Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[C:14](F)=[CH:15][C:16]([F:26])=[C:17]([CH:25]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CC(C)([O-])C.[K+]>CS(C)=O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:14]3[C:13]([Cl:12])=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[C:16]([F:26])[CH:15]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: OC1CCC2(CC1)OCCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OC2CCC3(CC2)OCCO3)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.1 %

Procedure:
To a mixture of 1,4-dioxaspiro[4.5]decan-8-ol (2.40 g, 15.20 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (3.78 g, 15.20 mmol) in anhydrous dimethyl sulfoxide was added potassium tert-butoxide (2.56 g, 22.80 mmol) and the reaction mixture was stirred for 16 hours at ambient temperature. After dilution with ethyl acetate (200 mL), the organic phase was washed with water (3×10 mL), brine (10 mL), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave a residue which was purified by silica gel column chromatography using 0-30% ethyl acetate in hexanes as eluent to afford the title compound as a colorless oil (0.709 g, 12%): 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=7.8 Hz, 1H), 6.64 (d, J=12.3 Hz, 1H), 4.53-4.46 (m, 1H), 3.97-3.92 (m, 4H), 2.04-1.58 (m, 8H), 1.55 (d, J=1.0 Hz, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][C@@H:15]([CH3:17])[C@H:14]([CH2:18][C:19](O)=[O:20])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH2:22]([O:24][C:25]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)=[O:26])[CH3:23]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][C@@H:15]([CH3:17])[C@H:14]([CH2:18][C:19](=[O:20])[NH:31][C:30]3[CH:32]=[CH:33][C:27]([C:25]([O:24][CH2:22][CH3:23])=[O:26])=[CH:28][CH:29]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: C[C@@H]1Cc2cc(Br)cc3[nH]c(=O)c(=O)n(c23)[C@H]1CC(=O)O
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(NC(=O)C[C@H]2[C@H](C)Cc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Yield: 82.8 %

Procedure:
A procedure similar to that described in Example 52 was carried out with trans-9-bromo-5-carboxymethyl-6-methyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (50 mg, 0.14 mmol) and p-ethoxycarbonylaniline (24 mg, 0.15 mmol) to give 58 mg of the title compound (82%): mp 282°~292° C.; 1H NMR (270 MHz, DMSO-d6) δ12.09 (s, 1H), 10.33 (s, 1H), 7.90 (d, 2H, J=8.6 Hz), 7.70 (d, 2H, J=8.6 Hz), 7.21 (s, 1H), 7.18 (s, 1H), 4.92~5.02 (m, 1H), 4.28 (q, 2H, J =6.9 Hz), 3.20 (dd, 1H, J=17.8, 5.9 Hz), 2.52~2.66 (m, 3H), 2.28~2.42 (m, 1H), 1.32 (t, 3H, J=6.9 Hz), 0.87 (d, 3H, J=6.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([C@@H:14]([OH:26])[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)=[O:16])[C:9]2=[O:27])=[CH:4][CH:3]=1.[O-:28][C:29]#[N:30].[K+]>C(O)(C)=O.O.O>[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([C@@H:14]([OH:26])[C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)=[O:16])[C:9]2=[O:27])=[CH:4][CH:3]=1)(=[O:28])[NH2:30]
Reactant: N#C[O-]
Reactant: N#Cc1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(N)cc3)C2=O)cc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc(NC(=O)[C@H](O)[C@H]2OCCN(c3ccc(NC(N)=O)cc3)C2=O)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a solution of compound 26-5 (70 mg) in AcOH—H2O (6 mL-2 mL), was added a solution of potassium cyanate (KOCN; 31 mg) in water (2 mL). The reaction mixture was stirred at 40-50° C. for 3 hours and at room temperature overnight to precipitate. The resulting precipitate was collected by filtration, rinsed with waster and dried in vacuo to obtain compound 27-1 (70 mg) as a colorless amorphous solid.
Reaction SMILES: [OH-].[NH4+:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[O-][N+:15]1[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]2[N:25]([CH2:31][CH2:32][CH2:33][O:34][N:35]3C(=O)C4C(=CC=CC=4)C3=O)[C:26]([CH2:28][CH2:29][CH3:30])=[N:27][C:17]=2[CH:16]=1>C(Cl)(Cl)Cl>[NH2:35][O:34][CH2:33][CH2:32][CH2:31][N:25]1[C:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[N:15]=[C:16]([NH2:2])[C:17]=2[N:27]=[C:26]1[CH2:28][CH2:29][CH3:30]
Reactant: [NH4+]
Reactant: CCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCON1C(=O)c2ccccc2C1=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCON
Reaction time: 1 h

