Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C)C.[CH:5]1[CH:10]=[N+:9]([C@@H:11]2[O:15][C@H:14]([CH2:16][O:17][P:18]([O:21][P:22]([O:25][CH2:26][C@H:27]3[O:31][C@@H:30]([N:32]4[C:36]5[N:37]=[CH:38][N:39]=[C:40]([NH2:41])[C:35]=5[N:34]=[CH:33]4)[C@H:29]([O:42][P:43]([OH:46])([OH:45])=[O:44])[C@@H:28]3[OH:47])([OH:24])=[O:23])([OH:20])=[O:19])[C@@H:13]([OH:48])[C@H:12]2[OH:49])[CH:8]=[C:7]([C:50]([NH2:52])=[O:51])[CH:6]=1>CC(C)=O>[CH:38]1[N:39]=[C:40]([NH2:41])[C:35]2[N:34]=[CH:33][N:32]([C@@H:30]3[O:31][C@H:27]([CH2:26][O:25][P:22]([O:21][P:18]([O:17][CH2:16][C@H:14]4[O:15][C@@H:11]([N:9]5[CH:8]=[C:7]([C:50]([NH2:52])=[O:51])[CH2:6][CH:5]=[CH:10]5)[C@H:12]([OH:49])[C@@H:13]4[OH:48])([OH:20])=[O:19])([OH:24])=[O:23])[C@@H:28]([OH:47])[C@H:29]3[O:42][P:43]([OH:46])([OH:45])=[O:44])[C:36]=2[N:37]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Solvent: CC(C)O
Solvent: CC(C)=O
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1

Procedure:
This example illustrates a prescreening assay used to identify variant genes encoding ketoreductases capable of reducing isopropanol in the presence of NADP+ to produce acetone and NADPH. An E. coli colony containing a plasmid encoding an engineered ketoreductase was picked using a Q-Bot® robotic colony picker (Genetix USA, Inc., Boston, Mass.) into 96-well shallow well microtiter plates containing 180 μL Terrific Broth (TB), 1% glucose and 30 μg/mL chloramphenicol (CAM). Cells were grown overnight at 30° C. with shaking at 200 rpm. A 10 μL aliquot of this culture was then transferred into 96-deep well plates containing 390 μL Terrific Broth (TB), 1 mM MgSO4 and 30 μg/mL CAM. After incubation of the deep-well plates at 30° C. with shaking at 250 rpm for 2 to 3 hours, recombinant gene expression within the cultured cells was induced by addition of IPTG to a final concentration of 1 mM. The plates were then incubated at 30° C. with shaking at 250 rpm for 18 hours.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[CH:19][C:18]4=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[N:26][NH:27][CH:28]=5)[N:17]4[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>>[CH3:43][S:44]([N:26]1[CH:25]=[C:24]([C:23]2[N:17]3[C:18]([CH:19]=[N:20][C:15]([NH:14][C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)[CH:9]=4)=[N:16]3)=[CH:21][CH:22]=2)[CH:28]=[N:27]1)(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCN(c2cccc(Nc3ncc4ccc(-c5cn[nH]c5)n4n3)c2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cccc(Nc3ncc4ccc(-c5cnn(S(C)(=O)=O)c5)n4n3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
To a solution of [3-(4-Methyl-piperazin-1-yl)-phenyl]-[7-(1H-pyrazol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine (1.00E2 mg, 0.267 mmol) and N,N-Diisopropylethylamine (48.8 uL, 0.280 mmol) in N,N-Dimethylformamide (12.1 mL, 156 mmol) was added Methanesulfonyl chloride (21.7 uL, 0.280 mmol). The reaction was stirred at rt overnight. LCMS 453.0 (M+H), HPLC rt=2.180 min, 97% purity. The reaction mixture was concentrated to remove DMF, diluted with CH2Cl2, and washed with sat'd aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated. Product was isolated as a yellow solid (29 mg, 24%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.30 (s, 1H), 9.03 (s, 1H0, 8.97 (s, 1H), 8.71 (s, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.29 (d, J=4.6 Hz, 1H0, 7.22 (dd, J=8.3 Hz, 8.3 Hz, 1H), 7.05 (bm, 1H), 6.95 (d, J=4.6 Hz, 1H), 6.63 (dd, J=8.4 Hz, 1.4 Hz, 1H0, 3.62 (s, 3H), 3.12-3.10 (m, 4H), 2.45-2.43 (m, 4H), 2.21 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH2:17]([S:19](Cl)(=[O:21])=[O:20])[CH3:18].N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:19]([CH2:17][CH3:18])(=[O:21])=[O:20])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(N)c2c1C
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1oc2cccc(NS(=O)(=O)CC)c2c1C
Temperature: 25 °C
Yield: 69 %

