Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]([O:33][CH2:34][P:35]([O:40][CH2:41][CH3:42])([O:37][CH2:38][CH3:39])=[O:36])[CH2:21][O:22][N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH2:32])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC>FC(F)(F)C(O)=O.O>[CH2:41]([O:40][P:35]([CH2:34][O:33][C@H:20]([CH2:19][OH:18])[CH2:21][O:22][N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH2:32])([O:37][CH2:38][CH3:39])=[O:36])[CH3:42]
Reactant: CCOP(=O)(CO[C@@H](COn1cnc2c(N)ncnc21)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCCCCC
Product: CCOP(=O)(CO[C@H](CO)COn1cnc2c(N)ncnc21)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
(S)-9-[3-(t-Butyldiphenylsilyloxy)-2-(diethoxyphosphorylmethoxy)propoxy]adenine (0.61 g, 1 mmol) was dissolved in trifluoroacetic acid/water, 2:1 (6 ml) and the solution stirred at ambient temperature for 3 hours. Hexane (10 ml) was added and the mixture shaken. The aqueous phase was separated, washed once more with hexane (10 ml) and evaporated to dryness. The residue was treated with ethanolic ammonia solution (5 ml), at ambient temperature, for 5 minutes after which the solution was evaporated to dryness. The residue was chromatographed on silica gel using dichloromethane/methanol 90:10 as eluant to give (R)-9-[2-(diethoxyphosphorylmethoxy)-3-hydroxypropoxy]adenine as a colourless oil (0.3 g, 80%) which on prolonged standing, crystallised as white needles m.p. 98°-102°. IR: νmax (film) 3340, 3210, 2995, 2930, 2910, 1660, 1645, 1600, 1470, 1445, 1415, 1395, 1370, 1330, 1300, 1240, 1210, 1165, 1125, 1045. 1020, 980, 825, 95, 735 cm-1. 1H NMR: δH [(CD3)2SO] 1.23 (6H, t, J=7 Hz (OCH2CH3)2), 3.5-3.7 (2H, m, CH2OH), 3.75-3.85 (1H, m, CH), 3.95-4.15 (6H, m, (OCH2CH3)2, OCH2P), 4.38 (1H, dd, J=11.3 Hz, J=6.6 Hz, NOCHB), 4.55 (1H, dd, J= 11.3 Hz, J=3.0 Hz, NOCHA), 4.88 (1H, t, J=5.5 Hz, D2O exchangeable OH), 7.38 (2H, br.s., D2O exchangeable NH2), 8.15 (1H, s, H-2 or H-8), 8.43 (1H, s, H-2 or H-8). Found: C, 39.26; H, 6.05; N, 17.33%. C13H22N5O6P 1.25 H2O requires: C, 39.25; H, 6.20; N, 17 61%. m/z: (FAB, thioglycerol matrix) 376 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[S:14]([OH:16])=[O:15])(=[O:5])[CH3:4].I[CH2:18][C:19]#[N:20]>CN(C)C=O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:3](=[O:5])[CH3:4])=[C:8]([S:14]([CH2:18][C:19]#[N:20])(=[O:16])=[O:15])[CH:9]=1
Reactant: CC(=O)Nc1ccc(Cl)cc1S(=O)O
Reactant: N#CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Cl)cc1S(=O)(=O)CC#N
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Sodium hydride (0.10 g, 60% dispersion in mineral oil) was added at ambient temperature under nitrogen in small portions to a stirred solution of 2-acetylamino-5-chloro-benzenesulfinic acid (0.55 g) in dry dimethylformamide. After stirring for 35 min iodoacetonitrile (0.18 ml) was added and the temperature was raised to 70° C. for 45 min. Then the solvent was removed in vacuo. The residue was triturated with water (30 ml) and filtered. The filter cake was dried, stirred with a mixture of ether (5 ml) and petroleum ether (10 ml) for 1 h, filtered off and dried to give the title compound as white needles. Yield 0.52 g (81%), mp 173.5-174° C., 1H-NMR(DMSO-d6) δ (ppm): 9.69 (s, 1H); 8.06-7.87 (m, 3H); 5.37 (s, 2H), 2.16 (s, 3H); 13C-NMR (DMSO-d6) δ (ppm): 169.6, 136.6, 136.4, 130.5, 129.8, 129.5, 128.5, 112.0, 44.9, 24.3; IR(KBr) ν (cm−1): 3343(NH), 2258(CN), 1682(C═O), 1330(SO2), 1156 and 1140 (SO2).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C(C)C)=[C:12]([CH3:20])[CH:11]=2)=[N:4][N:5]([CH3:9])[C:6]=1[O:7][CH3:8].S(=O)(=O)(O)O>>[Cl:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:20])[CH:11]=2)=[N:4][N:5]([CH3:9])[C:6]=1[O:7][CH3:8]
Reactant: COc1c(Cl)c(-c2ccc(OC(C)C)c(C)c2)nn1C
Agent: O=S(=O)(O)O
Product: COc1c(Cl)c(-c2ccc(O)c(C)c2)nn1C
Temperature: 0 °C
Yield: 25 %

