Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]([C:7]1[N:8]([N:12]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[C:36]([Cl:41])[CH:35]=2)[C:13](=[O:32])[CH2:14][C:15]2[NH:20][C:19]3[CH:21]=[CH:22][C:23](CS(C)(=O)=O)=[CH:24][C:18]=3[S:17](=[O:31])(=[O:30])[N:16]=2)[CH:9]=[CH:10][CH:11]=1)=O)C=C.[O-]CC.[Na+].Cl>C(O)C.C(OCC)(=O)C>[Cl:41][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][C:37]=1[F:40])[CH2:33][N:12]1[C:13](=[O:32])[C:14]([C:15]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([NH:16][S:17]([CH3:18])(=[O:31])=[O:30])=[CH:24][C:18]=3[S:17](=[O:31])(=[O:30])[N:16]=2)=[C:5]([OH:4])[C:7]2=[CH:11][CH:10]=[CH:9][N:8]12
Reactant: C=CCOC(=O)c1cccn1N(Cc1ccc(F)c(Cl)c1)C(=O)CC1=NS(=O)(=O)c2cc(CS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccn3n(Cc3ccc(F)c(Cl)c3)c1=O)N2
Temperature: 60 °C
Reaction time: 12 h
Yield: 63.9 %

Procedure:
To a solution of 1-{(3-chloro-4-fluoro-benzyl)-[2-(7-methanesulfonylmethyl-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-1H-pyrrole-2-carboxylic acid allyl ester (Example 171, 304.5 mg, 0.488 mmol) in absolute ethanol (5 mL) was added a 21% solution of sodium ethoxide in ethanol (1.1 mL, 2.95 mmol). After stirring at 60° C. for 12 h, the mixture was diluted with ethyl acetate and acidified with 1.0 M aqueous hydrochloric acid solution upon which a precipitate formed. The solid was collected by vacuum filtration to afford the desired product, N-{3-[1-(3-chloro-4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (88.5 mg, 0.156 mmol, 32% yield) as an off-white solid. The filtrate was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by HPLC purification (Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 25%-100% in 12 min 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water) to afford more of the desired product, N-{3-[1-(3-chloro-4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (18.4 mg, 0.033 mmol, 7% yield; total 39% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 3.06 (3H, s), 5.61 (2H, s), 6.57 (1H, s) 6.98 (1H, s), 7.37 (2H, d, J=7.6 Hz), 7.52 (1H, dd, J1=8.5 Hz, J2=2.4 Hz), 7.59-7.68 (4H, m), 10.17 (1H, s). LC-MS (ESI) calcd for C22H17ClFN5O6S2 565.03. found 566.2 [M+H+].
Reaction SMILES: Cl[C:2]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:9]2[C:8](=[O:18])[N:7]([CH3:19])[C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(OCC)(=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:2]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:9]3[C:8](=[O:18])[N:7]([CH3:19])[C:6](=[O:20])[N:5]([CH3:21])[C:4]=3[N:3]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cn1c(=O)c2c(nc(Cl)n2-c2ccccc2Cl)n(C)c1=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2Cl)n(C)c1=O
Temperature: 150 °C
Reaction time: 4 h
Yield: 68.9 %

Procedure:
8-Chloro-7-(2-chlorophenyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione (142 mg) and piperazine-1-carboxylic acid tert-butyl ester (500 mg) were mixed, and the reaction mixture was stirred at 150° C. for 4 hours, diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 143 mg of the title compound from a fraction eluted with hexane-ethyl acetate (2:3).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH2:12][C:13]([OH:15])=[O:14])[CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(=O)(O)[O-].[Na+].[CH2:27](O)[CH3:28]>Cl>[CH2:27]([O:14][C:13](=[O:15])[CH2:12][CH:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][NH:2][CH2:1]2)=[CH:6][CH:7]=1)[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH3:28]
Reactant: O=C(O)CC(c1ccncc1)c1ccc2c(c1)CNCC2
Reactant: CCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)CC(c1ccncc1)c1ccc2c(c1)CNCC2
Reaction time: 8 h

