Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]=O.CO[C:10](=[O:23])[CH2:11][CH2:12][CH:13]([N+:20]([O-:22])=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[N+:20]([C:13]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:6][NH:5][C:10](=[O:23])[CH2:11][CH2:12]1)([O-:22])=[O:21]
Reactant: [NH4+]
Reactant: COC(=O)CCC(c1ccccc1)[N+](=O)[O-]
Reactant: C=O
Agent: CC(=O)[O-]
Solvent: CCO
Product: O=C1CCC(c2ccccc2)([N+](=O)[O-])CN1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2.11 g (26.88 mmol) ammonium acetate in 15 ml ethanol under nitrogen at room temperature, was added 980 ul (13.44 mmol) formaldehyde (37% in water), followed by a solution of 3 g (13.44 mmol) rac-4-Nitro-4-phenyl-butyric acid methyl ester in 7.5 ml ethanol. The mixture was refluxed for 26 hours then cooled to room temperature and the solvent was evaporated. Water was added. The resulting suspension was stirred for 15 minutes, filtered, rinsed with water, then with diethyl ether and dried in vacuo to provide 2.49 g (y: 84.1%) of the title compound as a white solid. MS (m/e): 221.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([NH2:22])[N:15]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.O1CCCCC1[O:31][CH2:32][CH2:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.O1CCCCC1OC1CCCCO1.Cl>>[NH2:22][C:16]1[N:15]=[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:37]5[CH:36]=[N:35][N:34]([CH2:33][CH2:32][OH:31])[CH:38]=5)[CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=1
Reactant: CC(C)n1nc(N)nc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: C1CCC(OC2CCCCO2)OC1
Agent: Cl
Product: CC(C)n1nc(N)nc1-c1nc2c(s1)CCOc1cc(-c3cnn(CCO)c3)ccc1-2

Procedure:
Similar to as described in General Procedure C, 5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylamine was reacted with 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. Subsequent to the Suzuki coupling, deprotection of the tetrahydropyranyl ether was accomplished by adding 2N HCl to the crude reaction mixture. Purification by reverse phase HPLC gave 403 as a colorless solid (16 mg). LCMS: 438.1
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([CH3:27])[C:25]=1[OH:26])[CH:21]=O>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14](=[O:16])[CH:15]=[CH:21][C:20]2[CH:23]=[C:24]([CH3:27])[C:25]([OH:26])=[C:18]([CH3:17])[CH:19]=2)=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: CCCCCCCc1ccc(C(C)=O)cc1
Product: CCCCCCCc1ccc(C(=O)C=Cc2cc(C)c(O)c(C)c2)cc1

Procedure:
This compound was synthesized from 4′-heptylacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier.
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:3]=1.[OH-:31].[K+].C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.Cl>O.O1CCOCC1>[OH:31][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:3]=1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2oc3c(O)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Temperature: 110 °C
Yield: 34.9 %