Procedure:
A mixture of 4-chloro-3-(4-isopropoxy-3-methyl-phenyl)-5-methoxy-1-methyl-1H-pyrazole (described in Reference Preparation example 111) 5.6 g and 30% aqueous sulfuric acid solution 60 ml was stirred with heating under reflux for 20 hours. Thereto was added ice water 10 ml and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 4-(4-Chloro-5-methoxy-1-methyl-1H-pyrazol-3-yl)-2-methyl-phenol 1.2 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH3:20])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([Cl:19])[CH:11]=3)[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>C(Cl)Cl>[Cl:19][C:12]1[CH:11]=[C:10]2[C:15]([C:16]([C:17]#[N:18])=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH:7]=[N:6][CH:5]=3)[N:9]2[CH3:20])=[CH:14][CH:13]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cn1c(-c2cncc(N)c2)c(C#N)c2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1
Reaction time: 8 h

Procedure:
To a solution of 2-(5-amino-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (Example 211, 85 mg, 0.3 mmol) in DCM (15 mL) is added triethylamine (122 mg, 1.2 mmol) and ethanesulfonyl chloride (77 mg, 0.6 mmol) and the reaction mixture is stirred overnight. The solvent is removed and the residue is redissolved in methanol (15 mL). Aqueous 1M NaOH (1 mL) is added and the reaction mixture is stirred overnight. The solvent is removed in vacuo and the residue is purified by silica gel flash chromatography (methanol in dichloromethane gradient) to give ethanesulfonic acid [5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (t, J=7.3 Hz, 3H), 3.23-3.33 (m, 2H), 3.79 (s, 3H), 7.36 (dd, J=8.6, 1.8 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.90 (t, J=2.3 Hz, 1H), 7.95 (d, J=1.5 Hz, 1H), 8.61 (d, J=2.3 Hz, 2H), 10.43 (s, 1H). HRMS (ESI) m/z 375.0692 [(M+H)+ Calcd for C17H16ClN4O2S: 375.0682].
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N:22]2[CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24][CH2:23]2)=[CH:4][N:3]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(N)c([N+](=O)[O-])c2)CC1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 49.5 %

Procedure:
A suspension of 350 mg of 2-amino-6-chloro-3-nitropyridine, 744 mg of N-(tert-butoxycarbonyl)piperazine and 552 mg of potassium carbonate in 4 ml of N-methylpyrrolidone was stirred in nitrogen atmosphere for 15 minutes at 160° C. The suspension was cooled to room temperature, to which 10 ml of water was added. Whereupon formed solid was recovered by filtration, washed with hexane and dried to provide 323 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Br[C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[CH:44]=[CH:45][N:46]=[C:47]2[NH2:52]>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:52][C:47]1[C:48]2[C:43](=[C:42]([C:5]3[N:4]=[C:3]4[C:8]([N:9]=[C:10]([CH2:11][N:12]5[CH2:13][CH2:14][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:16][CH2:17]5)[N:2]4[CH3:1])=[C:7]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:6]=3)[CH:51]=[CH:50][CH:49]=2)[CH:44]=[CH:45][N:46]=1
Reactant: Nc1nccc2c(Br)cccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-c3cccc4c(N)nccc34)nc21
Temperature: 140 °C
Yield: 18.2 %