Procedure:
To 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (563 mg, 2.57 mmol, 1 eq., prepared according to Example 60, Step 1), CH2Cl2 (12 mL) was added under argon and the reaction was cooled to <0° C. Then ethanesulfonyl chloride (243 uL, 2.57 mmol, 1 eq.), and pyridine (623 uL, 7.70 mmol, 3 eq.) were added and the reaction was stirred while slowly warming to room temperature. After work-up and flash column chromatography, 4-ethanesulfonylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained in 69% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (m, 6 H) 2.8 (s, 3 H) 3.2 (q, J=7.3 Hz, 2 H) 4.4 (m, J=7.1, 7.1, 7.1 Hz, 2 H) 7.2 (d, J=7.6 Hz, 1 H) 7.5 (m, 1 H) 7.6 (m, 1 H) 9.6 (s, 1 H).
Reaction SMILES: [OH:1][C@@H:2]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)[C@H:3]([CH3:16])[CH2:4][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].CS(O[CH2:29][CH:30]([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])(=O)=O>>[OH:1][C@@H:2]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:29][CH:30]([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])[CH:18]=1)[C@H:3]([CH3:16])[CH2:4][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]
Reactant: C[C@H](CN1C(=O)c2ccccc2C1=O)[C@@H](O)c1cccc(O)c1
Reactant: CCCC(CCC)COS(C)(=O)=O
Product: CCCC(CCC)COc1cccc([C@H](O)[C@H](C)CN2C(=O)c3ccccc3C2=O)c1

Procedure:
2-((2R,3R)-3-Hydroxy-3-(3-hydroxyphenyl)-2-methylpropyl)isoindoline-1,3-dione (82) was reacted with 2-propylpentyl methanesulfonate following the method described for Example 72 to give 2-((2R,3R)-3-hydroxy-2-methyl-3-(3-(2-propylpentyloxy)phenyl)propyl)isoindoline-1,3-dione as a colorless oil. Yield (0.414 g, 79%). 1H NMR (400 MHz, DMSO-d6) δ 7.75-7.80 (m, 4H), 7.13 (t, J=7.8 Hz, 1H), 6.83-6.88 (m, 2H), 6.67-6.70 (m, 1H), 5.30 (d, J=4.3 Hz, 1H), 4.38-4.41 (m, 1H), 3.78 (d, J=5.7 Hz, 2H), 3.70 (dd, J=5.3, 13.5 Hz, 1H), 3.41 (dd, J=9.4, 13.7 Hz, 1H), 2.21-2.28 (m, 1H), 1.67-1.75 (m, 1H), 1.23-1.42 (m, 8H), 0.85 (t, J=6.7 Hz, 6H), 0.65 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[NH:7][C:8](=O)[N:9]([CH3:12])[C:10](=[O:11])[C:5]=2[N:4]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=2[Cl:22])[N:3]=1.P(Cl)(Cl)([Cl:25])=O.C(N(CC)C(C)C)(C)C>>[Cl:25][C:8]1[N:9]([CH3:12])[C:10](=[O:11])[C:5]2[N:4]([C:14]3[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=3[Cl:22])[N:3]=[C:2]([CH3:1])[C:6]=2[N:7]=1
Reactant: Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c2c(=O)n(C)c(=O)[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c2c(=O)n(C)c(Cl)nc12
Temperature: 100 °C
Reaction time: 60 h

Procedure:
A mixture of 3,6-dimethyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[4,3-d]pyrimidine-5,7(4H,6H)-dione (20 mg, 0.0556 mmol), phosphorus oxychloride (0.52 ml) and N,N-diisopropylethylamine (0.21 ml) was stirred at 100° C. for 60 h. The solvent was evaporated under vacuum to give the title compound, which was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(O)C.[H-].[Na+].Cl.[C:17](=O)([O:21]CC)[O:18][CH2:19][CH3:20]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:17]([O:18][CH2:19][CH3:20])=[O:21])=[CH:4][CH:3]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of 4′-fluoroacetophenone (57.8 g, 0.307 mol) and ethanol (1 ml) in diethyl carbonate (300 ml) was added sodium hydride (24.5 g, 60% in oil, 0.63 mol) by small portions. Because heat is gradually generated, the mixture was ice-cooled and stirred at room temperature for 2 hrs. To the reaction solution was added 6N hydrochloric acid to quench the reaction. Water (300 ml) was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1-5:1) to give ethyl 3-(4-fluorophenyl)-3-oxopropionate (71.2 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13]O)[CH2:8]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][N:40]3[C:39](=[O:41])[C:38]4=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]4[C:36]3=[O:46])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: OCC1CCCN(Cc2ccc(Cl)cc2)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC1CCCN(Cc2ccc(Cl)cc2)C1
Reaction time: 1.5 h
Yield: 150.1 %

