Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH3:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.CO>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([CH3:21])=[CH:23][CH:24]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Yield: 83 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and 4-methylbenzoyl chloride (1.1 g, 8.0 mmol) in THF (40 mL): was heated to reflux for 36 h. To the mixture was added methanol (5 mL) to give a suspension. The suspension was filtered and washed with methanol (15 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-methyl-benzamide as a yellow solid (1.3 g, 83% yield): mp, 322-324° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H, CHH), 2.41 (s, 3H, CH3), 2.50-2.65 (m, 2H, CH2), 2.83-2.97 (m, 1H, CHH), 5.19 (dd, J=5.3, 12.6 Hz, 1H, NCH), 7.42 (d, J=8.1 Hz, 2H, Ar), 7.67 (d, J=7.2 Hz, 1H, Ar), 7.86-7.93 (m, 3H, Ar), 8.62 (d, J=8.4 Hz, 1H, Ar), 10.37 (s, 1H, N), 11.18 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.07, 21.99, 30.93, 48.99, 117.57, 118.58, 125.94, 127.28, 129.58, 130.44, 131.33, 136.34, 136.77, 142.96, 164.80, 166.65, 168.29, 169.69, 172.72; Anal Calcd for C21H17N3O5: C, 64.45; H, 4.38; N, 10.74. Found: C, 64.65; H, 4.17; N, 10.70.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][CH:6]=1.[CH2:9]([O:11][P:12]([O:16]CC)[O:13][CH2:14][CH3:15])[CH3:10]>>[CH2:9]([O:11][P:12]([CH2:7][C:4]1[S:3][C:2]([Br:1])=[CH:6][CH:5]=1)(=[O:16])[O:13][CH2:14][CH3:15])[CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: ClCc1ccc(Br)s1
Product: CCOP(=O)(Cc1ccc(Br)s1)OCC
Temperature: 140 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
2-Bromo-5-chloromethylthiophene described in Preparation Example 141 (7.3 g, 34.5 mmol) and triethylphosphite (6.35 g, 38.2 mmol) were stirred at 140° C. for 3 hours. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50), and the title compound (8.82 g, 31.2 mmol, 90.3%) was obtained as a reddish brown oil.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][N:24]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH3:59][C:60]([CH3:63])([O-])[CH3:61].[K+].O>CN(C)P(N(C)C)N(C)C>[C:3]1([CH2:2][N:37]([C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[CH2:36][CH2:35][CH2:34][N:33]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][N:24]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:23][CH2:22][CH2:21][N:20]([CH2:59][C:60]2[C:63]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:12]=[CH:11][CH:61]=2)[C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)NCCCN(CCCCCCCCN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)[O-]
Agent: CN(C)P(N(C)C)N(C)C
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N(CCCCCCCCN(CCCN(Cc1cccc2ccccc12)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCCN(Cc1cccc2ccccc12)C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
A solution of 1-chloromethylnaphthalene (1.7 g - 9.6 mmol) in 5 ml hexamethylphosphorous triamide (HMPA) is added to a mixture of 1,5,14,18-tetra(t-butoxycarbonyl)-1,5,14,18-tetraazaoctadecane (2.6 g) and potassium t-butoxide (1.07 gm) in HMPA (50 ml). The mixture is heated in an 80° C. oil bath for 4 hours, poured into 300 ml of water, and the aqeuous mixture is extracted with ethyl acetate (2×300 ml). The combined extracts are extracted with water (3×300 ml) and brine (300 ml). The organic layer is dried, evaporated and the residue is chromatographed (flash-silica gel column eluting with 4 to 1 toluene/ethylacetate to yield 800 mg of 1,18-bis-[(1-naphthyl)methyl]-1,5,14,18-tetra(t-butoxycarbonyl)-1,5,14,18-tetraazaoctadecane.