Procedure:
To a degassed mixture of 2-(1-((9-methyl-6-morpholino-2-(tributylstannyl)-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (256 mg, 0.386 mmol), 5-bromoisoquinolin-1-amine (86 mg, 0.386 mmol), copper(I) thiophene-2-carboxylate (74 mg, 0.386 mmol) in 1,4-dioxane (4 mL) was added Pd(PPh3)4 (45 mg, 0.039 mmol). The reaction mixture was heated in the microwave at 140° C. for 35 minutes. The reaction mixture was then loaded onto a Biotage Isolute SPE SCX-2 column The column was first washed with MeOH. The product was eluted with 2 M NH3 in MeOH and concentrated. The crude was further purified by RP-HPLC to give 147 (36.3 mg, 18.2%). LCMS: M+H+=517.3. 1H-NMR (400 MHz, DMSO-d6): δ 8.28 (d, 1H), 8.11 (d, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.53 (t, 1H), 6.80 (s, 2H), 4.23 (s, br, 4H), 4.09 (s, 1H), 3.81 (s, 3H), 3.73 (m, 6H), 2.90 (m, 2H), 2.02 (m, 2H), 1.66 (m, 2H), 1.19 (m, 3H), 1.02 (s, 6H)
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18]([NH:24][S:25]([CH:28]([CH:32]([CH3:34])[CH3:33])[C:29]([NH2:31])=O)(=[O:27])=[O:26])[N:17]=1.N1C=CC=CC=1.Cl>O1CCOCC1.O>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18]([NH:24][S:25]([CH:28]([CH:32]([CH3:34])[CH3:33])[C:29]#[N:31])(=[O:27])=[O:26])[N:17]=1
Reactant: COc1cc(OC)nc(NS(=O)(=O)C(C(N)=O)C(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: COc1cc(OC)nc(NS(=O)(=O)C(C#N)C(C)C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic anhydride (0.73 g) was added to a stirred, ice-cooled solution of the product of Example 20 in dioxan (10 ml) containing pyridine (0.5 g). After stirring for 11/2 hours at room temperature, the mixture was added to water (100 ml) and acidified with hydrochloric acid. The liberated product was extracted into ether, and the ether solution was washed with water (twice), dried over magnesium sulfate and run down. The residual oil was flash chromatographed on silica gel, eluting with 30% ethyl acetate in dichloromethane, to give, after trituration with petroleum ether (bp 40°-60° C.), 0.3 g of the desired product, mp 91°-93° C., as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6](=[O:20])[C:7]([F:19])([F:18])[CH:8]([OH:17])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)(=O)C(Cl)=O>CS(C)=O>[CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6](=[O:20])[C:7]([F:18])([F:19])[C:8](=[O:17])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)CCNC(=O)C(F)(F)C(O)CCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Product: CC(C)CCNC(=O)C(F)(F)C(=O)CCc1ccccc1

Procedure:
According to the procedure of Thaisrivongs et. al. (J. Med. Chem., 1986, 29, 2080), the resultant compound of Example 46 was treated with dimethylsulfoxide and oxalyl chloride to give the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1/[CH:5]=[CH:6]/[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26]([N:30]([S:40]([C:43]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][CH:44]=1)(=[O:42])=[O:41])[C@H:31]([C:37]([OH:39])=[O:38])[CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])[CH:27]([CH3:29])[CH3:28]>C1COCC1.C([O-])([O-])=O.[K+].[K+].Cl>[CH2:26]([N:30]([S:40]([C:43]1[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][CH:44]=1)(=[O:42])=[O:41])[C@H:31]([C:37]([OH:39])=[O:38])[CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:7](=[O:9])/[CH:6]=[CH:5]/[C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccccc1/C=C/C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccccc1/C=C/C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture of trans-2-methoxycinnamic acid (106 mg, 0.55 mmol) and carbonyldiimidazole (89 mg, 0.55 mmol) in THF (3 mL) was stirred at room temperature for 1 h, and then at 40° C. until gas evolution ceased. The mixture was cooled to room temperature and Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine (212 mg, 0.50 mmol) in solution in 1M K2CO3 was added. The reaction mixture was stirred at room temperature for 3 h, then diluted with 1N HCl and extracted with EtOAc. The organic layer was dried over MgSO4, concentrated in vacuo and purified by flash chromatography eluting with 70% EtOAc in hexane containing 0.4% AcOH to give the title compound (71% yield).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18]C)[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[O:21])=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(C)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Yield: 64.7 %

