methylmagnesium iodide [from methyl iodide (8.52 g) and magnesium turnings (1.7 g)] in dry diethyl ether (50 ml) (exotherm). After 1 hour at room temperature the reaction mixture was poured into a mixture of ice and dilute sulphuric acid, then extracted with diethyl ether. The extracts were washed with water, dried over magnesium sulphate, and concentrated under reduced pressure to give 2-(4-chlorophenyl)-5-hydroxy-5-methylhex-1-ene (5.8 g, quantitative) as a yellow oil, 1H nmr (CDCl3): δ1.22 (6H, singlet, CH3 ×2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.[H-].[Na+].Cl[C:13]1[N:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1>CN(C)C=O>[CH3:20][O:19][C:16]1[N:15]=[N:14][C:13]([CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:8]#[N:9])=[CH:18][CH:17]=1
Reactant: N#CCc1cccnc1
Reactant: COc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C#N)c2cccnc2)nn1
Temperature: -4 °C
Reaction time: 0.75 h
Yield: 69.1 %

Procedure:
Pyridin-3-ylacetonitrile (14.3 g, 0.119 mol) were dissolved in dimethylformamide (300 ml) at 21° C. under a nitrogen atmosphere. The solution was cooled to −4° C., and sodium hydride (60% suspension in paraffin oil, 9.96 g, 0.249 mol) was added in portions. The resultant brown suspension was stirred at 0° C. for 45 minutes, and 3-chloro-6-methoxypyridazine (34.47 g, 0.231 mol) was subsequently added. The mixture was heated to 70° C. and stirred for 3 hours. After cooling, conventional work-up gave 18.6 g (68% yield) of (6-methoxypyridazin-3-yl)pyridin-3-ylacetonitrile;
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]([O:13][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@@H:15]1Br)(=[O:12])[CH3:11]>[O-2].[Zn+2]>[C:10]([O:13][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:15]1[S:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])(=[O:12])[CH3:11]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: N#Cc1ccccc1S
Agent: [O-2]
Agent: [Zn+2]
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccccc2C#N)SC[C@H]1OC(C)=O
Yield: 60 %

Procedure:
If the procedure described in Preparation IV is followed starting from 10.7 g (79.2.10-3 mol) of 2-mercaptobenzonitrile, 30.2 g (85.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 6.3 g (77.4.10-3 mol) of zinc oxide (ZnO), 19.3 g (yield: 60%) of the expected product are obtained after crystallization from ether.
Reaction SMILES: [C:1]([OH:16])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]1[CH2:29][CH:28]([OH:30])[CH2:27][CH:26]1[CH:31]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[O:32][CH:33]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34]([CH:33]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[O:32][CH:31]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:26]2[CH2:27][CH:28]([OH:30])[CH2:29][N:25]2[C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:1](=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:35][CH:36]=1
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN)c2ccc(OC)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCCC(=O)NCCCCCC(=O)N1CC(O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1

