Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[C:4]([N:55]=CC1C=CC=CC=1)([CH2:30][C:31]1[N:32]=[CH:33][N:34]([C:36]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=1)[CH2:5][C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1>C1COCC1>[CH3:1][O:2][C:3](=[O:63])[C:4]([NH2:55])([CH2:5][C:6]1[N:7]=[CH:8][N:9]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:10]=1)[CH2:30][C:31]1[N:32]=[CH:33][N:34]([C:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:35]=1
Reactant: COC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)N=Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(N)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
The crude title compound of 53A was dissolved in anhydrous THF (40 ml). To the reaction was added 10 ml of a solution of 2.0 M aqueous hydrochloric acid (HCl) at 0° C. The mixture was stirred at ambient temperature for two hours. The reaction was subsequently concentrated under vacuum to remove the THF. The reaction was then partitioned between ethyl ether and water. The aqueous layer was washed two more times with ethyl ether. The pH of the aqueous layer was then adjusted to 9 with sodium carbonate (Na2CO3) and the solution is extracted with methylene chloride until virtually no product is left in the methylene chloride (CH2Cl2) layer. The CH2Cl2 extracts were combined, dried over MgSO4, filtered and concentrated under vacuum to give the crude product. The crude product was chromatographed on silica gel with MeOH—CHCl3—NH40H (1:99:0.1) as eluents to afford the title compound of 56B as a white foam, 10.78 g (14.7 mmol, 68% yield for two steps).
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:15])[C:10]([O:12]CC)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:16][CH2:17]C([O-])=O.[Na+].C(N(CC)CC)C.C([Mg]Cl)(C)(C)C.Cl>C1COCC1>[Cl:16][CH2:17][C:10](=[O:12])[C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH3:15]
Reactant: O=C([O-])CCl
Reactant: CCOC(=O)[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Mg]Cl
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)CCl
Reaction time: 1 h
Yield: 101.8 %

Procedure:
A mixture of 5.00 g (21.52 mmol) of ethyl (R)-2-(tert-butyldimethylsilyloxy)propionate, 3.76 g (32.3 mmol) of sodium chloroacetate, 2.18 g (21.5 mmol) of triethylamine, and 50 mL of THF was cooled in ice, and 37 mL (64.6 mmol) of a 1.75 M solution of tert-butylmagnesium chloride was added dropwise thereto over a period of 1 hour. After the completion of the dropwise addition, the reaction was allowed to proceed at 0° C. for 3 hours, and 6 M hydrochloric acid (about 20 mL) was added to the reaction solution to adjust the pH to 6.0. Subsequently, stirring was performed at 25° C. for 2 hours. A product was extracted with ethyl acetate (100 mL×2). The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 5.19 g of the title compound as a colorless oil (yield: 100%). 1H-NMR (400 MHz, CDCl3) δ: 0.10 (S, 6H), 0.92 (s, 9H), 1.24 (d, 3H, J=6.8 Hz), 4.35 (q, 1H, J=6.8 Hz), 5.50 (q, 2H, J=17.0 Hz).
Reaction SMILES: [CH2:1]([CH:3]([CH2:13][CH3:14])[C:4]([N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.[NH2:16][C@H:17]([C:22]([NH2:24])=[O:23])[CH2:18][CH2:19][S:20][CH3:21].C(N(CC)CC)C>CCO>[CH2:1]([CH:3]([CH2:13][CH3:14])[C:4]([N:6]1[CH2:11][CH2:10][C:9]2([NH:24][C:22](=[O:23])[C@H:17]([CH2:18][CH2:19][S:20][CH3:21])[NH:16]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CSCC[C@H](N)C(N)=O
Reactant: CCC(CC)C(=O)N1CCC(=O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCC(CC)C(=O)N1CCC2(CC1)NC(=O)[C@H](CCSC)N2