Reaction SMILES: [C:1]1([C@H:7]2[N:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:10][CH:9]([CH2:16][OH:17])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:21]1[C:26]([C:27]#[N:28])=[CH:25][CH:24]=[CH:23][N:22]=1.O>CN(C)C=O>[C:1]1([C@H:7]2[N:11]([C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:10][CH:9]([CH2:16][O:17][C:21]3[C:26]([C:27]#[N:28])=[CH:25][CH:24]=[CH:23][N:22]=3)[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)N1CC(CO)O[C@H]1c1ccccc1
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)N1CC(COc2ncccc2C#N)O[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To (S)-2-phenyl-3-tert. butyl-5-hydroxymethyl- oxazolidine (7 grams, 0.03 moles) in 35 ml. of N,N-dimethyl- formamide (DMF) is added 1.3 grams (0.03 moles of sodium hydride (57% dispersion in mineral oil). This mixture is heated 5 minutes over steam and then is allowed to stir 15 minutes at room temperature. 4.1 grams (0.03 moles) of 2-chloro-3-cyanopyridine in 20 ml of DMF is then added and the resultant reaction mixture is stirred four hours at room temperature. Water is then added and an oil separates. This oil is extracted three times with 25 ml of chloroform each time. This chloroform extract is dried over sodium sulfate and concentrated under reduced pressure (20 mm) over steam to yield the product, (S)-2-phenyl-3-tert. butyl-5-(3-cyano-2-pyridyloxymethyl)oxazolidine, as an oil. This oil is then suspended in 1N HCl (50 ml), heated 5 minutes over steam and then is stirred for 15 minutes at room temperature. The solution obtained is then extracted twice with 25 ml of diethylether each time. The extracted aqueous layer is made basic by addition of saturated aqueous sodium carbonate solution. This aqueous solution is then extracted with ethyl acetate (3 × 25 ml) and the ethylacetate solution is dried over sodium sulfate. The dried ethyl acetate solution is then concentrated under reduced pressure (20 mm) over steam to yield an oil. This oil is chromatographed on alumina. The chromatographic fractions are concentrated to yield an oil which is dissolved in diethyl ether. Ethanolic HCl (saturated solution is added to this ether solution until solid separation is substantially complete. The separated semi-solid is recrystallized from isopropanol/ether (ether added to isopropanol to the point of turbidity) to yield 1 gram of (S)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-cyanopyridine hydrochloride, melting at 161°-163° C.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][O:12][CH:11]([CH2:15][N:16]([C:23]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1)C1C=CC=CC=1.[H][H]>O.C(O)C.[Pd]>[ClH:1].[O:25]([C:23]([N:16]([CH2:15][CH:11]1[O:12][CH2:13][CH2:14][NH:9][CH2:10]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:24])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: [H][H]
Reactant: O=C(Oc1ccccc1)N(CC1CN(Cc2ccccc2)CCO1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(Oc1ccccc1)N(CC1CNCCO1)c1ccccc1

Procedure:
A solution of 4-benzyl-2-(N-phenoxycarbonylanilino)methylmorpholine hydrochloride (9 g.) in water (75 ml.) and ethanol (200 ml.) is shaken in an atmosphere of hydrogen in the presence of palladium on charcoal catalyst (0.5 g.; 5%) until no further hydrogen is absorbed. The catalyst is removed by filtration and the filtrate is then evaporated to give a white residue which is recrystallised from methanol/ether to give 2-(N-phenoxycarbonylanilino)methylmorpholine hydrochloride, m.p. 179°-181° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH:47]3[CH2:49][CH2:48]3)(=[O:46])=[O:45])=[C:40]([CH:50]3[CH2:52][CH2:51]3)[CH:39]=2)/[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.CC1(C)[O:58][C@@H:57]([CH2:59][N:60]2[CH:64]=[CH:63][C:62]([NH2:65])=[N:61]2)[CH2:56][O:55]1>ClCCl.N1C=CC=CC=1.O>[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH:47]3[CH2:48][CH2:49]3)(=[O:46])=[O:45])=[C:40]([CH:50]3[CH2:51][CH2:52]3)[CH:39]=2)/[C:35]([NH:65][C:62]2[CH:63]=[CH:64][N:60]([CH2:59][C@H:57]([OH:58])[CH2:56][OH:55])[N:61]=2)=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C(O)/C(=C/C1CCCC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Reactant: CC1(C)OC[C@H](Cn2ccc(N)n2)O1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccn(C[C@H](O)CO)n1)/C(=C/C1CCCC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