Procedure:
Using the above procedure Myristic acid (2.30 g, 10 mmol) was coupled with the amine 100 (6.10 g, 11.45 mmol) using HBTU (4.54 g, 1.2 eq.) and DIEA (5 mL, 3.00 eq). After work-up and column purification the pure amide 102c was isolated as a pale yellow solid (Yield, 6.10 g, 80%). 1H NMR (DMSO-d6, 400 MHz) δ=7.72-7.65 (m, 1H), 7.35-7.26 (m, 4H), 7.27-7.12 (m, 5H), 6.90-6.80 (m, 4H), 4.99 (d, J=3.91 Hz, 1H), 4.89 (d, J=3.91 Hz, 1H), 4.41-4.10 (m, 2H), 3.71 (s, 6H), 3.57-3.42 (m, 1H), 3.37-3.11 (m, 2H), 3.05-2.91 (m, 3H), 2.25-1.80 (m, 6H), 1.52-1.08 (m, 28H), 0.83 (t, J=6.34 Hz, 3H). 13C NMR (DMSO-d6, 400 MHz) δ=171.84, 170.93, 170.82, 158.11, 157.98, 145.09, 144.75, 135.87, 135.72, 135.47, 135.42, 129.60, 129.55, 127.84, 127.75, 127.72, 126.56, 113.17, 113.08, 85.78, 85.12, 68.58, 67.45, 65.19, 63.33, 55.61, 55.06, 54.99, 53.44, 39.08, 38.87, 38.22, 38.02, 36.31, 35.44, 34.18, 32.54, 31.32, 29.09, 29.04, 28.99, 28.80, 28.74, 28.64, 26.20, 25.34, 24.55, 24.15, 22.11, 13.93.
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[C:22]1[N:23]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:25][CH:26]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](O)=[O:4].[CH:34]1([NH2:37])[CH2:36][CH2:35]1.ClCCl.CCN(C(C)C)C(C)C>>[CH:34]1([NH:37][C:3](=[O:4])[CH:2]([OH:1])[CH:6]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]=2[C:22]2[N:23]=[C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[S:25][CH:26]=2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:36][CH2:35]1
Reactant: NC1CC1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-c1csc(-c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NC1CC1)c1cccnc1-c1csc(-c2ccccc2)n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of 2-hydroxy-4-phenyl-3-(2-(2-phenylthiazol-4-yl)nicotinamido)butanoic acid (230 mg, 0.501 mmol) and cyclopropylamine (40 μL, 0.570 mmol) in dichloromethane (30 ml) 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU) (230 mg, 0.605 mmol) and DIPEA (100 μL, 0.605 mmol) were added at 5° C. The mixture was stirred for 1 hour at 5° C. and then for 5 hours at room temperature. The mixture was concentrated under reduced pressure, 40 ml of water added, the precipitate formed filtered off with suction, washed with water and dried in vacuo to give 227 mg of a white amorphous solid;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:11]2[S:15][C:14]([C:16](O)=[O:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[C:4]([CH3:19])[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1.Cl.[CH3:31][O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH3:31][O:32][C:33](=[O:37])[CH2:34][CH2:35][NH:36][C:16]([C:14]1[S:15][C:11]([CH:9]([O:8][C:6]2[CH:7]=[C:2]([CH3:1])[C:3]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=3)=[C:4]([CH3:19])[CH:5]=2)[CH3:10])=[CH:12][CH:13]=1)=[O:17]
Reactant: COC(=O)CCN
Reactant: Cc1cc(OC(C)c2ccc(C(=O)O)s2)cc(C)c1-c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCNC(=O)c1ccc(C(C)Oc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)s1
Yield: 74.6 %

Procedure:
To a mixture of (-±)-5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carboxylic acid (0.545 g, 1.30 mmol), 3-amino-propionic acid methyl ester hydrochloride (0.199 g, 1.43 mmol), and 1-hydroxybenzotriazole hydrate (HOBt, 0.217 g, 1.60 mmol) in DMF (13.0 mL) is added N,N-diisopropylethylamine (0.67 mL, 3.84 mmol), then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 0.330 g, 1.72 mmol) and stirred overnight. The reaction mixture is poured into H2O (25 mL) and extracted with EtOAc (3×25 mL). Combined organic extracts are washed with H2O, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 75% to provide (±)-3-({5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.490 g, 75%) as a white foam. MS (ES): 504.3 [M−H]−.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][NH:5][C:6]1[N:11]=[C:10]2[N:12]([Si](C(C)C)(C(C)C)C(C)C)[CH:13]=[CH:14][C:9]2=[CH:8][CH:7]=1.[CH3:26][N:27](C=O)C.ClS(N=C=O)(=O)=O.[Na+].[Cl-]>C(#N)C>[CH3:25][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]1[N:11]=[C:10]2[NH:12][CH:13]=[C:14]([C:26]#[N:27])[C:9]2=[CH:8][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(NCCN(C)C)nc21
Reactant: CN(C)C=O
Agent: O=C=NS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Product: CN(C)CCNc1ccc2c(C#N)c[nH]c2n1
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 82 %

Procedure:
In a 25 mL round-bottomed flask, N1,N1-dimethyl-N2-(1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)ethane-1,2-diamine (405 mg, 1.12 mmol) was combined with DMF (14.9 ml) to give a colorless solution. The reaction mixture was cooled to −20° C. and stirred for 5 min. Chlorosulfonyl isocyanate (477 mg, 293 μl, 3.37 mmol, Eq: 3) in acetonitrile (14.9 ml) was added dropwise and the resultant cooled reaction was stirred at −20° C. and stirred for 3 hrs The reaction mixture was poured into 25 mL sat NaCl and extracted with EtOAc (3×20 ml). After evaporation, crude material was purified by flash chromatography (silica gel, 12 g, 5% to 10% MeOH in DCM) to obtain 6-(2-(dimethylamino)ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (211 mg, 82%).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[K+].[CH2:30](I)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(O)CCC>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[CH:26]=[CH:25][C:24]([O:27][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(-c2nc3cc(O)ccc3o2)cc1
Reactant: CCCCCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCCCCCCOc1ccc(-c2nc3cc(OCCCCCCCC)ccc3o2)cc1
Yield: 52.1 %