Procedure:
A solution of 1-(2-ethylbutyryl)-piperidin-4-one (1.6 g, 8.1 mmol), (S)-methioninamide hydrochloride (1.5 g, 8.1 mmol), and triethylamine (820 mg, 8.1 mmol) in EtOH (66 mL) was heated under reflux over a period of 16 h. Following removal of the solvent, water (50 mL) and CH2Cl2 (50 mL) were added to the residue and the mixture was basified with concentrated sodium hydroxide solution. The aqueous phase was extracted with CH2Cl2 (3×20 mL) and the combined organic phases were dried over Na2SO4. Following removal of the solvent and vacuum drying, there was obtained the product 8-(2-ethylbutyryl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5-]-decan-2-one in a yield of 1.8 g (69%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[I:15].C1OCCOCCOCCOCCOC1.[C:31]1([CH2:37][CH:38]=[CH:39][CH2:40]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>C1COCC1>[I:15][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:4]=1[O:3][CH2:40]/[CH:39]=[CH:38]/[CH2:37][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1ccc(O)c(I)c1
Reactant: BrCC=CCc1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC/C=C/Cc2ccccc2)c(I)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.3 %

Procedure:
To a suspension of NaH (0.82 g, 20.5 mmol) in THF (40 ml), a solution of ethyl 4-hydroxy-3-iodo-benzoate (5.0 g, 17.1 mmol) in THF (40 ml), then 15-crown-5 (4.0 ml, 25.6 mmol) and finally a solution of 4-phenylbut-2-enyl bromide (5.41 g, 25.6 mmol) in THF (50 ml) were added subsequently at 0° C. The reaction mixture was kept under stirring at room temperature for 10 minutes and then warmed to 50° C. for 6 h. After equilibration at room temperature, 3 N HCl was added (30 ml) and the mixture poured into a separatory funnel. The organic layer was separated and the aqueous layer extracted with ethyl acetate (3×30 ml). The collected organic layers were washed with saturated aqueous sodium chloride and dried over sodium sulfate. The solvent was eliminated with a rotary evaporator. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate=95/5) affording 5.94 g of the title compound (82% yield).
Reaction SMILES: I[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.Cl.[C:31]([C:33]1([CH3:39])[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]1)#[CH:32]>>[CH3:27][O:26][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH2:9][N:6]1[C:5]2[CH:28]=[CH:29][C:2]([C:32]3[N:35]4[CH2:34][C:33]([CH3:39])([CH2:38][CH2:37][CH2:36]4)[CH:31]=3)=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: C#CC1(C)CCCNC1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)ccc43)cc2OC)cn1
Agent: Cl
Product: COc1ccc(COc2ccc(Cn3cnc4cc(C5=CC6(C)CCCN5C6)ccc43)cc2OC)cn1

Procedure:
1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(5-methyl-1-azabicyclo[3.2.1]oct-6-en-7-yl)-1H-benzo[d]imidazole was prepared from 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole and 3-ethynyl-3-methylpiperidine hydrochloride using the procedure outlined for the synthesis of Example 3-30: 1H NMR (500 MHz, CDCl3) δ 8.22-8.21 (m, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.69 (dd, J=8.5, 2.5 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.28-7.26 (m, 1H, partially obscured by CHCl3), 6.89 (d, J=8.5 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.75-6.73 (m, 2H), 5.93 (s, 1H), 5.28 (s, 2H), 5.04 (s, 2H), 3.95 (s, 3H), 3.80 (s, 3H), 3.21 (dd, J=9.5, 1.5 Hz, 1H), 2.92-2.90 (m, 2H), 2.79 (d, J=10.0 Hz, 1H), 1.87-1.83 (m, 1H), 1.57-1.43 (m, 3H), 1.14 (s, 3H) ppm; (M+1)=497.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:17])[C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[C:9]([Cl:16])[CH:8]=[CH:7][CH:6]=2.[NH2:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[CH:24][N:25]2[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:21][CH:20]=1.C(N(CC)CC)C>C1C=CC=CC=1.C(OCC)(=O)C>[C:32]([O:31][C:29](=[O:30])[CH2:28][N:25]1[C:26]2[C:22](=[CH:21][CH:20]=[C:19]([NH:18][CH2:2][C:3]3[N:4]([CH3:17])[C:5]4[C:10]([C:11]=3[C:12]([O:14][CH3:15])=[O:13])=[C:9]([Cl:16])[CH:8]=[CH:7][CH:6]=4)[CH:27]=2)[CH:23]=[CH:24]1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(N)cc21
Reactant: COC(=O)c1c(CBr)n(C)c2cccc(Cl)c12
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1c(CNc2ccc3ccn(CC(=O)OC(C)(C)C)c3c2)n(C)c2cccc(Cl)c12
Temperature: 25 °C
Yield: 55 %

