Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(O)C.C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[O:31]=[C:32]([N:46]1[CH2:51][CH2:50][N:49]2[C:52]([C:55]([F:58])([F:57])[F:56])=[N:53][N:54]=[C:48]2[CH2:47]1)[CH2:33][CH:34]([NH2:45])[CH2:35][C:36]1[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=1[F:44]>CO>[O:31]=[C:32]([N:46]1[CH2:51][CH2:50][N:49]2[C:52]([C:55]([F:58])([F:57])[F:56])=[N:53][N:54]=[C:48]2[CH2:47]1)[CH2:33][C@@H:34]([NH2:45])[CH2:35][C:36]1[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=1[F:44]
Reactant: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: CO
Solvent: CC(C)O
Product: N[C@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 62.5 °C
Reaction time: 1 h

Procedure:
In a 100 mL three neck flask IPA (25 mL) and Dibenzoyl-D-tartaric acid (8.8 g) were taken. It was heated to 60-65° C. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (10 g, purity-91.8%) dissolved in methanol (30 mL) was added slowly into the reaction mixture at 60-65° C. It was stirred for 1 h at 60-65° C. Solid salt was precipitated. It was gradually cooled to room temperature and stirred for 3 h. The salt was filtered and washed with a mixture of IPA: MeOH (2:1). An enantiomerically enriched desired Dibenzoyl-D-tartaric acid salt of mixture of (2R) and (2S)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine was obtained (Wt.-7.2 g, % Y-38.4%, Purity by HPLC-98.2%, % Chiral purity by HPLC of S-isomer 71.7%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].B(O)O>O1CCCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cnc(Cl)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 13.7 %

Procedure:
A mixture of 5.0 g 2,4-dichloro-5-fluoropyrimidine, 4.683 g p-chlorophenylboronic acid, 1.730 g tetrakistriphenylphosphinpalladium and 8.278 g potassium carbonate in 125 mL tetrahydrofuran and 125 mL water was heated to reflux for 3 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The phases were separated and the organic phase was washed with brine dried over sodium sulfate and evaporated. The solid residue was triturated in ca 60 mL methanol for 30 min. The solids were collected by filtration to yield 5.2 g of an off white solid (contains some boronic acid which gives a start spot). The mother liquor was evaporated and the residue was purified by chromatography on silica gel with heptane:ethyl acetate=8:2 to 1:1 to yield 1.0 g of the product as white solid. Both crops were combined and dissolved in ca 50 mL dichloromethane and filtered over ca 50 g silica gel with dichloromethane to remove a polar start spot. The filtrate was concentrated under aspirator vacuum whereby precipitation occurred. The solid was collected by filtration to yield 5.76 g of the title compound as white crystals, MS 230.1 and 228.1 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([C:22](O)=[O:23])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].B>C1COCC1>[OH:23][CH2:22][C:17]12[CH2:18][CH2:19][C:14]([C:7]3[NH:6][C:5]4[C:4](=[O:25])[N:3]([CH2:26][CH2:27][CH3:28])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=4[N:8]=3)([CH2:21][CH2:20]1)[CH2:15][CH2:16]2
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Agent: B
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCC(CO)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 17 h

Procedure:
4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylic acid, IX, Example 85b, 0.82 kg) and tetrahydrofuran (9.02 l) are mixed under nitrogen and borane.tetrahydrofuran complex (1 M) in THF (4.18 l) is added at such a rate as to maintain the internal temperature between 10 to 20°. The reaction mixture is stirred at 10 to 20° for 17 hours until all of the starting material is consumed (TLC; dichloromethane/methanol, 9/1; visualization UV then potassium permanganate). Methanol (3.44 l) is added to the reaction mixture, and the mixture is heated to reflux for 1 hr. The reaction is cooled to between 15 and 40° and the solvent removed by reduced pressure at 40 to 45°. The residue is partitioned between ethyl acetate (13.61 l) and hydrochloric acid (1 M, 2.23 l) and the aqueous layer is removed with any undissolved solid material. The mixture is clarified and the residual organic phase from the filtration of the aqueous layer/solid mixture is combined with the bulk organic layer. Saturated sodium hydrogen carbonate (2.23 l) is added and the layers separated, retaining any solids with the aqueous phase. The aqueous phase/solid mixture is filtered and the residual organic phase from these