Procedure:
In a manner similar to that used in Example 2, 1 g (3 mmol) of [2-(4-methoxyphenyl)-6-methoxybezo[b]thien-3-yl][4-methylphenyl]methanone was converted with 20 mL of 1M BBr3 in CH2Cl2 to 700 mg of the title compound. The final product was isolated a light yellow amorphous powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][NH:19][C:20](=O)[C:12]3=[C:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]=2[CH:9]=1.O>O1CCCC1>[Cl:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][NH:19][CH2:20][C:12]3=[C:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]=2[CH:9]=1
Reactant: O=C1NCCn2c1c(-c1ccccc1)c1cc(Cl)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)c(-c1ccccc1)c1n2CCNC1

Procedure:
To a stirred solution of lithium aluminum hydride (1 gram, 0.026 mole) in 20 ml dry tetrahydrofuran (THF) is added slowly a suspension of 1,2,3,4-tetrahydro-8-chloro-10-phenylpyrazino[1,2-a] indole-1-one (5.2 grams, 0.018 mole) in 40 ml of dry THF. This reaction mixture is stirred and refluxed for 8 hours after which it is cooled and decomposed by the slow addition of 3 ml of water. After stirring 1 hour the suspension is filtered. The filtercake is washed with isopropanol, THF, and acetone. The combined filtrate is taken to dryness and recrystallized from ethanol. The product is filtered off, washed with ether, and dried. The above titled product has a m.p. 163°-64° C. yield 4.5 grams (90%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[O:38]>C1COCC1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]([CH:37]([OH:38])[CH2:36][CH2:35][CH2:34][CH2:33][Cl:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=CCCCCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C(O)CCCCCl)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.32 mL (2.2 mmol) of diisopropylamine in 10 mL of THF at 0° C. was treated with 0.92 mL (2.3 mmol) of 2.5 M n-butyllithium in sol'n in hexanes. The resulting solution was stirred at 0° C. for 10 min, then cooled to −78° C. A solution of 0.51 g (1.8 mmol) of (1-tert-butoxycarbonylpiperidin-4-yl)acetic acid, ethyl ester (from Piperidine 35, Step A) in 2 mL of THF was added. After stirring for 30 minutes, a solution of 0.26 g (2.1 mmol) 5-chloropentanal in 2 mL of THF was added (J. Org. Chem. 1981, 46, 2007). The reaction was stirred for 1.75 hours at −78° C. and 3.5 hours at 0° C. After quenching the reaction with saturated NH4Cl, volatiles were removed under reduced pressure. The residue was partitioned between 100 mL of Et2O and 100 mL of H2O. After separating phases, the organic layer was washed with 100 mL of 0.5 N HCl and 100 mL of 1 N NaHCO3, dried over MgSO4 and concentrated. The residue was purified with a 40M Biotage column using 3:1 v/v of hexanes/EtOAc as the eluant to afford impure title compound: RF: 0.27 (7:3 v/v hexanes/EtOAc); 1H-NMR (500 MHz) δ 1.24–2.08 (m, 23H), 2.38 (t, J=6.2, 1H), 2.63–2.71 (m, 2H), 3.53–3.56 (m, 2H), 3.92 (m, 1H), 4.09–4.19 (m, 4H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[C:20]([OH:21])=[C:19]([O:22][CH3:23])[C:18]([O:24][CH3:25])=[C:17]([O:26][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C:16]=1[CH3:44])(=O)C.Cl.[Cl:46][CH2:47][C:48]1[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[ClH:46].[CH3:23][O:22][C:19]1[C:18]([O:24][CH3:25])=[C:17]([OH:26])[C:16]([CH3:44])=[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])[C:20]=1[O:21][CH2:47][C:48]1[CH:53]=[CH:52][N:51]=[CH:50][CH:49]=1
Reactant: COc1c(O)c(CCCCCCCCCCOC(C)=O)c(C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1OC
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(O)c(C)c(CCCCCCCCCCO)c(OCc2ccncc2)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
A mixture of 6-(10-acetoxydecyl)-4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methylphenol (3.70 g) obtained in Example B-1, 4-chloromethylpyridine hydrochloride (1.96 g), potassium carbonate (5.00 g) and dimethylformamide (30 ml) was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (30 ml). Tetrabutylammonium fluoride trihydrate (1 g) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. Methanol (50 ml) and 1N sodium hydroxide solution (10 ml) were added to the residue, and the mixture was stirred at room temperature for 16 hours. After concentration, the residue was subjected to column chromatography on silica gel and eluted with ethyl acetate. The desired fraction was concentrated. The residue was dissolved in ethanol (30 ml), and conc. hydrochloric acid (0.7 ml) was added. The crystals obtained after concentration under reduced pressure were separated by filtration and washed with ether to obtain the desired compound (1.2 g).
Reaction SMILES: [Si]([N:8]1[CH:11]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:10]([NH:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:37])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:13]([O:12][CH:11]1[NH:8][C:9](=[O:37])[CH:10]1[NH:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)COC1C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N1[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)COC1NC(=O)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of (3RS,4RS)-1-(tert-butyldimethylsilyl)-4-(isobutoxy)-3-(triphenylmethylamino)azetidin-2-one (160 mg, 0.3 mmol) in tetrahydrofuran (4 mL) was cooled in an ice bath and treated with acetic acid (25 mg, 0.4 mmol) followed by dropwise addition of 1M tetrabutylammonium fluoride (0.6 mL, 0.6 mmol). The mixture was stirred for 20 min and passed through silica gel (10 g) eluted with ethyl acetate. The eluate was concentrated and the residue was chromatographed on silica gel eluted with 20% ethyl acetate:hexane to give the title compound. MS(ES) m/e 423 [M+Na]+.
Reaction SMILES: C(OC(C)(C)C)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[C:12]([CH2:14][CH2:15][C:16](Cl)=[O:17])#[N:13]>CCOCC>[O:17]=[C:16]([CH2:2][C:3](=[O:4])[CH3:5])[CH2:15][CH2:14][C:12]#[N:13]
Reactant: N#CCCC(=O)Cl
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: CCOCC
Product: CC(=O)CC(=O)CCC#N