Procedure:
A solution of 3-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-3-(pyrid-4-yl)-propionic acid, enantiomer A {Reference Example 18(a)} in ethanol (50 mL) was treated with concentrated hydrochloric acid (two drops) and then heated at reflux temperature, under nitrogen, for 8 hours. The pH of the reaction mixture was adjusted to ˜5 by dropwise addition of sodium bicarbonate solution (5%) and this mixture was then evaporated to give the title compound which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:16]2[CH2:18][CH2:17]2)[CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11])=[CH:4][C:3]=1[NH:19][C:20](=[O:35])[C@H:21]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24].O.[OH-].[Li+].Cl>CO.C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:16]2[CH2:18][CH2:17]2)[CH:9]([CH3:15])[C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[NH:19][C:20](=[O:35])[CH:21]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24]
Reactant: CCOC(=O)C(C)C(c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1)C1CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C(=O)O)C(c1ccc(Cl)c(NC(=O)C(c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1)C1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
250 mg (0.47 mmol) of ethyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropyl-2-methylpropanoate (diastereomer mixture; Example 129A) were dissolved in a mixture of 1.0 ml of methanol, 0.5 ml of THF and 0.5 ml of water, and 40 mg (0.94 mmol) of lithium hydroxide monohydrate were added at 0° C. The mixture was stirred initially at 0° C. for 1 h and then at RT overnight. Another 40 mg (0.94 mmol) of lithium hydroxide monohydrate were then added, and the reaction solution was warmed to 50° C. After further stirring at this temperature overnight, 1 ml of methanol was metered into the reaction mixture, and the mixture was stirred at 60° C. for a further 12 h. The solution was then diluted with water and acidified with 1 N hydrochloric acid (pH about 2). The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. This gave 204 mg (86% of theory) of the title compound as a diastereomer mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:11]([OH:26])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[NH:19][C:20](=O)[C:21]([CH3:24])([CH3:23])[CH3:22].O1CCCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C@@H:11]([OH:26])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[NH:19][CH2:20][C:21]([CH3:23])([CH3:22])[CH3:24]
Reactant: COc1cccc([C@@H](O)c2ccc(Cl)cc2NC(=O)C(C)(C)C)c1OC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cccc([C@@H](O)c2ccc(Cl)cc2NCC(C)(C)C)c1OC
Temperature: 10 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
A four-necked flask of 1 L capacity was charged with 60 g (0.159 mol) of (S)-α-(2,3-dimethoxyphenyl)-4-chloro-2-(pivaloylamino)benzyl alcohol, 240 ml of tetrahydrofuran, and 60 ml of methylene chloride and after the atmosphere in the flask was purged with N2 gas, the mixture was stirred with cooling at 10° C. Then, 144 ml of 70% NaAlH2 (OCH2CH2OCH3)2 (Red-Al)/toluene maintained at 10-25° C. was added dropwise under constant stirring. After completion of dropwise addition, the mixture was allowed to stand at room temperature overnight. Next morning, 100 ml of water was added dropwise under ice-cooling and stirring and the mixture was extracted with 923 ml of ethyl acetate. The aqueous layer was further extracted with 923 ml of ethyl acetate. The extracts were combined, and 100 g of anhydrous MgSO4 and 6 g of activated carbon powder for decolorization were added. The mixture was stirred for 10 minutes and, then, filtered. The residue on the filter was washed with 462 ml of ethyl acetate. The filtrate and wash were combined and concentrated under reduced pressure. By this procedure, the objective compound was obtained as a viscous oily residue. Crude yield 62.16 g (optical purity 92.9%, yield 99.6%).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.OP([O-])(O)=O.[K+].OP([O-])([O-])=O.[K+].[K+].[Cl-].[K+].[C:28]([O:34][CH2:35][CH3:36])(=[O:33])[CH2:29][C:30]([CH3:32])=[O:31].COC1C=CC(C=O)=CC=1>C(O)C>[OH:31][C@H:30]([CH3:32])[CH2:29][C:28]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)CC(C)=O
Agent: COc1ccc(C=O)cc1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])(O)O
Solvent: CCO
Product: CCOC(=O)C[C@@H](C)O
Reaction time: 48 h
Yield: 68.9 %