Procedure:
Methyl 2-(bromo-methyl)-4-chloro-1-methyl-1H-indole-3-carboxylate (1.10 mmol, 1.0 equiv.) and tert-butyl 2-(6-amino-1H-indol-1-yl)acetate (intermediate A) (1.10 mmol, 1.0 equiv.) were dissolved in benzene (5 ml) and triethylamine (1.3 mmol, 1.2 equiv.) and refluxed for 16 h. The reaction mixture was cooled to 25° C., diluted with ethyl acetate and washed with water and sat. NaCl solution. Drying over Na2SO4 was then carried out, followed by concentration under reduced pressure. The crude product was purified by column chromatography (40% ethyl acetate in hexane). Yield: 55%
Reaction SMILES: [Al].O[CH:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:4]([O-:6])=O.[Mg+2].O[CH:25]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]CC)[C:26]([O-])=O>>[CH2:42]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:3][CH2:4][OH:6])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCC(O)C(=O)[O-]
Agent: [Al]
Agent: [Mg+2]
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO

Procedure:
aluminium and magnesium hydroxystearate: 10;
Reaction SMILES: Br[CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1.[N-:30]=[N+:31]=[N-:32].[Na+].CC(C)=O>O>[N:30]([CH2:2][C:3]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1)=[N+:31]=[N-:32]
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(CN=[N+]=[N-])S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 14.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.08 g), sodium azide (0.26 g), acetone (20 ml) and water (4 ml) was stirred for 4 hours at room temperature. After removing acetone under reduced pressure, the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water, with a saturated sodium bicarbonate queous solution and further with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and a small amount of ether was added to the residue. Precipitated crystals were filtered off and the solvent was distilled off from the filtrate. The crystalline residue was purified by column chromatography on silica gel using chloroform as developing solvent to give 2,2,2-trichloroethyl 2-azidomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (150 mg). This substance was crystallized by adding a small amount of a mixture of ether and petroleum ether and the crystals were recrystallized from ether to give pure compound, mp 105° to 106° C.
Reaction SMILES: NC1(C[O:8]C2C=CC(C#N)=CC=2)CCCC1.[C:17]([C:19]1[CH:39]=[CH:38][C:22]([O:23][CH2:24][C:25]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)#N>>[CH:17]([C:19]1[CH:39]=[CH:38][C:22]([O:23][CH2:24][C:25]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)=[O:8]
Reactant: CC(C)(C)OC(=O)NC1(COc2ccc(C#N)cc2)CCCC1
Reactant: N#Cc1ccc(OCC2(N)CCCC2)cc1
Product: CC(C)(C)OC(=O)NC1(COc2ccc(C=O)cc2)CCCC1

Procedure:
Synthesized from 4-(1-aminocyclopentylmethoxy)benzonitrile according to an analogous synthetic method to Preparation Example 19, tert-butyl [1-(4-cyanophenoxymethyl)cyclopentyl]carbamate (1.0 g) was used according to an analogous synthetic method to Preparation Example 20 to provide the title compound (688 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].Br/[C:12](/[CH3:18])=[CH:13]\[C:14]([O:16][CH3:17])=[O:15]>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8]/[C:13](=[CH:12]\[CH3:18])/[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)/C=C(/C)Br
Reactant: Oc1cccc(I)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C/C=C(\Oc1cccc(I)c1)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 11 g (0.05 mol) of 3-iodophenol is added dropwise at 0 to 5° C. to a solution of 3 g (0.055 mol) of KOH in 30 ml of dimethylformamide. 9 g (0.05 mol) of methyl 3-bromocrotonate are added at this temperature, and stirring of the solution is continued for one hour at room temperature. The mixture is treated with ice-water and extracted using methyl tert-butyl ether, and the methyl tert-butyl ether phase is dried over Na2SO4 and concentrated in vacuo. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate: 99/1). This gives 9.7 g (61% of theory) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=O)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O:22][C:23](=[O:33])[C@H:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH2:25])C>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([NH:25][C@H:24]([C:23]([OH:33])=[O:22])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:16])(=[O:10])=[O:11])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Product: O=C(O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Yield: 45 %