Procedure:
A mixture of the product of Example 44, step C (1.41 g, 3.14 mmol), di-palladium-tris(dibenzylideneacetone) (575 mg, 0.62 mmol), potassium hydroxide (387 mg, 6.91 mmol) and 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-1,1′-biphenyl (121 mg, 0.25 mmol) in water (14 mL) and 1,4-dioxane (14 mL) was heated to 110° C. for 24 h. After cooling to ambient temperature, the reaction mixture was neutralized with 1N aqueous HCl, filtered through celite bed and extracted with ethyl acetate (4×30 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product which was purified by column chromatography (SiO2, 7:3 hexanes/ethyl acetate) providing tert-butyl 6-hydroxy-8-phenylsulfonyl-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (470 mg, 34%): 1H NMR (CDCl3, 300 MHz) δ 7.93-7.90 (m, 2H), 7.62 (br s, 1H), 7.55-7.43 (m, 3H), 7.39 (d, J=1.8 Hz, 1H), 4.54 (s, 2H), 3.81 (t, J=5.4 Hz, 2H), 2.83 (t, J=5.7 Hz, 2H), 1.51 (s, 9H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].[CH2:14]1[NH:19][CH2:18][CH2:17][N:16]2[CH2:20][CH2:21][CH2:22][C@H:15]12.C(=O)([O-])[O-].[Na+].[Na+].[F:29][C:30]([F:39])([F:38])[C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1>ClCCl.CO>[CH2:14]1[N:19]([C:8]([C:7]2[CH:6]=[C:5]([S:2]([NH:35][C:34]3[CH:36]=[CH:37][C:31]([C:30]([F:29])([F:38])[F:39])=[CH:32][CH:33]=3)(=[O:4])=[O:3])[CH:13]=[CH:12][CH:11]=2)=[O:9])[CH2:18][CH2:17][N:16]2[CH2:20][CH2:21][CH2:22][C@H:15]12
Reactant: C1C[C@@H]2CNCCN2C1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(c1cccc(S(=O)(=O)Nc2ccc(C(F)(F)F)cc2)c1)N1CCN2CCC[C@@H]2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 3-(chlorosulfonyl)benzoyl chloride (0.359 g, 1.5 mmol) in anhydrous dichloromethane (80 mL) was added (R)-octahydropyrrolo[1,2-a]pyrazine (0.189 g, 1.5 mmol) in dichloromethane (4 mL) slowly over 10 minutes at room temperature. Then sodium carbonate (0.32 g, 2 mmol) was added, and the mixture was stirred at room temperature for 5 hours. Subsequently 4-(trifluoromethyl)aniline (2.42 g, 15 mmol) was added. The mixture was stirred at room temperature for 3 days, and then sodium carbonate (0.32 g, 3 mmol) and methanol (5 mL) were added. The mixture was stirred for 20 minutes, then filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (methanol/ethyl acetate=1:10) to give the titled compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.90 (m, 6H), 2.10 (m, 1H), 2.70-3.15 (m, 5H), 4.40-4.60 (m, 1H), 7.30 (d, 2H, J=7 Hz), 7.63 (m, 4H), 7.76 (br s, 1H), 7.90 (m, 1H), 10.85 (br s, 1H); MS (ESI) m/z 454 (M+H)+.
Reaction SMILES: O[N:2]1[C:23](=[O:24])[NH:22][C@H:21]2[C@@H:3]1[CH2:4][S:5][C@H:6]2[CH2:7][CH2:8][CH2:9][CH:10](N1C(=O)CCC1=O)[C:11](=[O:13])[OH:12].[CH:25]1[C:30](N=C=S)=[CH:29][C:28]2[C:34]([O:36][C:37]3([C:47]4[CH:48]=[CH:49][C:50]([OH:52])=[CH:51][C:46]=4[O:45][C:39]4[CH:40]=[C:41]([OH:44])[CH:42]=[CH:43][C:38]3=4)[C:27]=2[CH:26]=1)=[O:35]>>[OH:13][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C@@H:21]2[C@@H:3]([NH:2][C:23]([NH:22]2)=[O:24])[CH2:4][S:5]1)=[O:12].[CH:25]1[CH:30]=[CH:29][C:28]([C:34]([OH:36])=[O:35])=[C:27]([C:37]2[C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][C:39]=3[O:45][C:46]3[C:47]=2[CH:48]=[CH:49][C:50]([CH:51]=3)=[O:52])[CH:26]=1
Reactant: O=C(O)C(CCC[C@@H]1SC[C@H]2[C@@H]1NC(=O)N2O)N1C(=O)CCC1=O
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12