Procedure:
Ammonium hydroxide (75 mL) and p-toluenesulfonyl chloride (4.87 g, 25.6 mmol) were added to a solution of 2-[3-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propoxy]-1H-isoindole-1,3(2H)-dione (10.0 g, 23.2 mmol) in chloroform (100 mL), and the resulting mixture was stirred vigorously for one hour.) A white precipitate was removed by filtration, and the filtrate layers were separated. The organic solution was washed with brine (2×150 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a yellow solid. The solid was purified by column chromatography on silica gel (eluting with dichloromethane:methanol:ammonium hydroxide ranging in ratios from 94:5:1 to 91:8:1) to provide 4.31 g of 1-[3-(aminooxy)propyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a beige powder, melting point (mp) 145-148° C.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>N1C=CC=CC=1>[NH2:17][C:16]1[S:27][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C#N)NC(=O)c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(-c2ccccc2)sc1N
Yield: 40.3 %

Procedure:
To a stirred solution of compound ethyl 2-benzamido-2-cyanoacetate (0.46 g, 2 mmol) in pyridine (20 mL) was added Lawesson's reagent (0.81 g, 2 mmol). The reaction mixture was heated at reflux for 15 hr. It was then concentrated and diluted with EtOAc (40 mL). The diluted mixture was washed with water (3×20 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (10:1 PE/EtOAc) to afford ethyl 5-amino-2-phenylthiazole-4-carboxylate (0.2 g, 40%) as yellow solid: 1H-NMR (CDCl3, 500 MHz) δ (ppm): 7.80 (d, J=6.5 Hz, 1H), 7.36-7.41 (m, 3H), 4.43 (q, J=7.0 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 249 [M+H+].
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29]([CH2:30][CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:37](=[O:48])[NH:38][C@@H:39]([C:41]4[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=4)[CH3:40])[CH:26]=3)[C:21]2=[O:49])=[CH:16][CH:15]=1.C1CCN2C(=NCCC2)CC1.[CH:61]1([S:64]([NH2:67])(=[O:66])=[O:65])[CH2:63][CH2:62]1>O1CCCC1>[CH:61]1([S:64]([NH:67][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][C:29]2[N:20]([C:17]3[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=3)[C:21](=[O:49])[C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([C:37]([NH:38][C@@H:39]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[CH3:40])=[O:48])=[CH:24][CH:23]=3)(=[O:66])=[O:65])[CH2:63][CH2:62]1
Reactant: C[C@@H](NC(=O)c1ccc2c(=O)n(-c3ccc(F)cc3)c(CCCCC(=O)O)cc2c1)c1ccc(F)cc1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)c1ccc2c(=O)n(-c3ccc(F)cc3)c(CCCCC(=O)NS(=O)(=O)C3CC3)cc2c1)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
CDI (13.50 mg, 0.083 mmol) was added to a stirred, room temperature mixture of (R)-5-(2-(4-fluorophenyl)-6-((1-(4-fluorophenyl)ethyl)carbamoyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoic acid (28 mg, 0.055 mmol) in tetrahydrofuran (2 mL) and the mixture was stirred at 70° C. for 2 h. DBU (0.017 mL, 0.111 mmol) and cyclopropylsulfonamide (10.09 mg, 0.083 mmol) were added, the resultant mixture was kept stirring at room temperature overnight. The mixture was concentrated, and the residue was purified via PTLC (Emerck 1 mm), eluted with CH2Cl2/MeOH=10:1 to give (R)-3-(5-(cyclopropanesulfonamido)-5-oxopentyl)-2-(4-fluorophenyl)-N-(1-(4-fluorophenyl)ethyl)-1-oxo-1,2-dihydroisoquinoline-6-carboxamide (16 mg) as a white solid. LCMS [M+H]+=608. 1H NMR (500 MHz, DMSO) δ ppm: 9.06 (d, J=7.88 Hz, 1H), 8.20 (d, J=8.20 Hz, 1H), 8.15 (s, 1H), 7.36-7.50 (m, 6H), 7.18 (t, J=8.99 Hz, 2H), 6.69 (s, 1H), 5.22 (t, J=7.25 Hz, 1H), 3.16-3.19 (m, 1H), 2.87-2.94 (m, 1H), 2.26 (br. s, 2H), 2.16 (br. s, 2H), 1.51 (d, J=7.25 Hz, 3H), 1.43 (br. s, 3H), 0.98-1.05 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[Br:25][C:26]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:27]=1[NH2:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[Br:25][C:26]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:27]=1[NH:28][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1