Procedure:
3,5-Dichlorophenyl-sulfonyl-L-proline was coupled to L-phenylalanine ethyl ester using the procedure described in Method 3 to give the ethyl ester of the title compound (348 mg, 45%).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C@H:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@@H:11]2[CH3:23])[CH3:9])=[CH:4][C:3]=1[C:24]1[N:32]=[C:31]([CH3:33])[N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1.[F:40][C:41]1[CH:42]=[C:43]([NH2:49])[CH:44]=[N:45][C:46]=1[O:47][CH3:48].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[F:40][C:41]1[CH:42]=[C:43]([NH:49][C:2]2[N:7]=[CH:6][C:5]([C@H:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12][C@@H:11]3[CH3:23])[CH3:9])=[CH:4][C:3]=2[C:24]2[N:32]=[C:31]([CH3:33])[N:30]=[C:29]3[C:25]=2[N:26]=[CH:27][N:28]3[CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[CH:44]=[N:45][C:46]=1[O:47][CH3:48]
Reactant: COc1ncc(N)cc1F
Reactant: Cc1nc(-c2cc([C@@H](C)N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)cnc2F)c2ncn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc([C@@H](C)N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cc1F
Temperature: -20 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
A mixture of (3S)-tert-butyl 4-((1R)-1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (0.323 g, 0.599 mmol) and 5-fluoro-6-methoxypyridin-3-amine (0.170 g, 1.197 mmol) in THF (15 mL) was chilled to −20° C. in a diluted dry ice/acetone bath, then lithium bis(trimethylsilyl)amide (1.0 M in THF, Aldrich; 1.796 mL, 1.796 mmol) was added slowly via syringe into the reaction mixture. After the addition, the ice bath was removed and the mixture was allowed to stir under inert atmosphere for 1 h. The mixture was diluted with chloroform (20 mL) and water (10 mL). The organic layer was extracted with chloroform (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was adsorbed onto silica gel and purified by chromatography through a silica-gel column (80 g) eluting with 100% EtOAc to give (3S)-tert-butyl 4-((1R)-1-(6-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (0.155 g, 0.234 mmol, 39.1% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 12.63 (s, 1H) 9.71 (d, J=2.15 Hz, 1H) 8.32 (dd, J=12.52, 2.15 Hz, 1H) 8.22 (s, 1H) 8.17 (d, J=2.35 Hz, 1H) 8.03 (d, J=2.15 Hz, 1H) 5.80 (dd, J=10.56, 2.15 Hz, 1H) 4.12 (s, 2H) 3.96 (s, 3H) 3.76 (d, J=2.54 Hz, 1H) 3.53 (m, 1H) 3.23 (m, 1H) 2.84 (s, 5H) 2.41 (m, 1H) 2.08 (s, 1H) 2.03 (s, 1H) 1.97 (s, 1H) 1.64 (s, 3H) 1.58 (s, 2H) 1.45 (d, J=6.85 Hz, 3H) 1.32 (s, 9H) 1.07 (d, J=5.87 Hz, 3H). m/z (ESI, +ve ion) 662.2 (M+H)+.
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[CH3:10][C:11](C1C=CC(O)=CC=1)([C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)[CH3:12].CC(C1C=CC(O)=CC=1)(C1C=CC(O)=CC=1)C.C(C1C=CC(O)=CC=1)(C1C=CC=CC=1)(C)C.O=C([O-])[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Na+].C(Cl)(Cl)=O>C(N(CC)CC)C.O.C(Cl)Cl>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]([C:6]2[CH:5]=[CH:4][C:2]([OH:3])=[C:1]([O:8][CH3:9])[CH:7]=2)([CH3:12])[CH3:10])=[CH:14][CH:15]=1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: COc1ccccc1O
Agent: CC(C)(c1ccccc1)c1ccc(O)cc1
Agent: O=C(Cl)Cl
Agent: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(C)(C)c2ccc(O)cc2)ccc1O