Procedure:
To a solution of 1-(p-chlorobenzyl)-3-hydroxymethyl piperidine (4.0 g, 19 mmol) in THF (40 ml) were added successively triphenylphosphine (5.60 g, 21.3 mmol), phthalimide (3.14 g, 21.4 mmol) and diethyl azodicarboxylate (3.4 ml, 21 mmol) under ice-cooling and the mixture was stirred for 1.5 hours. The solvent was distilled off from the reaction mixture under reduced pressure to give 10.52 g of crude 1-(p-chlorobenzyl)-3-phthalimidomethylpiperidine. This compound was used for the subsequent reaction without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[C:9]([CH3:11])=[CH2:10])=[CH:4][CH:3]=1.[CH2:13](Cl)[CH:14]=[CH2:15].P(=O)(O)(O)O>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(OC)(C)C>[CH2:15]([O:12][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:9]([CH3:11])=[CH2:10])[CH:14]=[CH2:13]
Reactant: C=CCCl
Reactant: C=C(C)C(O)c1ccc(C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P(O)(O)O
Agent: [I-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: C=CCOC(C(=C)C)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 80.2 %

Procedure:
Solid sodium tert-butylate (66.65 g, 0.589 mol) was dissolved under nitrogen in dry THF (350 ml) and 1-(4-methylphenyl)-2-methyl-2-propen-1-ol (41.16 g, 0.239 mol) in dry THF (25 ml) was added in 15 minutes without external cooling. The reaction was further stirred at room temperature for 50 minutes. Tetra butyl ammonium iodide (5.04 g, 0.014 mol) was added followed by allyl chloride (40 g, 0.518 mol) in 25 minutes (exothermic to 47° C.). The reaction was stirred for 24 hours, before adding more tetra butyl ammonium iodide (2.30 g, 0.006 mol) and allyl chloride (9.30 g, 0.120 mol). After stirring for 24 hours at room temperature, the reaction was poured onto ice, diluted with MTBE and acidified with aqueous phosphoric acid. The organic phase was washed with brine, saturated aqueous sodium bicarbonate and brine and dried over solid anhydrous sodium sulfate. The solid was filtered off, rinsed with MTBE and solvents were removed under vacuum. The product was purified by distillation through a 35-cm Fisher column. 38.78 g of the desired allyl ether were obtained (yield=80%). B.P.=79° C./1.6 mbar
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]([N:5]2[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=3[N:8]3[C:9](=[O:12])[N:10]([CH3:11])[C:2]([CH3:17])([CH3:1])[N:3]=[C:4]23)=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Product: CN1C(=O)N2C(=NC1(C)C)N(C(=O)Nc1ccc(Cl)c(Cl)c1)c1ccccc12

Procedure:
The procedure of Example 10 was employed to prepare the title compound from 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one and 3,4-dichlorophenyl isocyanate. The confirmatory elemental analysis for the product, mp 198°-200° C., is shown in Table III.
Reaction SMILES: [OH:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1.[CH3:21][S:22]([CH2:25][C:26]([NH2:34])([CH3:33])[C:27]1[N:31]=[C:30]([CH3:32])[O:29][N:28]=1)(=[O:24])=[O:23]>>[OH:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([NH:34][C:26]([C:27]3[N:31]=[C:30]([CH3:32])[O:29][N:28]=3)([CH3:33])[CH2:25][S:22]([CH3:21])(=[O:24])=[O:23])=[O:14])=[N:10][CH:11]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2(O)CCC2)cn1
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OCC(F)(F)F)c(C3(O)CCC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(1-hydroxycyclobutyl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (Example 129b) and 2-Methanesulfonyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (example 109d) as starting materials and isolated (25 mg, 37%); MS (ESI, m/z): 493.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CC2
Reactant: CS(=O)(=O)Cl
Product: COc1cccc2c1C(NC1=Nc3ccc(NS(C)(=O)=O)cc3CO1)CC2
Yield: 43.4 %