Procedure:
In a 20 ml-round-bottomed flask, 0.25 g (0.68 mM) of 2-(4-decyloxyphenyl)-5-hydroxybenzoxazole, 0.08 g (1.21 mM) of potassium hydroxide and 3 ml of butanol were placed and heated to provide a solution. To the solution, 0.18 ml (1.00 mM) of octyl iodide was added, followed by heat-refluxing for 5 hours and 40 minutes under stirring. After the reaction, the solvent in the reaction mixture was distilled off under reduced pressure. To the residue, ethyl acetate and water were added, followed by stirring at room temperature. The organic layer was successively washed with 2%-sodium thiosulfate aqueous solution and water, followed by drying with anhydrous sodium sulfate and reduced pressure distillation. The resultant residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (acetone-methanol) to obtain 0.17 g of 2-(4-decyloxyphenyl)-5-octyloxybenzoxazole (Yield: 52.1%). ##STR82##
Reaction SMILES: [C:1]([CH:9]([OH:34])[C@H:10]1[O:14][C@@H:13]([N:15]2[C:31]3[N:30]=[CH:29][N:28]=[C:19]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[N:17]=[CH:16]2)[C@H:12]([OH:32])[C@@H:11]1[OH:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[Sn](O[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC.[C:62]1([N:68]=[C:69]=[O:70])[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]([CH:9]([OH:34])[C@H:10]1[O:14][C@@H:13]([N:15]2[C:31]3[N:30]=[CH:29][N:28]=[C:19]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[N:17]=[CH:16]2)[C@H:12]([O:32][C:69](=[O:70])[NH:68][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C@@H:11]1[OH:33])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:1]([CH:9]([OH:34])[C@H:10]1[O:14][C@@H:13]([N:15]2[C:31]3[N:30]=[CH:29][N:28]=[C:19]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[N:17]=[CH:16]2)[C@H:12]([OH:32])[C@@H:11]1[O:33][C:69](=[O:70])[NH:68][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(c1ccccc1)C(O)[C@H]1O[C@@H](n2cnc3c(NCc4ccccc4)ncnc32)[C@H](O)[C@@H]1O
Agent: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)O[C@@H]1[C@H](O)[C@@H](C(O)C(=O)c2ccccc2)O[C@H]1n1cnc2c(NCc3ccccc3)ncnc21
Product: O=C(Nc1ccccc1)O[C@H]1[C@@H](O)[C@H](n2cnc3c(NCc4ccccc4)ncnc32)O[C@@H]1C(O)C(=O)c1ccccc1

Procedure:
The toluene-DMF mixed solvent solution of 5′-benzoyl-N6-benzyladenosine (0.1 mmol) and bis(tributyltin) oxide (0.05 mmol) and phenyl isocyanate (0.2 mmol) was stirred at −78° C. to −48° C. for 49 hours, to obtain 5′-benzoyl-N6-benzyl-2′-O-phenylcarbamoyladenosine with the yield of 60% and 5′-benzoyl-N6-benzyl-3′-O-phenylcarbamoyladenosine with the yield of 40%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:7](N(CC)CC)[CH3:8].[CH3:14][CH2:15][CH2:16][C:17](=O)[CH2:18][CH2:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C.ClCCl>[CH2:7]([O:5][C:4](=[O:6])[CH2:3][CH2:2][NH:1][CH:17]([CH2:18][CH2:19][CH3:20])[CH2:16][CH2:15][CH3:14])[CH3:8]
Reactant: NCCC(=O)O
Reactant: CCCC(=O)CCC
Reactant: CCN(CC)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCCC(CCC)NCCC(=O)OCC
Reaction time: 24 h