Procedure:
The magnesium complex of t-butyl acetoacetate (135 gm; 635 mmole) is suspended in 250 ml of anhydrous ether in a three-neck one liter round bottom flask and beta-cyano propionyl chloride (78.05 gm: 664 mmole) added dropwise over fifteen minutes while the mixture is stirred from overhead. The dropping funnel is removed and the mixture refluxed for thirty minutes. The mixture is cooled and 250 ml of 2N aqueous sulfuric acid is slowly added. The mixture is transferred to a one liter separatory funnel and the layers separated. The aqueous layer is extracted with ether (2×150 ml) and the combined ether extracts washed with water (4×100 ml). The ether is evaporated and to the residual red oil is added 800 mg of toluene sulfonic acid monohydrate. The mixture is heated in an oil bath (with reflux condenser) to 175 degrees until evolution of gas has ceased. The mixture is cooled and taken up in 500 ml of ether. The ether is extracted with ice-cold 2M aqueous sodium hydroxide (175, 90, 50 , and 35 ml). The extracts were run from the separatory funnel directly into 250 ml of ice-cold 1.8M aqueous sulfuric acid. The acidic suspension is extracted with methylene chloride (3×150 ml) and the combined organic extracts washed with 5% aqueous sodium bicarbonate (2×100 ml) and brine (100 ml). The residue after evaporation of the methylene chloride may be purified by silica gel flash column chromatography using ethyl acetate:hexane 1:4 as eluant.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.C[N:37]1[CH:41]=[C:40]([CH2:42][C:43](O)=[O:44])[N:39]=[CH:38]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:43](=[O:44])[CH2:42][C:40]4[N:39]=[CH:38][NH:37][CH:41]=4)[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Reactant: Cn1cnc(CC(=O)O)c1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)Cc4c[nH]cn4)CC3)cc2C2=CCCCC2)n1

Procedure:
The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (as prepared in Example 14, step (b)), according to the procedure in Example 29 using (1-methyl-1H-imidazol-4-yl)-acetic acid. 1H-NMR (400 MHz, CD3OD): δ 8.88 (s, 1H), 8.12 (d, 1H), 8.02 (s, 1H), 7.44 (s, 1H), 7.20 (dd, 1H), 7.10 (d, 1H), 5.82 (m, 1H), 4.70 (m, 1H), 4.18 (m, 1H), 4.06 (m, 2H), 3.36 (m, 1H), 2.84 (m, 2H), 2.30 (m, 4H), 2.00-1.70 (m, 7H), 1.64 (m, 1H). Mass spectrum (ESI, m/z): Calcd. for C27H29N7O2, 484.2 (M+H). found 484.2.