Procedure:
The following materials were obtained from Sigma Chemical Co.: avidin, N-hydroxysuccinimidobiotin, fluorescein isothiocyanate, and goat antirabbit IgG IgG, IgG fraction. Rabbit IgG fraction was obtained from Pel-Freez Biologicals. All solvents and buffers were of reagent grade quality. Biotin-fluorescein was synthesized as described above.
Reaction SMILES: [CH2:1]([P:4]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3C2CCCCO2)=[CH:11][CH:10]=1)([CH2:6][CH2:7][CH3:8])=[O:5])[CH2:2][CH3:3].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH2:1]([P:4]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][NH:20]3)=[CH:11][CH:10]=1)([CH2:6][CH2:7][CH3:8])=[O:5])[CH2:2][CH3:3]
Reactant: CCCP(=O)(CCC)c1ccc(Nc2nc(C(C)C)nc3c2ncn3C2CCCCO2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCP(=O)(CCC)c1ccc(Nc2nc(C(C)C)nc3[nH]cnc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-(4-(Dipropylphosphoryl)phenyl)-2-isopropyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (0.23 g) was added 50%/50% TFA/DCM (6 mL) and the resulting solution was stirred at rt for 15 min. HPLC showed the completion of the reaction. Solvent was removed on a rotavapor. The residue was dissolved in 30 mL ethyl acetate and the organic solution was washed 5% NaHCO3 (10 mL), brine (10 mL) and dried over anhydrous Na2SO4. The final product was obtained by flash column chromatography on silica gel (10% MeOH/DCM).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:12][C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=1.CN(C=O)C.CC(C)([O-])C.[K+]>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:12][C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:15][CH:14]=2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: Clc1cc(Br)c2nccn2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
In a 250 ml round bottom flask, under a nitrogen atmosphere, was added 8-bromo-6-chloroimidazo[1,2-b]pyridazine (5.0 g, 18.6 mmol) from Example I(1), step 1b, tert-butyl 4-aminobenzoate (3.95 g, 20.5 mmol), and DMF (30 ml). The solution was cooled to 0° C. and 1.0 M potassium tert-butoxide in THF (46 ml) was added dropwise via syringe over 30 minutes. The reaction was allowed to stir at room temperature for 30 minutes and then warmed to 50° C. for 2 hrs and then concentrated in vacuo to remove THF. The resulting solution was taken up in ethyl acetate, washed with H2O (3×300 ml) and then brine (1×50 ml). The organic layers were combined, dried over Na2SO4 and filtered. Following solvent evaporation, 6.0 g of crude product was obtained. Further purification was done via triteration with 3:1 diethyl ether/heptane to give 2.2 g of tert-butyl 4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)benzoate as a brown solid after filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:16](=[O:21])[CH2:17][CH2:18][C:19]#[CH:20])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.Br[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:16](=[O:21])[CH2:17][CH2:18][C:19]#[C:20][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH:5]=[CH:6][CH:7]=1.[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:16](=[O:21])[CH2:17][CH2:18][C:19]#[CH:20])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccccn1
Agent: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1cccc(Cl)c1
Product: CC(C)(C)OC(=O)N(C(=O)CCC#Cc1ccccn1)c1cccc(Cl)c1

Procedure:
The title compound was prepared in accordance with the general method of Example 244(C), from tert-butyl 3-chlorophenyl(pent-4-ynoyl)carbamate (250 mg, 0.82 mmol) and 2-bromopyridine (129 mg, 0.82 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column cyclohexane/AcOEt: 70/30 as eluent) to afford 226 mg of tert-butyl 3-chlorophenyl(pent-4-ynoyl)carbamate as a brown oil (Yield: 72%).
Reaction SMILES: C1(O[C:8]([N:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[O:9])CCCCC1.[CH:17]1(OC(Cl)=O)[CH2:22]CCC[CH2:18]1.[NH:27]1CCC(=O)CC1>>[CH:17]([NH:27][C:8]([N:10]1[CH2:11][CH2:12][C:13](=[O:16])[CH2:14][CH2:15]1)=[O:9])([CH3:22])[CH3:18]
Reactant: O=C1CCNCC1
Reactant: O=C1CCN(C(=O)OC2CCCCC2)CC1
Reactant: O=C(Cl)OC1CCCCC1
Product: CC(C)NC(=O)N1CCC(=O)CC1