Reactant: Cc1ccc(N)c(Br)c1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)CCCn1c(Nc2ccc(C)cc2Br)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 130 °C
Reaction time: 12 h
Yield: 67.6 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 1.50 g, 4.04 mmol), 2-bromo-4-methylaniline (1.0 mL, 8.08 mmol), p-toluenesulfonic acid monohydrate (822.2 mg, 4.32 mmol) and xylene (5.0 mL) was stirred at 130° C. for 12 hr. After cooling, the reaction mixture was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as an oil (1.42 g, 2.73 mmol, 68%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:11]1([NH:14][C:15]2[N:20]3[N:21]=[CH:22][C:23](/[CH:24]=[C:25]4/[C:26](=[O:31])[NH:27][C:28](=[O:30])[NH:29]/4)=[C:19]3[N:18]=[C:17](S(C)(=O)=O)[N:16]=2)[CH2:13][CH2:12]1.C1(NC2N3N=CC(/C=C4/C(=O)NC(=O)N/4)=C3N=C(S(C)=O)N=2)CC1>CN1C(=O)CCC1.O>[CH2:1]([O:8][C:17]1[N:16]=[C:15]([NH:14][CH:11]2[CH2:13][CH2:12]2)[N:20]2[N:21]=[CH:22][C:23](/[CH:24]=[C:25]3/[C:26](=[O:31])[NH:27][C:28](=[O:30])[NH:29]/3)=[C:19]2[N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Reactant: OCc1ccccc1
Agent: CS(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)nc(OCc4ccccc4)nc23)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl alcohol (14.2 μL, 0.138 mmol) was dissolved in NMP (0.2 ml). Sodium Hydride (60%, 5.5 mg, 0.138 mmol) was added and the reaction stirred at room temperature for one hour. A (1:1) mixture of (Z)-5-((4-(cyclopropylamino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione and (Z)-5-((4-(cyclopropylamino)-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione (10 mg, 0.027 mmol) was added and the mixture was stirred at room temperature for one hour. Water was added and the material was extracted with ethyl acetate. After concentration at the rotary evaporator, addition of methanol formed a precipitate that was filtered and dried. (Z)-5-((2-(benzyloxy)-4-(cyclopropylamino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione was isolated as a solid (5.6 mg). LCMS (ES): >95% pure, m/z 392 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:26]([O:62][CH3:63])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:60][CH3:61])[C@@H:36]([CH3:59])[C:37]([NH:39][C@@H:40]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(=[O:44])=[O:43])=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:69][CH2:70][CH2:71][C:72]([OH:74])=[O:73].C([BH3-])#N.[Na+].O1CCOCC1>O1CCOCC1.O>[C:72]([CH2:71][CH2:70][CH2:69][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:26]([O:62][CH3:63])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:60][CH3:61])[C@@H:36]([CH3:59])[C:37]([NH:39][C@@H:40]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(=[O:44])=[O:43])=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:12])[CH3:13])([OH:74])=[O:73]
Reactant: O=CCCC(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)CS(=O)(=O)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)CS(=O)(=O)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
19.3 mg (20 μmol) N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzylsulphonyl)-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetate were dissolved in 1.2 ml of dioxane/water and, analogously to the preparation of Intermediate 61, reacted with 15% aqueous solution of 4-oxobutanoic acid in the presence of sodium cyanoborohydride. After lyophilization from dioxane, 8.6 mg (45% of theory) of the title compound were obtained in the form of a solid.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=[O:6])=[CH2:3].C(O)CCCCCCC.[OH-].[Na+:20]>CCCCCCC>[C:1]([O-:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=[O:6])=[CH2:3].[Na+:20]
Reactant: C=C(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: CCCCCCCCO
Product: C=C(CC(=O)O)C(=O)[O-]
Reaction time: 8 h