mother liquors are combined with the bulk organic layer. The combined organic layers are washed with saturated saline (2.23 l), the layers are separated and residual solids are retained with the aqueous phase. The aqueous layer/solid mixture is filtered and organics in the mother liquors from the filtration are combined with the bulk organic layer, dried with magnesium sulfate (0.41 kg), filtered, washed with ethyl acetate (0.82 l) and the solvent removed under reduced pressure at 40 to 45° to give the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[NH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[C@:14]3([CH2:31][CH2:30][C@H:29]4[C@@H:19]([CH2:20][CH:21]=[C:22]5[C@:27]4([CH3:28])[CH2:26][CH2:25][C@H:24]([OH:32])[CH2:23]5)[C@@H:16]3[CH2:17][CH:18]=2)[CH3:15])[N:12]=1.Br.CCO.C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[NH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[C@:14]3([CH2:31][CH2:30][C@H:29]4[C@@H:19]([CH2:20][CH:21]=[C:22]5[C@:27]4([CH3:28])[CH2:26][CH2:25][C:24](=[O:32])[CH2:23]5)[C@@H:16]3[CH2:17][CH:18]=2)[CH3:15])[N:12]=1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3csc(N)n3)=CC[C@@H]12
Agent: Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: C[C@]12CCC(=O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3csc(N)n3)=CC[C@@H]12
Temperature: -55 °C
Reaction time: 0.5 h

Procedure:
Dissolve oxalyl chloride (8.86 mL of a 2.0M solution in methylene chloride, 17.73 mmol) in methylene chloride (65 mL) under an atmosphere of nitrogen and cool the solution to -55° C. Add dimethylsulfoxide (1.47 mL, 20.68 mmol) dropwise and stir for 3 minutes. Then add a solution of (3β)-17-(2-amino-4-thiazolyl)-androsta-5,16-dien-3-ol.HBr.CH3CH2OH (2.94 g, 5.91 mmol) prepared in either example 1a or 1b, dissolved in methylene chloride (20 mL) and dimethylsulfoxide (10 mL) to the reaction slowly over 4 minutes and stir for 30 minutes. Then add triethylamine (5.77 mL, 41.36 mmol) and after 5 minutes of stirring allow the reaction to warm to room temperature. Dilute the reaction with methylene chloride (180 mL) and wash with dilute sodium bicarbonate (4×225 mL) and brine/saturated sodium bicarbonate, 3:1 (200 mL). Dry the organic phase over anhydrous magnesium sulfate, filter and concentrate under vacuum to provide a brown foam. Purify by flash chromatography (ethyl acetate/hexane, silica gel) followed crystallization from ethyl acetate/hexane to provide the title compound (135 mg) as a light orange solid after drying under high vacuum at 56° C. for 2 hours, (Rf =0.38, 50% ethyl acetate/hexane, SiO2); 1H NMR (DMSO-d6) δ 6.85 (broad singlet, 2H), 6.45 (s, 1H), 6.06 (broad triplet, 1H, J=1.9, 3.0 Hz), 5.35-5.31 (m, 1H), 3.43 (dq, 1H, J=2.6, 15.9 Hz), 2.67 (dd, 1H, J=1.8, 16.0 Hz), 1.21 (s, 3H), 0.97 (s, 3H); MS (CI/CH4) m/z (rel. intensity) 369 (MH+, 100), 368 (23); HRMS C22H29N2OS MH+) calcd 369.2001, observed 369.1989.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[C:3](=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:9]=2)[CH:7]=[O:8])[O:2]1.[Mn]([O-])(=O)(=O)=[O:16].[K+].[OH-].[K+]>O>[CH2:1]1[O:11][C:10]2[C:3](=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:9]=2)[C:7]([OH:16])=[O:8])[O:2]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=Cc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2c(cc1[N+](=O)[O-])OCO2
Reaction time: 3 h

Procedure:
To a slurry of 78 g of 4,5-methylenedioxy-2-nitrobenzaldehyde and 1.5 liter of water there was added a solution of 90 g of potassium permanganate in 1.5 liter of water over a period of 45 minutes. The mixture was then stirred at 70°-80° C. for an additional hour and then made alkaline with 400 ml of aqueous 10% potassium hydroxide. The mixture was filtered while hot to remove the precipitate which was washed with 2 portions of hot water. The filtrate was cooled for 16 hours and the solid which formed was separated by filtration to give recovered starting material. The new filtrate was acidified with concentrated hydrochloric acid and allowed to stand for 3 hours. The yellow solid which formed was separated by filtration to give crude product. The filtrate obtained was extracted with 4 portions of ethyl acetate and the combined extracts were dried over sodium sulfate and added to a solution of the previously obtained crude product in ethyl acetate. The ethyl acetate solution was concentrated, the resulting solid was slurried with chloroform, separated by filtration and dried to give 4,5-methylenedioxy-2-nitrobenzoic acid melting at about 160°-163° C.