Procedure:
Prepared from rac-N2-(7-methoxy-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 10) (155 mg, 0.50 mmol, HPLC 0.776 min) and methanesulfonyl chloride (43 ul, 0.55 mmol) according to the procedure described for Example 27. Obtained the title compound as a light brown solid (84 mg, 43%, HPLC 1.178 min), MS (ISP) m/e=388.3 [(M+H)+].
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][O:8][N:9]([C:18](=[O:28])[CH:19]=[C:20]1[C:24](=[O:25])[O:23][C:22]([CH3:27])([CH3:26])[O:21]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:26][C:22]1([CH3:27])[O:21][C:20](=[CH:19][C:18]([N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[O:8][CH2:7][C:6]([OH:29])=[O:5])=[O:28])[C:24](=[O:25])[O:23]1
Reactant: CC(C)(C)OC(=O)CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)OC(=O)C(=CC(=O)N(Cc2ccc(F)cc2)OCC(=O)O)O1
Reaction time: 2 h
Yield: 100.2 %

Procedure:
A solution [[2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetyl]-(4-fluorobenzyl)-aminooxy]-acetic acid tert-butyl ester (0.60 g, 1.46 mmol) in dichloromethane (15 ml) was treated at 22° C. with trifluoroacetic acid (4 ml) and the resulting mixture was stirred for 2h. Evaporation of the solvent in vacuo gave 0.517 g (100% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.79 (6H, s, CH3), 4.41 (2H, s, CH2), 4.88 (2H, s, CH2), 6.4 (1H, broad, CH), 7.09 (2H, m, aromatics), 7.35 (2H, m, aromatics). HRMS (ES+) calculated for C16H17FNO7[M+H]+: 354.098905. Found: 354.098878.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20]C(=O)C)=[CH:16][CH:15]=1.C[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1
Reactant: CC(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N)cc2)C1

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of N-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)acetamide (2 g, 5.73 mmol, 1.00 equiv) in ethanol (20 mL). This was followed by the addition of sodium methanolate (5 g, 92.59 mmol, 16.16 equiv) in several batches, while the temperature was maintained at reflux. The resulting solution was heated to reflux overnight. The reaction was then quenched by the addition of 50 mL of water/ice. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. This resulted in 1.5 g (85%) of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenamine as yellow oil. 1H-NMR (300 MHz, DMSO, ppm): δ 7.42-7.42 (1H, d, J=1.5 Hz), 6.83-6.86 (2H, d, J=8.1 Hz), 6.78-6.78 (1H, d, J=1.2 Hz), 6.48-6.51 (2H, d, J=8.4 Hz), 4.98 (2H, s), 4.02-4.06 (1H, m), 3.62-3.67 (1H, d, J=16.2 Hz), 3.43-3.48 (1H, d, J=15.9 Hz), 2.80-2.86 (1H, m), 2.37 (3H, s). MS (ES, m/z): 307 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([O:15][CH3:16])=[O:14])[C:9]([OH:11])=[O:10].[CH2:17](NC(C1C=CC=CC=1)C(O)=O)[CH3:18]>>[CH2:17]([N:12]([CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)[C:9]([OH:11])=[O:10])[C:13]([O:15][CH3:16])=[O:14])[CH3:18]
Reactant: CCNC(C(=O)O)c1ccccc1
Reactant: COC(=O)NC(C(=O)O)c1ccccc1F
Product: CCN(C(=O)OC)C(C(=O)O)c1ccccc1

Procedure:
(Ethyl-methoxycarbonyl-amino)-phenyl-acetic acid was prepared using the procedure used to prepare (2-Fluoro-phenyl)-methoxycarbonylamino-acetic acid using Ethylamino-phenyl-acetic acid. LCMS-ESI+: calc'd for C12H15NO4: 237.10 (M+); Found: 238.03 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:36])[C@@H:5]([O:33][CH2:34][CH3:35])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)C.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:26]([O:25][C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:33][CH2:34][CH3:35])[C:4]([OH:36])=[O:3])=[CH:12][CH:11]=2)=[CH:17][CH:18]=1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NC(=O)OCc3ccccc3)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NC(=O)OCc3ccccc3)cc2)cc1)C(=O)O
Yield: 94.4 %