Procedure:
Two hollow fiber modules (4×13, LiquiCell X40, Membrana) were assembled such that 3 continuous loops could be operated: (1) itaconic acid solution (2) solvent system (3) stripping solution. An itaconic acid solution (2 L, 60.0 g/L acid, pH 2.2) was circulated through the shell side of module 1. The ternary organic solvent system (20% TOA, 20% octanol, heptane) was circulated through the lumen of both modules. Lastly, aqueous sodium hydroxide (0.46 M) was circulated shell side of module 2. The volume ratios were 1:1:1. The three loops were run at 0.5 L/min. The simultaneous extraction and stripping were monitored for IA concentration and pH. In 7 hours 63% was recovered (5.4 g/L-hr) and the pH dropped to 4.7. The run was allowed to proceed overnight (25 hours total) resulting in an overall 78% recovery in the form of monosodium itaconate from the fermentation broth.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[CH:21]=[C:22]([CH3:31])[N:23]3[C:28]=2[C:27]([Cl:29])=[CH:26][C:25]([Cl:30])=[CH:24]3)[C:11]1=[O:32])[CH2:7][CH2:8][CH3:9])C.[Li+].[OH-]>O1CCOCC1.O>[Cl:30][C:25]1[CH:26]=[C:27]([Cl:29])[C:28]2[N:23]([C:22]([CH3:31])=[CH:21][C:20]=2[CH2:19][N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:33])=[O:3])[C:11]2=[O:32])[CH:24]=1
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(C)n3cc(Cl)cc(Cl)c23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2cc(C)n3cc(Cl)cc(Cl)c23)c2ccccc21
Reaction time: 4 h

Procedure:
To a solution of 3-[3-(6,8-Dichloro-3-methyl-indolizin-1-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (20 mg, 0.041 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added LiOH (2 mg, 0.082 mmol) at room temperature. The solution was stirred at the same temperature for 4 hours. The solution was concentrated and water was added to the residue. The solution was acidified by 12N HCl in an ice-bath. The solid that preciptate out from the solution was collected by filtration. The solid was dried under vacuum and was confirmed to be the desirable product. LCMS (ESMS): m/z 460.17 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl.[C:22](Cl)(=[O:32])[O:23][C@@H:24]1[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1>CC#N.CCOC(C)=O.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:13]([C:22]([O:23][C@@H:24]2[CH:29]3[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]3)[CH2:25]2)=[O:32])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(F)cc(CNc2ccccc2F)c1
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)cc(CN(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2F)c1
Temperature: 100 °C

Procedure:
A suspension of methyl 3-fluoro-5-(((2-fluorophenyl)amino)methyl)benzoate (133 mg, 0.48 mmol) and (R)-quinuclidin-3-yl carbonochloridate hydrochloride (163 mg, 0.72 mmol) in anhydrous CH3CN (6 mL) was heated to 100° C. for 30 minutes under microwave irradiation. After cooling to room temperature, the mixture was diluted with EtOAc (30 mL) and saturated aqueous NaHCO3 (20 mL). The layers were separated and the organic phase was dried over Na2SO4. The mixture was filtered and the solvent was removed in vacuo to yield the title compound which was used directly in the next step without any further purification.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18])=O.Cl.[CH:20]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH:20]1([N:29]2[CH2:34][CH2:33][N:32]([CH2:1][CH2:3][CH2:4][CH2:5][C:6]34[CH2:17][CH2:16][CH2:15][C:13]5[C:14]3=[C:9]([CH:10]=[CH:11][CH:12]=5)[NH:8][C:7]4=[O:18])[CH2:31][CH2:30]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: c1ccc2c(c1)CCC2N1CCNCC1
Reactant: O=CCCCC12CCCc3cccc(c31)NC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C1Nc2cccc3c2C1(CCCCN1CCN(C2CCc4ccccc42)CC1)CCC3