Reaction SMILES: [Li+].CCC[CH2-].C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH:20](OCC)=[O:21]>C1COCC1>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:20]=[O:21]
Reactant: CCOC=O
Reactant: Clc1cccnc1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1ccncc1Cl
Temperature: -70 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
THF (200 mL) is chilled to −70° C. in a dry flask under N2, and N-butyllithium (24.4 mL, 55.0 mmol) is added drop-wise. The reaction is placed in an ice bath and diisopropyl amine (7.71 mL, 55.0 mmol) in THF (20 mL) is added drop-wise. The solution is again chilled to −70° C., and 3-chloropyridine (4.75 mL, 50.0 mmol) in THF (20 mL) is added drop-wise. The reaction is allowed to stir for 4 h at −70° C. and ethyl formate (4.44 mL, 55.0 mmol) in THF (20 mL) is added. The reaction is stirred for an additional 3 h at −70° C. and quenched with H2O (500 mL). The layers are allowed to separate, and the aqueous layer is extracted with EtOAc (3×250 mL). The combined organic layer is dried over MgSO4, filtered, and concentrated to a dark brown solid. The crude material is chromatographed over 250 g slurry-packed silica, eluting with 50% EtOAc/hexane. The fractions with the desired compound are collected and concentrated to give 3-chloroisonicotinaldehyde (C120) as an off-white solid (55% yield). MS (EI) for C6H4ClNO, m/z: 141 (M)+.
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4]O.C(O)C.Cl.[Na].O.[C:12]([CH2:20][C:21]([O:23]CC)=O)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(O)C.O.O.C(O)C>[C:13]1([C:12]2[O:19][N:4]=[C:21]([OH:23])[CH:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: Oc1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
200 ml of water and 300 ml of ethanol were added to 40 g of sodium hydroxide to dissolve the sodium hydroxide. 69.5 g of hydroxylamine hydrochloride was added thereto, and the pH of the solution was adjusted to 10.0 by adding a 2N sodium hydrochloride ethanol/water (3:2) solution mixture. Under cooling with ice, 192 g of ethyl benzoylacetate and a 2N sodium hydroxide in ethanol/water (3:2) solution mixture were added dropwise simultaneously to the reaction solution so that the pH of the reaction solution was 10±0.3. After completion of the addition and stirring for 3 hours at room temperature, the reaction mixture was poured to a mixture of 500 g of concentrated hydrochloric acid and 500 g of ice, then 2.5 liters of ethanol was added to the reaction mixture and after the reaction mixture was heated for 3 hours under reflux, 2 liters of water was added thereto followed by cooling. The precipitated crystals were filtered, washed with water and dried.