Procedure:
Geotrichum candidum (ATCC 34614) is cultured according to the method of Buisson and Azerad (Tet. Lett. 27, 2631-2634 (1986), herein incorporated by reference) in one liter of a medium of glucose (30 grams), KH2PO4 (1 gram), K2HPO4 (2 grams), corn steep liquor (10 grams) MgSO4.7H2O (0.5 gram), NaNO3 (2 grams), FeSO4.7H2O (0.02 gram), and KCl (0.5 gram) with rotary shaking at 25° C. Two grams of ethyl acetoacetate are dissolved in 2 ml of 95% ethanol, the resulting solution is added to the culture, and shaking is resumed. The reaction is followed by TLC (staining with anisaldehyde) to monitor the consumption of starting material and the production of product alcohol. After approximately 48 hours the reaction is judged complete, and the reaction is terminated by removing from the shaker and adding 20-30 grams of Celite. The resulting suspension is suction filtered through a pad of Celite and the clear yellow filtrate is extracted with ethyl acetate (4×200 ml). The extracts are combined, dried over MgSO4, filtered, and rotary evaporated to leave 1.4 grams of (R)-ethyl 3-hydroxybutyrate as a yellow oil.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:20]=[C:19]2[C:14]([CH:15]=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:18]2)=[N:13]1)(=[O:5])=[O:4])[CH3:2].[Cl:25]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Cl:25][C:20]1[N:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[N:13]=[C:14]2[C:19]=1[CH:18]=[CH:17][C:16]([C:21]([F:23])([F:24])[F:22])=[CH:15]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCS(=O)(=O)c1ccccc1-n1cc2ccc(C(F)(F)F)cc2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccccc1-n1nc2cc(C(F)(F)F)ccc2c1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 100.8 %

Procedure:
A mixture of 226 mg of 2-(2-ethylsulfonylphenyl)-6-trifluoromethyl-2H-indazole, 86 mg of N-chlorosuccinimide and 2 ml of DMF was stirred at room temperature for 10 hours. A 10% aqueous sodium thiosulfate solution was poured to the reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The resulting residue was washed with n-hexane to obtain 250 mg of 3-chloro-2-(2-ethylsulfonylphenyl)-6-trifluoromethyl-2H-indazole (hereinafter, referred to as Compound of Present Invention 3).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].C[O:8][C:9]([C:11]1[CH:16]=[N:15][C:14](Cl)=[CH:13][N:12]=1)=[O:10].CC1(C)C(C)(C)OB([C:26]2[O:30][C:29]([Si](C(C)C)(C(C)C)C(C)C)=[N:28][CH:27]=2)O1>CN(C)C=O>[O:30]1[C:26]([C:14]2[N:15]=[CH:16][C:11]([C:9]([OH:8])=[O:10])=[N:12][CH:13]=2)=[CH:27][N:28]=[CH:29]1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(-c2cnco2)cn1
Temperature: 80 °C

Procedure:
Aqueous Na2CO3 solution (2 M, 14.5 mL) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium dichloromethane complex (950 mg) are added to a mixture of 5-chloropyrazine-2-carboxylic acid methyl ester (2.00 g) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[tris(isopropyl)silyl]-oxazole (4.70 g) in N,N-dimethylformamide (20 mL) under an argon atmosphere. The reaction mixture is stirred over night at 80° C. After cooling to room temperature, the solvents are evaporated, the residue is mixed water and acidified with 4 N hydrochloric acid (12 mL). A precipitate is formed upon addition of ethyl acetate, which is filtered off, washed with ethyl acetate and methanol, and dried. LC (method 7): tR=0.46 min; Mass spectrum (ESI−): m/z=190 [M−H]−.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17](C3C=CC4N(C)N=NC=4C=3)[S:18][C:14]=2[C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:39][C:40]1[N:41]=[C:42]([CH3:58])[N:43]2[CH:48]=[CH:47][C:46](B3OC(C)(C)C(C)(C)O3)=[CH:45][C:44]=12>>[C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:46]3[CH:47]=[CH:48][N:43]4[C:42]([CH3:58])=[N:41][C:40]([CH3:39])=[C:44]4[CH:45]=3)[S:18][C:14]=2[C:13]=1[C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)nnn4C)sc2c1-c1ccc(Cl)cc1
Reactant: Cc1nc(C)n2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccn4c(C)nc(C)c4c3)sc2c1-c1ccc(Cl)cc1