Procedure:
3-[4-{2-(4-[Benzyloxycarbonylamino]phenyl)ethoxy}phenyl]-(S)-2-ethoxypropanoic acid ethyl ester (described in Example 52) (0.16 g; 0.32 mmole) was dissolved in tetrahydrofuran and lithium hydroxide (9 mg; 0.38 mmole) dissolved in water (1 ml) was added. The resulting mixture was stirred over night. Hydrochloric acid (1M; 1 ml) was added. Tetrahydrofuran was evaporated and the remaining water residue was extracted three times with ethyl acetate. The organic phase was dried with magnesium sulfate and evaporated to give 0.14 g (92.8% yield) of 3-[4-{2-(4-[benzyloxycarbonylamino]-phenyl)ethoxy}phenyl]-(S)-2-ethoxypropanoic acid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31](O)[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:37]2)=[CH:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31]([O:9][C:8](=[O:10])[CH:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=2)[CH2:11][CH3:12])[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH2:37]2)=[CH:24]1)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: CCC(Oc1ccc(F)cc1)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCC(Oc1ccc(F)cc1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 98 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 0.72 g of (2RS)-2-(4-fluorophenoxy)butyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.30 g of the title compound as a colorless foam.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].Cl.[N:7]1([CH2:12][CH:13]([N:15]2[C:28]3[CH:27]=[C:26]([C:29]([NH2:31])=[NH:30])[CH:25]=[CH:24][C:23]=3[S:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH3:14])[CH2:11][CH2:10][CH2:9][CH2:8]1>C(O)C.ClCCCl>[CH3:4][C:3]1[N:30]=[C:29]([C:26]2[CH:25]=[CH:24][C:23]3[S:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH:13]([CH3:14])[CH2:12][N:7]4[CH2:11][CH2:10][CH2:9][CH2:8]4)[C:28]=3[CH:27]=2)[NH:31][CH:2]=1
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=N)N)cc21
Reactant: CC(=O)CCl
Agent: Cl
Solvent: CCO
Solvent: ClCCCl
Product: Cc1c[nH]c(-c2ccc3c(c2)N(C(C)CN2CCCC2)c2ccccc2S3)n1

Procedure:
Chloroacetone (0.44 cc) and 4 A molecular sieve (1 g) are added to a solution of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamidine hydrochloride (1.76 g) in dry ethanol (17 cc). The suspension is maintained under reflux for 20 hours. After cooling, the suspension is filtered and concentrated to dryness at 40° C. under reduced pressure (30 mm Hg; 4 kPa) to give a residue which is diluted in 1,2-dichloroethane (200 cc). The organic phase is washed with distilled water (3×100 cc) and then with saturated sodium chloride solution (100 cc), dried over magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (30 mm Hg; 4 kPa) to give a residue which is purified by chromatography on a column (height: 15 cm; diameter: 2.4 cm) of silica (0.04-0.06 mm), eluting with a 90:10 (by volume) mixture (800 cc) of 1,2-dichloroethane and methanol and collecting 50-cc fractions. The first 300 cc of eluate are discarded and fractions 4 to 10 are concentrated to dryness at 40° C. under reduced pressure (30 mm Hg; 4 kPa) to give 2-(4-methyl-2-imidazolyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]phenothiazine(0.33g) in the form of a golden yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH3:11])=[N:6][CH:5]=1.CO.[OH-].[Na+]>O>[F:10][C:8]1[C:7]([CH3:11])=[N:6][CH:5]=[C:4]([CH:9]=1)[C:3]([OH:12])=[O:2]
Reactant: COC(=O)c1cnc(C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ncc(C(=O)O)cc1F
Temperature: 50 °C
Yield: 88.4 %

Procedure:
To a suspension of 5-fluoro-6-methyl-nicotinic acid methyl ester (0.21 g, 1.24 mmol) in a 1:1 mixture of MeOH:water (20 mL) is added sodium hydroxide as a 10% aqueous solution (1.0 mL, 2.5 mmol). The mixture is heated to 50° C. for 1 h then cooled to room temperature and concentrated under reduced pressure to remove volatile organics. The pH of the resulting solution is adjusted to slightly acidic (approximately pH 5) by the addition of a 2N solution of HCl. The mixture is extracted with EtOAc and the combined organic phase is dried over anhydrous sodium sulfate and concentrated to provide 0.170 g of 5-fluoro-6-methyl-nicotinic acid as a solid.