Reaction SMILES: [Na].Br[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].C(OCC)C.[Cl-].[Na+].[C:15]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH2:3]([CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15]([O:23][CH2:24][CH3:25])=[O:22])[CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CCCCBr
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: C=CCCCC(C(=O)OCC)C(=O)OCC
Reaction time: 2 h
Yield: 58.2 %

Procedure:
7.05 g of sodium were dissolved in a solution of 40 g of diethyl malonate in 175 ml of ethanol. The still warm solution (50° C.) was treated dropwise within 15 minutes with 45.6 g of 5-bromo-1-pentene and the mixture was heated to boiling for 2 hours. After cooling the reaction mixture was poured into 500 ml of diethyl ether and 300 ml of semi-saturated sodium chloride solution. The aqueous phase was separated and back-extracted twice with 200 ml of diethyl ether each time. The organic phases were washed twice with 150 ml of semi-saturated sodium chloride solution each time dried over sodium sulphate, filtered and concentrated. Chromatographic separation of the resulting, yellow liquid (55.2 g) on silica gel with hexane/ethyl acetate (vol. 95:5) gave 33.2 g of diethyl (4-pentenyl)malonate as a colourless liquid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.C(O)(=O)C>C(O)C.O.[Zn]>[CH3:14][S:13][C:4]1[N:3]=[CH:2][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnc(SC)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.1 %

Procedure:
Commercially available ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (5.00 g, 21.5 mmol) was dissolved in ethanol (72 mL) and water (14 mL), and zinc powder (14.0 g, 214 mmol) was added to the solution. Then, the mixture was added with acetic acid (2.95 mL, 51.5 mmol) in three portions, followed by stirring at room temperature for 2 hours. After removing the insoluble material by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform, and the organic layer was separated from the aqueous layer. The organic layer was sequentially washed with water and saturated brine, and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:20) to obtain ethyl 2-(methylthio)pyrimidine-5-carboxylate (1.54 g, 36%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>C(N(CC)CC)C.O>[CH2:15]([N:14]([CH2:18][CH2:19][CH3:20])[C:12]([C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:13])[CH2:16][CH3:17]
Reactant: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(C#C[Si](C)(C)C)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A solution of methyl 3-bromo-5-[(dipropylamino)carbonyl]benzoate (25) (200 mg, 0.58 mmol), PdCl2(Ph3P)2 (16 mg, 0.03 mol %) and CuT (6 mg, 0.05 mol %) in triethylamine (1.2 mL) was heated to reflux. (Trimethylsilyl) acetylene (100 μL, 0.7 mmol) was added, and the bright yellow solution quickly turned orange then went brown within a minute. The reaction mixture was stirred for 3 h, cooled to room temperature, diluted with H2O (20 mL), and extracted with CHCl3 (3×15 mL). The combined organics were washed with saturated NaCl (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 3-[(dipropylamino)carbonyl]-5-[(trimethylsilyl)ethynyl]benzoate 26 (185.5 mg): 1H NMR (300 MHz, CDCl3): δ 7.95 (s, 1H), 7.75 (s, 1H), 7.43 (s, 1H), 3.74 (s, 3H), 3.25 (br s, 2H), 2.95 (br s, 2H), 1.49 (br s, 2H), 1.34 (br s, 2H), 0.79 (br s, 3H), 0.56 (br s, 3H), 0.06 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:4]=1[C:5]#[N:6]>CO.[Pd]>[C:5]([C:4]1[C:3]([O:2][CH3:1])=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:11])#[N:6]
Reactant: COc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: CO
Product: COc1cccc(N)c1C#N

Procedure:
One hundred ten grams (0.617 mol) of 2-methoxy-6-nitro-benzonitrile are dissolved in 1 liter of methanol and hydrogenated in the presence of 10% palladium on charcoal at ambient temperature and under a hydrogen pressure of 5 bar over a period of one hour. The catalyst is removed by filtration, the solvent is distilled off, and the residue is recrystallized from ethanol/diisopropyl ether.