Procedure:
Prepared in manner similar to (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)benzo[d]thiazol-6-yl)acetate, but using 1,3-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine instead of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,2,3]triazole. 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.82 (s, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.51 (dt, J=14.3, 7.8 Hz, 5H), 5.15 (s, 1H), 4.21 (dd, J=5.9, 3.5 Hz, 2H), 2.67 (s, 3H), 2.59 (s, 3H), 2.54 (s, 3H), 1.25 (t, J=6.0 Hz, 3H), 0.98 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[C:13]3[S:15][C:16]([NH:18][C:19](=[O:22])[CH2:20]Cl)=[N:17][C:12]3=[CH:11][CH:10]=2)=[CH:6][C:5]([NH:23][C:24](=[O:36])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([C:34]#[N:35])([CH3:33])[CH3:32])[CH:26]=2)=[C:4]([F:37])[CH:3]=1.C(N(CC)CC)C.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[C:13]3[S:15][C:16]([NH:18][C:19](=[O:22])[CH2:20][N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[N:17][C:12]3=[CH:11][CH:10]=2)=[CH:6][C:5]([NH:23][C:24](=[O:36])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([C:34]#[N:35])([CH3:32])[CH3:33])[CH:26]=2)=[C:4]([F:37])[CH:3]=1
Reactant: C1COCCN1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CCl)sc4n3)c(Cl)cc2F)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CN5CCOCC5)sc4n3)c(Cl)cc2F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
N-[4-Chloro-5-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-fluorophenyl]-3-(1-cyano-1-methylethyl)benzamide synthesized above was dissolved in tetrahydrofuran (3.0 mL), triethylamine (85.6 μL, 0.621 mmol) and morpholine(54.3 μL, 0.621 mmol) were added, and the mixture was stirred at 80° C. for 8 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), washed with water (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→85/15), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/hexane to give the title compound (101 mg, 80%) as a colorless amorphous powder.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[S:13][C:12](=[O:14])[N:11]([C@@H:15]3[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:16]3[O:17][C:18](=[O:20])[CH3:19])[C:9]=2[N:10]=1)(=[O:3])[CH3:2].C([O-])(=O)C.[Na+]>[Pd].C(O)C>[C:1]([NH:4][C:5]1[N:6]=[CH:7][C:8]2[S:13][C:12](=[O:14])[N:11]([C@@H:15]3[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:16]3[O:17][C:18](=[O:20])[CH3:19])[C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(Cl)c2sc(=O)n([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1ncc2sc(=O)n([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Reaction time: 48 h
Yield: 90.2 %

Procedure:
10% Palladium on carbon (862 mg) was added to a solution of 81 (2.07 mg, 4.12 mmol), sodium acetate (675 mg, 8.23 mmol) and absolute ethanol (100 mL) under nitrogen. The mixture was stirred under 250-300 psi H2 (g) in a bomb for a period of 48 h. The mixture was filtered through Celite®, washed with ethyl acetate (200 mL), and concentrated to a yellow solid. The mixture was diluted with H2O (200 mL) and extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified via Flash chromatography (SiO2, 10% Acetone-CHCl3) to afford 82 (1.74 g, 90%) as a white powder: 1H NMR (400 MHz, d6-DMSO) δ 10.78 (s, 1H), 8.82 (s, 1H), 6.10 (d, J=4.0 Hz, 1H), 6.04 (dd, J=6.0, 4.0 Hz, 1H), 5.77 (t, J=6.0 Hz, 1H), 4.41 (dd, J=11.6, 3.2 Hz, 1H), 4.30 (m, 1H), 4.23 (dd, J=12.0, 6.8 Hz, 1H), 2.20 (s, 3H), 2.12 (s, 3H), 2.10 (s, 3H), 2.03 (s, 3H); [M+H]+ 469.4.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][NH2:7])=[CH:11][CH:12]=2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 94.8 %