Procedure:
Run 3—1% guaiacol BPA: Methylene chloride (23 L), water (8 L), BPA (4500 g, 19.8 mol), monomethoxyBPA (55 g of the above mixture), p-cumylphenol (135 g, 0.64 mol), triethylamine (40 ml) and sodium gluconate (10 g) was charged to a 75 L reactor equipped with mechanical agitation, condenser, and caustic scrubber vent system. Phosgene (2300 g, 23.2 mol) was added at a rate of 80 g/min to the reactor while 33 wt % caustic was added at a rate to maintain pH=10. The reactor contents were purged with nitrogen then transferred to another tank and centrifuged to remove the brine layer. The organic layer containing the polymer was washed on a centrifuge train with 1N HCl and then with deionized water until residual chloride levels were <5 ppm. The polymer was isolated by steam precipitation followed by drying under hot nitrogen. The final dried resin weighed 4.1 lbs, had Mw=27652 daltons and PDI=2.5 by GPC vs PC standard, <1 ppm TEA, 0.6 ppm chloride ion, <10 ppm residual free BPA, and <0.05 ppm Fe. The glass transition temperature was determined to be 153 C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:12])[N:9]([CH3:11])[N:10]=2)[N:7]=1.[C:13]1([CH:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:23][CH2:22]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:31]1([CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][NH:30][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8](=[O:12])[N:9]([CH3:11])[N:10]=4)[N:7]=3)[CH2:23][CH2:22]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: Cn1nc2ccc(Cl)nn2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1=O
Temperature: 145 °C
Reaction time: 1 h
Yield: 26.8 %

Procedure:
0.277 g of 6-chloro-2-methyl[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was dissolved in 2 ml of N,N-dimethylformamide; 0.487 g of 4-(diphenylmethoxy)-1-piperidinepropanamine was added, followed by stirring in an oil bath (bath temperature 140-150° C.) for 1 hour. After cooling, ice water and an aqueous solution of sodium hydrogen carbonate were added; the reaction mixture was extracted with ethyl acetate; the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (90:10:1). The desired fraction was collected and concentrated; the crystal obtained was filtered, washed with diethyl ether, and dried, to yield 0.19 g of the title compound.
Reaction SMILES: [CH3:1][S:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@H:18]3[C:22]([F:25])([F:24])[F:23])=[N:15][CH:16]=2)[N:6]=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:41]1([C:52](=[O:53])[C:51]2[N:50]([CH2:54][C:55](O)=[O:56])[CH:49]=[N:48][C:47]=2[N:45]([CH3:46])[C:43]1=[O:44])[CH3:42]>N1C=CC=CC=1.C(Cl)Cl>[CH3:42][N:41]1[C:52](=[O:53])[C:51]2[N:50]([CH2:54][C:55]([N:4]([CH2:3][S:2][CH3:1])[C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([C:11]4[CH:16]=[N:15][C:14]([N:17]5[CH2:21][CH2:20][CH2:19][C@H:18]5[C:22]([F:25])([F:23])[F:24])=[N:13][CH:12]=4)[N:6]=3)=[O:56])[CH:49]=[N:48][C:47]=2[N:45]([CH3:46])[C:43]1=[O:44]
Reactant: Cn1c(=O)c2c(ncn2CC(=O)O)n(C)c1=O
Reactant: CSCNc1cccc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSCN(C(=O)Cn1cnc2c1c(=O)n(C)c(=O)n2C)c1cccc(-c2cnc(N3CCC[C@H]3C(F)(F)F)nc2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
A solution of (S)—N-((methylthio)methyl)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridine-2-amine (Intermediate 4.17 g, 46.0 mmol) and DCC (18.99 g, 92 mmol) in pyridine (230 mL) was heated for 30 minutes at 60° C. before theophylline 7-acetic acid (21.92 g, 92 mmol) was added in one portion. The reaction mixture was stirred at 60° C. and monitored by LCMS. After 2 hours, additional theophylline 7-acetic acid (21.92 g, 92 mmol) and DCC (18.99 g, 92 mmol) were added to drive the reaction to completion. The reaction mixture was diluted with CH2Cl2. The resulting precipitate (DCC urea) was filtered over Celite® and washed with CH2Cl2 (3×). The mixture was diluted with water and adjusted to pH 3 with aqueous 3M HCl. The organic and aqueous layers were separated and the aqueous layer was extracted with additional CH2Cl2 (3×). The combined organic layers were washed with aqueous 1M HCl (2×), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified using silica gel chromatography, eluting with EtOAc:Hex (70:30) to yield 18.5 g (31.4 mmol, 68%) of the title product as a thick oil; 1H NMR (300 MHz, DMSO-d6) δ 9.21 (s, 2H), 8.16-8.03 (m, 2H), 7.99 (d, J=7.6 Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 5.33 (s, 2H), 5.12 (m, 3H), 3.82-3.65 (m, 2H), 3.43 (s, 3H), 3.18 (s, 3H), 2.31-2.09 (m, 4H), 2.06 (s, 3H); m/z found [M+H]+=590.37.