Procedure:
1-(cyclohexyloxycarbonyl)-4-piperidone, (from cyclohexylchloroformate and 4-piperidone); or
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([O:8][CH2:9][CH2:10][NH2:11])([O-:7])=[O:6].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[S:24][C:23](=[O:25])[NH:22][CH:21]2[C:26](O)=[O:27])=[CH:16][CH:15]=1>>[N+:5]([O:8][CH2:9][CH2:10][NH:11][C:26]([CH:21]1[CH:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)[S:24][C:23](=[O:25])[NH:22]1)=[O:27])([O-:7])=[O:6]
Reactant: COc1ccc(C2SC(=O)NC2C(=O)O)cc1
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Product: COc1ccc(C2SC(=O)NC2C(=O)NCCO[N+](=O)[O-])cc1

Procedure:
A procedure similar to that described in Example 1 was repeated, but using 401 mg of N-(2-nitrooxyethyl)amine nitrate and 500 mg of 5-(4-methoxyphenyl)-2-oxothiazolidine-4-carboxylic acid, to obtain 408 mg of the title compound as colorless crystals, melting at 142°-143° C. (after recrystallization from methylene chloride).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[CH2:24][CH2:23][C@:22]([CH:27]4[CH2:29][CH2:28]4)([C:25]#[N:26])[C:21]3=[O:30])[CH:17]=[CH:16][N:15]=2)[CH:10]=[N:9]1)([CH3:7])[CH3:6].C(N(CC)CC)C.[CH3:38][O:39][CH2:40][C:41]([Cl:43])=[O:42].O>O1CCCC1>[ClH:43].[C:25]([C@@:22]1([CH:27]2[CH2:28][CH2:29]2)[CH2:23][CH2:24][N:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:11]3[CH:10]=[N:9][N:8]([C:5]([CH3:7])([CH3:6])[CH2:4][NH:3][C:41](=[O:42])[CH2:40][O:39][CH3:38])[CH:12]=3)[N:19]=2)[C:21]1=[O:30])#[N:26]
Reactant: COCC(=O)Cl
Reactant: CC(C)(CN)n1cc(Nc2nccc(N3CC[C@@](C#N)(C4CC4)C3=O)n2)cn1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COCC(=O)NCC(C)(C)n1cc(Nc2nccc(N3CC[C@@](C#N)(C4CC4)C3=O)n2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.1 %

Procedure:
To a solution of (3S)-1-(2-((1-(1-amino-2-methylpropan-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-cyclopropyl-2-oxopyrrolidine-3-carbonitrile dihydrochloride (100 mg) obtained in Example 115 in tetrahydrofuran (5 mL) were added successively dropwise triethylamine (0.15 mL) and methoxyacetyl chloride (26 mg) at 0° C. under nitrogen atmosphere, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol). To a solution of the residue (89 mg) in ethanol (5.0 mL) was added 1 M hydrochloric acid (0.20 mL), and the mixture was stirred at room temperature for 5 min. The solvent was evaporated under reduced pressure, and the residue was recrystallized (diisopropyl ether/ethyl acetate) to give the title compound (81 mg).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4].I[CH2:17][CH3:18].CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[CH2:17]([O:1][CH2:2][C@@H:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4])[CH3:18]
Reactant: CCI
Reactant: C[C@@H](CO)N1C(=O)c2ccccc2C1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC[C@H](C)N1C(=O)c2ccccc2C1=O
Reaction time: 15 h
Yield: 73.8 %