Procedure:
To a 12 L 3-neck flask equipped with a mechanical stirrer and nitrogen inlet was charged 400 g (2.6 mol) of β-alanine, 2250 L of dichloromethane and 2.3 L of ethanol. Agitation was begun and 1.09 L (7.8 mol, 3 eq) of triethyl amine and 364 mL (2.6 mol, 1 eq) of 4-heptanone were added. The mixture was cooled to <10° C. and 1.65 Kg (7.8 mol, 3 eq) of sodium triacetoxy borohydride. Mixture kept <15° C. and stirred for 24 hrs.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].C(N(CC)CC)C.[C:18](Cl)(=[O:22])[CH:19]([CH3:21])[CH3:20]>C1COCC1>[Br:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([F:9])=[C:6]([NH:7][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:8]=1
Reactant: Nc1cc(Br)c(F)cc1F
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cc(Br)c(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
Into a solution of 2.6 g (12.6 mmol) of 5-bromo-2,4-difluoroaniline and 2.1 mL (15.1 mmol) of triethylamine in 50 mL THF at 0° C. was slowly added 1.6 mL (15.1 mmol) of isobutyryl chloride. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in EtOAc and washed with H2O, saturated aqueous Na2CO3 and brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give 3.3 g (11.8 mmol, 94%) of N-(5-bromo-2,4-difluorophenyl)-2-methylpropanamide: ESMS m/e: 278.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:24][NH:25][O:26][CH3:27].CCOCC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[N:25]([CH3:24])[O:26][CH3:27])[CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCOCC
Product: CON(C)C(=O)c1ccnc(Cl)c1
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a suspension of 2-chloroisonicotinic acid (18.0 g, 0.105 mol) in 250 mL of methylenechloride was added 1,1′-carbonyldiimidazole (17.0 g, 0.105 mol) portionwise. The mixture was stirred for 0.5 h and N,O-dimethylhydroxylamine hydrochloride (10.2 g, 0.105 mol) was added rapidly. The reaction mixture was stirred at room temperature overnight. Ether was added and the organic layer was washed with water, dried, dried over magnesium sulfate and filtered. The filtrate was concentrated to give 14.5 g (70%) of product as a yellow oil. This was used in next step without purification.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20](O)[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[CH2:27][OH:28])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[H-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[C:14]([Si:1]([O:18][CH2:19][CH:20]1[O:28][CH2:27][C:23]2=[N:24][CH:25]=[CH:26][N:22]2[CH2:21]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[Si](OCC(O)Cn1ccnc1CO)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCC1Cn2ccnc2CO1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Separately, prepare a −78° C. solution of 1-[tert-butyl(diphenyl)silyl]oxy-3-[2-(hydroxymethyl)imidazol-1-yl]propan-2-ol (9.4 g; 1.0 equiv; 22.89 mmoles) in dichloromethane (100 mL). Add the in situ prepared iodinating reagent dropwise to this solution with the orange color quickly fading to nearly colorless. Maintain the solution at −78° C. for 30 minutes, then allow it to warm to 0° C. and maintain for 10 minutes. Recool the solution to −78° C., and add tetrahydrofuran (150 mL) followed by 60% sodium hydride (2.20 g; 2.4 equiv; 54.95 mmoles). Slowly warm the solution to 0° C. over 30 minutes, and then to ambient temperature for 1 hour. Pour the mixture slowly into 50% saturated sodium bicarbonate solution and extract with dichloromethane (4×100 mL). Dry the combined organic extracts over magnesium sulfate, filter, and concentrate. Purify the crude product by column chromatography (10 to 100% ethyl acetate in hexanes) to afford the desired product contaminated with triphenylphosphine oxide. Further purify by SCX ion-exchange chromatography (10% methanol in dichloromethane to 10% (4N ammonia in methanol) in dichloromethane) to afford the desired tert-butyl-(6,8-dihydro-5H-imidazo[2,1-c][1,4]oxazin-6-ylmethoxy)-diphenyl-silane (5.96 g; 66%) as a colorless gum. MS (m/z): 393(M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:28]=[C:29]([OH:31])[CH:30]=1)[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]1)[CH3:4].Cl[CH2:33][C:34]1[N:35]=[C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[S:37][CH:38]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:28]=[C:29]([O:31][CH2:33][C:34]2[N:35]=[C:36]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[S:37][CH:38]=2)[CH:30]=1)[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]1)[CH3:4]
Reactant: CCOC(=O)CCc1cn(Cc2cc(O)cc(OCC)c2)cc1-c1ccccc1
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2cc(OCC)cc(OCc3csc(-c4ccccc4)n3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.9 %

Procedure:
Sodium hydride (60%, oily, 50.0 mg) was added to a solution of ethyl 3-[1-(3-ethoxy-5-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (492 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-phenylthiazole (262 mg) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[3-ethoxy-5-(2-phenyl-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (601 mg, yield: 85%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=O)C.[CH2:28]([N:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)[CH2:32][CH2:31]1)[CH3:29].C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH2:28]([N:30]1[CH2:31][CH2:32][N:33]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[Cl:27])=[CH:14][CH:15]=3)=[O:3])=[N:41][CH:42]=2)[CH2:34][CH2:35]1)[CH3:29]
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Reactant: CCN1CCN(Cc2ccc(N)nc2)CC1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(-c4c(F)c(OC)cc(OC)c4Cl)c4nccnc34)nc2)CC1
Temperature: 80 °C
Reaction time: 7 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 26.1; purified by silica gel column chromatography), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 7 h at 80° C., pouring it onto a saturated aqueous solution of NaHCO3 and DCM. Title compound: ESI-MS: 564.8 [M+H]+; tR=3.57 min (System 1); TLC: Rf=0.25 (DCM/MeOH/NH3aq, 94:5:1).