To a solution of triphenylphosphine (320 mg) in dichloromethane (10 mL) was added N-bromosuccinimide (217 mg) under ice-cooling, followed by stirring for 15 minutes under ice-cooling. A solution of (2E)-3-cyclopentyl-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]acrylic acid (200 mg) in dichloromethane (10 mL) was added thereto under ice-cooling, followed by stirring at room temperature for 0.5 hour. A solution of 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-1H-pyrazol-3-amine (142 mg) in dichloromethane (5 mL) and pyridine (0.09 mL) were added thereto at room temperature, followed by stirring at room temperature overnight. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was sequentially washed with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:2). To a solution of the obtained oily substance in THF (15 mL) was added 1 M hydrochloric acid (15 mL), followed by stirring overnight. Saturated brine was added thereto, followed by extraction with a solvent (chloroform:isopropyl alcohol=4:1). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (chloroform:methanol=1:0-20:1) to obtain (2E)-3-cyclopentyl-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-{1-[(2S)-2,3-dihydroxypropyl]-1H-pyrazol-3-yl}acrylamide (197 mg) as a white amorphous substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+]([O-])=O)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([SH:21])[CH:18]=[CH:19][CH:20]=1.CN(C=O)C.[H-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([S:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: COc1cccc(S)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(Sc2cc(Br)cnc2C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
A 10 mL round-bottomed flask was charged with 5-bromo-3-nitropicolinonitrile (300 mg, 1.31 mmol), 3-methoxybenzenethiol (0.150 mL, 1.31 mmol), and DMF (12 mL). NaH (37.8 mg, 1.58 mmol) was added and reaction stirred at room temperature for 10 minutes. The reaction was poured into water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified on silica gel (10% EtOAc in Hexanes) to afford the title compound (345 mg, 81%).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[N:8]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCN1CCNc2ccc(C(=O)OC)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCN1CCN(S(C)(=O)=O)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold, stirred solution of methyl 4-butyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (180 mg) and triethylamine (62 μL) in methylene chloride (2 mL) was added methanesulfonyl chloride (101 μL) and the mixture was stirred for 1 h. The mixture was warmed to room temperature, diluted with methylene chloride, washed with washed with 1 N hydrochloric acid, and brine. The organic layer was then dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:3 ethyl acetate/hexanes) provided 150 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.57, 7.41, 7.32, 3.90, 3.84, 3.45, 3.38, 1.61, 1.41, 0.98.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[C:8]([O:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[C:6]=2[CH:7]=1.CS(C)=[O:30]>>[CH:2]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[C:8]([O:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[C:6]=2[CH:7]=1)=[O:30]
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CBr)oc2c1
Reactant: CS(C)=O
Product: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(C=O)oc2c1
Yield: 84 %

Procedure:
A solution of ethyl 2-(bromomethyl)-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylate (320 mg, 0.706 mmol) and IBX (395 mg, 1.41 mmol) in DMSO (2 mL) was heated at 65° C. for 3 h. The reaction was quenched with water and the product was extracted with CHCl3. The combined organic layers were washed with water (2×), dried over MgSO4, and concentrated. The product was purified by gradient chromatography on silica gel using hexanes/EtOAc (100/0 to 40/60) to give the title compound (230 mg, 84%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.40 (t, J=7.16 Hz, 3 H) 3.09 (s, 3H) 4.41 (q, J=7.16 Hz, 2 H) 7.14-7.23 (m, 2 H) 7.46 (d, J=0.94 Hz, 1 H) 7.62 (d, J=0.94 Hz, 1 H) 7.89-8.02 (m, 2 H) 8.15 (t, J=0.94 Hz, 1 H) 9.89 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[C:13]([CH:20]=[O:21])=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:10]=3[C:9]=2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:4][CH:3]=1.[CH2:28]([OH:31])[CH2:29]O.[CH3:32]C1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:32])[C:11]3[C:13]([CH:20]4[O:31][CH2:28][CH2:29][O:21]4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:10]=3[C:9]=2[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc2c(C3CCCCC3)c(-c3ccc(Cl)cc3)[nH]c2c1C=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1sc2c(C3CCCCC3)c(-c3ccc(Cl)cc3)n(C)c2c1C1OCCO1
Yield: 89 %

Procedure:
A solution (0.15 M) of methyl 5-(4-chlorophenyl)-6-cyclohexyl-3-formyl-4H-thieno[3,2-b]pyrrole-2-carboxylate, ethylene glycol (10 eq.) and a catalytic amount of p-TsOH in toluene was refluxed (Dean-Stark) for 3 h. After cooling down to RT solid NaHCO3 was added and the mixture was diluted with AcOEt and water. The layers were separated and the aqueous layer was extracted with AcOEt. The combined organic phase was dried. Evaporation of the solvent under reduced pressure afforded a residue that was purified by flash chromatography on silica gel (1:3 AcOEt/petroleum ether) to afford the title compound (89%) as a yellow solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]2[CH2:20][CH2:19][NH:18][C:17]2=[O:21])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:33][C:34]([O:36][CH2:37]C)=[O:35]>C1COCC1>[C:34]([O:36][CH3:37])(=[O:35])[CH3:33].[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]2[CH2:20][CH2:19][NH:18][C:17]2=[O:21])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)OC(=O)N1CCC(CCC2CCNC2=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)=O
Temperature: -20 °C

Procedure:
To a stirred solution of 36a (340 mg, 1.1 mmol) in THF (10 mL) at -78° C. was added NaN(TMS)2 (1.0M in THF, 1.1 mL). After 15 minutes ethyl bromoacetate (250 uL, 2.2 mmol) was added and the reaction mixture to warm to -20° C. After 2 hours the reaction was quenched with HOAc (0.1 mL) and then concentrated. Flash chromatography (silica gel, 50% ethyl acetate/hexanes) gave 37a (380 mg, 90%) as an oil. TLC Rf=0.66 (10% methanol/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 4.22 (q, J=7 Hz, 2H), 4.10 (m, 2H), 4.08 (s, 2H), 3.24 (m, 2H), 2.70 (m, 2H), 2.44 (m, 1H), 2.26 (m, 1H), 2.00-1.65 (m, 4H), 1.48 (s, 9H), 1.50-1.30 (m, 4H), 1.31 (t, J=7 Hz, 3H), 1.12 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)C=O.[H-].[Na+].I[CH2:24][CH3:25]>O>[CH2:24]([N:11]1[N:12]=[N:13][C:9]([CH2:8][C:7]2[CH:14]=[CH:15][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:10]1)[CH3:25]
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc(Cc2nnn[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nnc(Cc2ccc([N+](=O)[O-])cc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
To a mixture of 5-(4-nitrobenzyl)-1H-tetrazole (5.0 g) and N,N-dimethylformamide (200 mL) was added sodium hydride (60% in oil, 1.17 g) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr. and iodoethane (5.69 g) was added at 0° C. The reaction mixture was stirred at 0° C. for 2 hrs. and water was poured into the reaction mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-ethyl-5-(4-nitrobenzyl)-2H-tetrazole as a brown oil (2.70 g, yield 48%) from a fraction eluted with hexane-ethyl acetate (2:1-1:2, v/v).