Procedure:
To a solution of 2-[(1S)-2-hydroxy-1-methyl-ethyl]isoindoline-1,3-dione (47 g, 229 mmol) and iodoethane (89.3 g, 572.5 mmol) in THF (376 mL) is added potassium tert-butoxide (64.25 g, 572.5 mmol) in one portion. The mixture is stirred under a nitrogen atmosphere for 15 h. The mixture is diluted with ethyl acetate (200 mL) and washed with brine (200 mL). The aqueous phase is extracted with ethyl acetate (2×100 mL). The combined organic extracts are dried over MgSO4, filtered, concentrated under reduced pressure, and then dried under high vacuum to afford the title compound (39.4 g, 74%) as an orange solid that is used without further purification. LC-ES/MS m/z 234 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:27][C:28]2[CH:36]=[CH:35][C:31]3[O:32][CH2:33][O:34][C:30]=3[CH:29]=2)[S:7](=[O:26])(=[O:25])[C:8]2[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=2[C:10]=1[S:11][C:12]1[CH:20]=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)=[O:4].CO.[Li+].[OH-]>C1COCC1.O.Cl>[O:32]1[C:31]2[CH:35]=[CH:36][C:28]([CH2:27][N:6]3[C:5]([C:3]([OH:4])=[O:2])=[C:10]([S:11][C:12]4[CH:20]=[CH:19][C:15]5[O:16][CH2:17][O:18][C:14]=5[CH:13]=4)[C:9]4[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=4[S:7]3(=[O:26])=[O:25])=[CH:29][C:30]=2[O:34][CH2:33]1
Reactant: COC(=O)C1=C(Sc2ccc3c(c2)OCO3)c2ccccc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1=C(Sc2ccc3c(c2)OCO3)c2ccccc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.9 %

Procedure:
To 2-benzo[1,3]dioxol-5-ylmethyl-4-(benzo[1,3]dioxol-5-ylsulfanyl)-1,1-dioxo-1,2-dihydro-1λ6 -benzo[e][1,2]thiazine-3-carboxylic acid methyl ester (0.467 g, 0.89 mmol) in THF:methanol:water (5 mL:2 mL:2 mL) was added LiOH(0.46 g, 19 mmol). Stirred at room temperature for 5 hours, diluted with water (80 mL) and 50% HCl (10 mL) then extracted with chloroform (3×80 mL). Dried with magnesium sulfate and removed solvent to afford the title compound as a foam (0.4 g, 88%);
Reaction SMILES: OC(COC1C=CC=CC=1)CC(O)=O.OC(CCCOC1C=CC=CC=1)CC(O)=O.O[CH:32]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:33][C:34]([OH:36])=[O:35]>>[O:42]([CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(O)CC(O)CCCCCOc1ccccc1
Agent: O=C(O)CC(O)CCCOc1ccccc1
Agent: O=C(O)CC(O)COc1ccccc1
Product: O=C(O)CCCCCCCOc1ccccc1

Procedure:
Result indicates that PHA copolymer containing three units of 3-hydroxy-4-phenoxybutyric acid (3HPxB), 3-hydroxy-6-phenoxyhexanoic acid (3HPxHx) and 3-hydroxy-8-phenoxyoctanoic acid (3HPxO) can be produced by the strain YN2 with a substrate 8-phenoxyoctanoic acid.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].C([C:10](=[CH2:14])[C:11]([NH2:13])=[O:12])CCC.[CH:15]([C:17]1C=CC=C[C:18]=1C=C)=[CH2:16].O>C(O)C>[C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH2:16]([NH:13][C:11](=[O:12])[CH:10]=[CH2:14])[CH2:15][CH2:17][CH3:18]
Reactant: C=C(CCCC)C(N)=O
Reactant: C=Cc1ccccc1C=C
Agent: C=CC(N)=O
Solvent: O
Solvent: CCO
Product: C=CC(=O)NCCCC

Procedure:
Polystyrenesulfonate (22.5 mmoles, 3.918 g), acrylamide (3.45 mmoles, 0.245 g), n-butylacrylamide (3.45 mmoles, 0.439 g) and divinylbenzene (0.6 mmoles, 85.5 microL) were dissolved in 15 mL ethanol and 5 mL water in a 40 mL vial fitted with a septa cap. The solution was degassed by bubbling nitrogen through and 1 mole % AIBN was added as a solution. The polymerization solution was further degassed and the placed in a heated reaction block at 60° C. for 18 h. A clear, light yellow gel formed.
Reaction SMILES: N1C=CN=C1.C(NCC(O)=O)(=O)C.P(Cl)(Cl)(Cl)=O.[CH3:19][N:20]([CH3:30])/[C:21](=[C:23]1/[N:24]=[C:25]([CH3:29])[O:26][C:27]/1=[O:28])/[CH3:22].[O-:31][CH2:32][CH3:33]>CC(N(C)C)=O>[C:32]([NH:24]/[C:23](=[C:21](/[N:20]([CH3:30])[CH3:19])\[CH3:22])/[C:27]([O:26][CH2:25][CH3:29])=[O:28])(=[O:31])[CH3:33]
Reactant: CC1=N/C(=C(\C)N(C)C)C(=O)O1
Reactant: CC[O-]
Agent: CC(=O)NCC(=O)O
Agent: c1c[nH]cn1
Solvent: CC(=O)N(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)/C(NC(C)=O)=C(/C)N(C)C
Temperature: 45 °C
Yield: 50 %