Procedure:
2a-(3-Formylpropyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (210 mg, 0.90 mmol), 1-(1-indanyl)piperazine hydrochloride (270 mg, 1.0 mmol), acetic acid (540 mg, 9.0 mmol) and sodium triacetoxyborohydride (380 mg, 1.8 mmol) were stirred at room temperature for 20 hours in 1,2-dichloroethane (3 ml). The reaction solution was mixed with ethyl acetate (80 ml), washed with sodium hydroxide aqueous solution (1 N) and saturated brine and dried with anhydrous sodium sulfate, the solvent was removed by evaporation under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 430 mg (1.0 mmol, 100% in yield) of the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[C@H](N(C)C)[C@H](O)C1C=CC=CC=1.C(N1C=CC=CC1N)C.[CH3:29][N:30]1[CH2:49][C:43]2[CH:44]=[CH:45][C:46]([O:47][CH3:48])=[C:41]3[C:42]=2[C@:33]2([C@@H:39]([O:40]3)[CH2:38][C:36](=[O:37])[CH:35]=[CH:34]2)[CH2:32][CH2:31]1>CCOCC>[CH3:29][N:30]1[CH2:49][C:43]2=[C:42]3[C:41](=[C:46]([O:47][CH3:48])[CH:45]=[CH:44]2)[O:40][C@@H:39]2[C@:33]3([CH:34]=[CH:35][C@H:36]([OH:37])[CH2:38]2)[CH2:32][CH2:31]1
Reactant: COc1ccc2c3c1O[C@H]1CC(=O)C=C[C@@]31CCN(C)C2
Agent: CCN1C=CC=CC1N
Agent: C[C@@H]([C@H](O)c1ccccc1)N(C)C
Agent: [Al+3]
Solvent: CCOCC
Product: COc1ccc2c3c1O[C@H]1C[C@@H](O)C=C[C@@]31CCN(C)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
Lithium aluminium hydride (1M in ether, 1.2 ml, 1.20 mmol) was placed in a two necked round bottom flask fitted with a reflux condenser and nitrogen inlet. (-)-N-methylephedrine (0.23 g, 1.26 mmol) in ether (1 ml) was added dropwise and the solution was heated at reflux for 1 hour then cooled to room temperature. N-Ethyl-2-amino-pyridine (0.31 g, 2.52 mmol) in ether (1 ml) was added and the bright yellow solution was heated under reflux for a further 1 hour. The solution was cooled to -78° C. and solid racemic narwedine (0.10 g, 0.35 mmol) was added. The suspension was stirred for 3 hours at -78° C. and then allowed to warm to room temperature over 1 hour. The reaction was quenched with hydrochloric acid (3M, 2 ml). The aqueous layer was removed and basified with KOH to pH 14. The remaining mixture was extracted with dichloromethane (3×10 ml) and the combined organic layers were washed with water (5 ml) and brine (5 ml) and dried over magnesium sulphate. Filtration and evaporation gave an orange oil which was flash chromatographed on silica in dichloromethane-methanol 10:1 to yield (-)-galanthamine (50% e.e.) as a white solid (0.036 g, 36%), pure by NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[CH:21][CH:20]=1)=[O:17]>ClCCl.CN(C)C=O.C(OCC)(=O)C>[F:34][C:32]([F:33])([F:35])[C:29]1[CH:30]=[CH:31][C:26]([O:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][C:16]([N:11]3[CH2:12][CH2:13][CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=4)[CH2:9][CH2:10]3)=[O:17])=[CH:20][CH:21]=2)=[N:27][CH:28]=1
Reactant: Nc1cccc(C2CCNCC2)c1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1cccc(C2CCN(C(=O)Oc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3)CC2)c1

Procedure:
The title product was prepared from 4-(3-aminophenyl)piperidine (released form the correspondent hydrochloride by a standard procedure) and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (reaction performed in a mixture of dichloromethane and dimethylformamide, 5:3). 1.7 M HCl in ethyl acetate was added to the pooled fractions containing the title product, and the fractions was evaporated to dryness (7%, light yellow solid). HPLC-MS m/z=(M+1) 458.0, Rt: 3.09 min.