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[C@@H:3]([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:4]([NH:6][C@H:7]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1)[CH3:8])=[O:5].[OH-].[Na+]>C1COCC1>[CH3:1][CH:2]([CH3:29])[C@@H:3]([O:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:4]([NH:6][C@H:7]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH3:8])=[O:5]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H](OCCOc2ccccc2)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)[C@@H](OCCOc1ccccc1)C(=O)N[C@@H](C)c1ccc(C(=O)O)cc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a solution of methyl 4-[(1S)-1-[[(2R)-3-methyl-2-(2-phenoxyethoxy)butanoyl]amino]ethyl]benzoate (30 g, 75.1 mmol) in THF (300 mL) is added 2N NaOH (94 mL, 188 mmol). The mixture is stirred at 55° C. overnight, cooled, and concentrated to remove THF. The aqueous residue is diluted with water (200 mL) and extracted with ethyl acetate (2×200 mL). The organic layers are discarded. The aqueous layer is acidified to pH 2 using conc. HCl (25 mL) and extracted with ethyl acetate (2×200 mL). The combined ethyl acetate layers are dried with MgSO4, filtered, and concentrated. The material is slurried with heptane (500 mL) at 60° C. for 2 h, cooled to room temperature, and filtered. The resulting solid is slurried with water (500 mL) at 60° C. for 2 h, cooled to room temperature, filtered, and dried at 40° C. to provide the title compound as a white solid (20 g, 69%). MS (m/z): 386.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH:35]Cl)(=[O:34])=[O:33])=[CH:30][CH:31]=1.CO.C(Cl)(Cl)Cl>C(Cl)Cl.[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][S:11](=[N:35][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=2)(=[O:33])=[O:34])[CH2:12][CH2:13]1
Reactant: CC(=O)NCC1CN(c2ccc(N3CCSCC3)c(F)c2)C(=O)O1
Reactant: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCS(=NS(=O)(=O)c4ccc(C)cc4)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
The N-[[3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (213 mg, 0.603 mmol) was dissolved in dry CH2Cl2 (11.5 mL) and then treated with hexadecyl-tributylphosphonium bromide (138 mg, 0.271 mmol). To this clear, colorless solution, the chloramine-T (165 mg, 0.723 mmol) was added. The resultant cloudy solution was stirred at room temperature for three hours. At this time, the reaction was determined to be complete by TLC (10% MeOH/CHCl3, UV short wave). The reaction mixture was transferred to a separatory funnel and diluted with CH2Cl2 (10 mL). This solution was washed with cold 5% NaOH (20 mL), water (20 mL), and brine (20 mL). The aqueous portions were combined and then back-extracted with more CH2Cl2 (3×20 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resultant material was chromatographed on silica gel (100 g), eluting with a gradient of 0%-6% MeOH in 10% CH3CN/CHCl3 to give 314 mg (99%) of the title compound as a white solid which decomposes at 79° C. and has a HRMS (FAB) calculated for C23H28FN4O5S2 (M+H)+, 523.1485, found 523.1477.
Reaction SMILES: [C:1]([C:5]1[N:6]([CH3:21])[S:7](=[O:20])(=[O:19])[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[S:12][C:9]=2[C:10]=1[OH:11])(OC)=[O:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C1(C)C(C)=CC=CC=1>CO>[OH:11][C:10]1[C:9]2[S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:8]=2[S:7](=[O:19])(=[O:20])[N:6]([CH3:21])[C:5]=1[C:1]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[O:2]
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1ccccn1
Solvent: CO
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccccn2)=C(O)c2sc3ccccc3c2S1(=O)=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
5 g. of 3-carbomethoxy-4-hydroxy-2-methyl-2H-[1]benzothieno[2,3-e]-1,2-thiazine 1,1-dioxide and 3 g. of 2-aminopyridine are treated with 150 ml. of a xylene isomer mixture and heated so that the resulting methanol distils off azeotropically. After 6 hours, the mixture is left to cool to room temperature. The cyrstals obtained are filtered off under suction and washed with a xylene mixture. After recrystallization from dimethylformamide and addition of methanol, there is obtained 4-hydroxy-2-methyl-N-(2-pyridyl)-2H-[1]benzothieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide in the form of yellow crystals of melting point 222°-224° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>C1COCC1.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(I)ccn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-4-iodo-pyridine (10.0 g, 41.8 mmol) was dissolved in 200 mL dry THF and 17.5 mL triethyl amine. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (329 mg, 1.25 mmol) and bis(triphenylphosphine)palladium(II) chloride (1.47 g, 2.09 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper(I) iodide (239 mg, 1.25 mmol) and trimethylsilylacetylen (6.28 g, 6.39 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 500 mL water and extracted three times with ethyl acetate (500 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (cyclohexane/ethyl acetate 80:20). The desired product was obtained as a light brown semi solid (10 g, >100%). This material was used without any further purification for the next step.