Procedure:
Another approach toward imidazole intermediate is described in Reaction Scheme 3. The original reaction sequence was published by F. Hoffmann-La Roche A G [F. Hoffmann-La Roche A G, WO 2005/003117, 2005]. N-acetylglycine (14) and phosphorous oxychloride are mixed and dimethylacetamide is added thereto dropwise slowly at low temperature (exothermic). The reaction mixture is then stirred and warmed at 45° C. In this way, (E)-4-(1-(dimethylamino)ethylidene)-2-methyloxazol-5(4H)-one (15) is generated in 50% yield. The oxazolone (15) is cleaved with in situ generated ethoxide to produce (E)-ethyl 2-acetamido-3-(dimethylamino)but-2-enoate (16). Next, an amine (17) is subjected to a reaction with the compound (16) in acetic acid at rt overnight to give a Michael adduct (18). The crude intermediate (18) is then refluxed together with fine powdered ammonium sulfate in hexamethyldisilazane at 145° C. to provide the corresponding imidazole ester (19) in 55˜73% yield for the three steps from the oxazolone (15). The imidazole ester (19) is hydrolyzed with sodium hydroxide to produce the corresponding sodium carboxylate (20) uneventfully.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)#[CH:2].[F:11][C:12]1[CH:21]=[CH:20][C:19](I)=[CH:18][C:13]=1[C:14]([NH:16][CH3:17])=[O:15].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:11][C:12]1[CH:21]=[CH:20][C:19]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=2)=[CH:18][C:13]=1[C:14]([NH:16][CH3:17])=[O:15]
Reactant: CNC(=O)c1cc(I)ccc1F
Reactant: C#Cc1cncc(OC)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CNC(=O)c1cc(C#Cc2cncc(OC)c2)ccc1F
Temperature: 60 °C
Yield: 72.2 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (64 mg, 0.091 mmol), copper (I) iodide (35 mg, 0.19 mmol), and 3-ethynyl-5-methoxypyridine, (prepared as described in PREPARATION 10), (250 mg, 1.9 mmol) to a solution of 2-fluoro-5-iodo-N-methylbenzamide, (prepared as described in PREPARATION 39), (0.63 g, 2.3 mmol) in triethylamine (3.8 mL, 27.3 mmol) and heat at 60° C. for 16 h. Cool to room temperature and concentrate. Purify by silica gel chromatography, eluting with 100:0 to 10:90 dichloromethane:ethyl acetate, followed by a second silica gel chromatography eluting with 50:50 to 75:25 ethyl acetate:hexanes, to give the title compound as a white solid (390 mg, 73%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[CH3:21][C:22]1[C:26]([C:27](Cl)=[O:28])=[C:25]([CH3:30])[O:24][N:23]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:27]([C:26]1[C:22]([CH3:21])=[N:23][O:24][C:25]=1[CH3:30])=[O:28]
Reactant: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1N
Reactant: Cc1noc(C)c1C(=O)Cl
Product: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1NC(=O)c1c(C)noc1C
Yield: 50 %

Procedure:
The title compound was prepared in a manner substantially the same as example 20 by coupling (2S,3R)-2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenylamine with 3,5-dimethyIsoxazole-4-carbonyl chloride in 50% yield.