Procedure:
{2-[4-(4-Chloro-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (600 mg, 1.72 mmol, 1 eq) and TFA (658 μl) were dissolved in 50 ml of dry DCM under argon atmosphere. The mixture was stirred at room temperature for 60 hours. The solvent was evaporated, the resulting crude was dissolved in 10 ml of MeOH and was purified using 20 g SCX column. The free base was rinsed from the column using 1 N NH3/ethanol solution. The solvent was evaporated and obtained was 2-[4-(4-chloro-phenoxy)-phenyl]-ethylamine (404 mg, yield=90.8%, purity=96%) in form of yellowish oil. MS: [M+H]+=248.21 1H NMR (300 MHz; CDCl3) δ/ppm 1.22 (s, 2H), 2.71 (t, J=6.62 Hz, 2H), 2.95 (t, J=6.62 Hz, 2H), 6.85-6.96 (m, 4H), 7.16 (d, J=7.60 Hz, 2H), 7.25 (d, J=7.60 Hz, 2H)
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[C:9]([O:20][CH3:21])=[CH:8][N:7]=1)(=[O:3])[CH3:2].[C:22](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:22])[C:9]([O:20][CH3:21])=[CH:8][N:7]=1)(=[O:3])[CH3:2]
Reactant: COc1cnc(COC(C)=O)cc1OS(=O)(=O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1cnc(COC(C)=O)cc1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
To a solution of 0.50 g of (5-methoxy-4-(((trifluoromethyl)sulfonyl)oxy)pyridin-2-yl)methyl acetate in 5 mL of dioxane, 0.63 g of potassium carbonate, 0.21 mL of trimethylboroxin and 0.18 g of tetrakis(triphenylphosphine)palladium(0) were added, and the mixture was stirred at 70 to 90° C. for 3 hours under a nitrogen atmosphere. The mixture was heated under reflux while further stirring for 3 hours, after cooling to room temperature, water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, the organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with hexane:ethyl acetate=80:20 to 50:50 to obtain 0.22 g of (5-methoxy-4-methylpyridin-2-yl)methyl acetate as a yellow oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH:8]=[CH:7]2)([O-])=O>CO.[OH-].[OH-].[Pd+2]>[N:14]1([C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[CH:12][CH:13]=[C:4]([NH2:1])[CH:5]=3)[N:10]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=[N+]([O-])c1ccc2nc(N3CCCCC3)ccc2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc2nc(N3CCCCC3)ccc2c1

Procedure:
The product (204 mg, 0.8 mmol) of Step C and palladium hydroxide on carbon (100 mg) was suspended in methanol. The resulting mixture was degassed then stirred under hydrogen atmosphere (balloon) until all the yellow solids had dissolved. The reaction mixture was filtered through filter aid and the solvent removed under vacuum to afford the product as a brown solid, MS: m/z 228 (MH+), which was used without further purification
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12]([NH2:14])=[S:13]>C(O)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:12]2[S:13][CH:5]=[C:3]([CH2:2][Cl:1])[N:14]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(C(N)=S)cc1OC
Reactant: O=C(CCl)CCl
Solvent: CCO
Product: COc1ccc(-c2nc(CCl)cs2)cc1OC
Yield: 59.1 %

Procedure:
1.5 g of 1,3-dichloroacetone and 2.3 g of 3,4-dimethoxythiobenzamide were suspended in 100 ml of ethanol. The suspension was heated for 3 hours to complete the reaction. The solvent was removed by distillation. The residue was purified by silica gel column chromatography to obtain 1.86 g of 2-(3,4-dimethoxyphenyl)-4-chloromethylthiazole as a colorless viscous oil.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2]>[Cl-].[Zn+2].[Cl-]>[C:1]([O:4][CH2:5][CH2:6][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(=O)OCCCCOC(C)=O
Temperature: 140 °C
Yield: 31 %

Procedure:
A 100-mL flask is charged with 1000 mol. wt. PTMEG (5.0 g), acetic anhydride (32 g), and zinc chloride (1.0 g). The mixture is refluxed for 4 h at 140° C. Tetramethylene glycol diacetate is obtained in 31% yield.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:17])[C:14]([OH:16])=O)=[CH:11][C:5]=2[O:4][CH2:3]1.[C:18]1([CH3:31])[CH:23]=[CH:22][C:21]([O:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:20][CH:19]=1>C(OCC)C>[O:16]=[C:14]([N:28]1[CH2:29][CH2:30][CH:25]([O:24][C:21]2[CH:22]=[CH:23][C:18]([CH3:31])=[CH:19][CH:20]=2)[CH2:26][CH2:27]1)[C:13]([NH:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2](=[O:1])[CH2:3][O:4][C:5]=2[CH:11]=1)=[O:17]
Reactant: Cc1ccc(OC2CCNCC2)cc1
Reactant: O=C1COc2cc(NC(=O)C(=O)O)ccc2N1
Solvent: CCOCC
Product: Cc1ccc(OC2CCN(C(=O)C(=O)Nc3ccc4c(c3)OCC(=O)N4)CC2)cc1

Procedure:
The title compound is prepared from N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-oxalamic acid (Example 53b) and 4-p-tolyloxy-piperidine according to the method described in Example 1c. Melting Point: 226-228° C. (diethylether)