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Br:10]Br>C(Cl)(Cl)Cl>[BrH:10].[Br:10][C:2]1[S:1][C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1
Reactant: c1cc2c(s1)CCNC2
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: Br
Product: Brc1cc2c(s1)CCNC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product from Step 1 (9.57 g, 40 mmol) was dissolved in CHCl3 (150 mL) at 0° C. and treated with bromine (2.1 mL, 40 mmol) dropwise over 10 minutes. The mixture was stirred for 16 h at room temperature then filtered to afford the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:14])[CH:3]=1.C(N(CC)CC)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45]>ClCCl>[C:44]([O:43][C:42]([NH:41][CH:36]1[CH2:37][CH2:38][CH2:39][CH2:40][CH:35]1[NH:34][C:23](=[O:25])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:14])[CH:3]=1)=[O:48])([CH3:45])([CH3:47])[CH3:46]
Reactant: CCOC(=O)Cc1ccc(N)cc1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC1CCCCC1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(NC(=O)NC2CCCCC2NC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(4-amino-2-chlorophenyl)acetate (178 mg, 0.833 mmol) in dry dichloromethane (5 mL), was added triethylamine (2.32 mL, 16.66 mmol) followed by triphosgene (247 mg, 0.833 mmol) solution in dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 1 h. To this mixture was then added tert-butyl 2-aminocyclohexylcarbamate (357 mg, 1.67 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 4 h and concentrated. The residue was dissolved in ethyl acetate and washed with water (2×20 mL), brine (10 mL), dried and concentrated. The crude product was purified by flash column chromatography to afford the desired product as a mixture of cis and trans diastereomers (220 mg, 0.485 mmol, 58%). 1H NMR: 1.23-1.28 (m, 6H), 1.38 (s, 9H), 1.70-1.73 (m, 2H), 2.01-2.08 (m, 2H), 3.29-3.32 (m, 1H), 3.53-3.58 (m, 1H), 3.68 (s, 2H), 4.11-4.19 (m, 2H), 5.01 (d, 1H, J=8.8 Hz), 5.57 (d, 1H, J=8 Hz), 7.13 (d, 1H, J=8.4 Hz), 7.20 (d, 1H, J=6.8 Hz), 7.41 (s, 1H), 7.46 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([C:29]([F:32])([F:31])[F:30])[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:14][N:13]=2)=[CH:8][CH:7]=1.[C:33](Cl)(=[O:42])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:33]([O:1][CH:2]([C:29]([F:31])([F:32])[F:30])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:14][N:13]=2)=[CH:10][CH:11]=1)(=[O:42])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(CCCC(O)C(F)(F)F)cc2)nc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCOc1cnc(-c2ccc(CCCC(OC(=O)CCCCCCCC)C(F)(F)F)cc2)nc1

Procedure:
1.1 g (2.5 mmol) of (-)-2-(4-(4-hydroxy-5,5,5-trifluoro-1-pentyl)phenyl)-5-decyloxypyrimidine was dissolved in 10 ml of pyridine, followed by addition of 0.53 g (3 mmol) of nonanoyl chloride and 2-hour reaction at 20°-30° C. The reaction mixture was diluted with 100 ml of toluene, and the toluene layer was washed with 4N hydrochloric acid, water, a 5% sodium bicarbonate solution and water successively in that order and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using toluene/ethyl acetate as eluent to obtain 1.25 g of (+)-2-(4-(4-nonanoyloxy-5,5,5-trifluoro-1-pentyl)phenyl-5-decyloxypyrimidine.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C@H:25]([NH2:27])[CH3:26])[CH:20]=1.[CH3:28][O:29][C:30]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33]>C(OCC)(=O)C>[CH3:28][O:29][C:30]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:31]=1[CH2:32][NH:33][C:4]1[N:3]=[C:2]([NH:27][C@@H:25]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)[CH3:26])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: C[C@@H](N)c1cccnc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2ccc([N+](=O)[O-])c(N[C@H](C)c3cccnc3)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2,6-dichloro-5-nitropyridine (46) (0.5 g) in THE (20 mL) was cooled to 0° C. and treated with 1.6 mL triethylamine followed by (R)-1-pyridin-3-yl-ethylamine (300 μL). The mixture was stirred for 1.5 h, then warmed to RT and stirred another 20 h. 2,4-Dimethoxybenzylamine (0.8 mL) was added and the mixture was heated at 50° C. for four hours. The mixture was diluted with ethyl acetate and washed twice with saturated sodium chloride solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. Column chromatography (50→100% ethyl acetate in hexanes) provided 761 mg of (R)—N6-(2,4-Dimethoxybenzyl)-3-nitro-N2-(1-(pyridin-3-yl)ethyl)pyridine-2,6-diamine (64).