Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:34][C:35]1[C:43]2[C:42]([N:44]3[CH2:49][CH2:48][CH:47]([NH2:50])[CH2:46][CH2:45]3)=[N:41][CH:40]=[N:39][C:38]=2[NH:37][CH:36]=1>C(Cl)Cl>[CH3:34][C:35]1[C:43]2[C:38]([NH:39][CH:40]=[N:41][C:42]=2[N:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[O:9])[CH2:46][CH2:45]2)=[N:37][CH:36]=1
Reactant: O=C(O)c1ccccn1
Reactant: Cc1c[nH]c2ncnc(N3CCC(N)CC3)c12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1cnc2[nH]cnc(N3CCC(NC(=O)c4ccccn4)CC3)c1-2
Reaction time: 0.17 h

Procedure:
To a mixture of 2-pyridine carboxylic acid (41.4 mg, 0.336 mmol), EDC (68.7 mg, 0.359 mmol), HOBt (54.9 mg, 0.359 mmol) and DIPEA (0.098 mL, 0.560 mmol) in DCM (1 mL), prestirred for 10 minutes, was added 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine hydrochloride D11 (60 mg) and the mixture stirred for 18 hours. The mixture was partitioned between DCM (4 mL) and aqueous sodium bicarbonate (4 mL) and the aqueous phase extracted with further DCM (4 mL). The combined organic fractions were concentrated in vacuo and purified by MDAP. The solvent was then removed in vacuo from the product-containing fractions, to afford E21 (34 mg), 1H NMR (d6-DMSO) δ 11.52 (1H, s), 8.69 (1H, d), 8.65 (1H, d), 8.21 (1H, s), 8.06 (1H, d), 8.00 (1H, t), 7.61 (1H, t), 7.06 (1H, s), 4.08 (1H, m), 4.00 (2H, d), 3.05 (2H, t), 2.37 (3H, s), 2.0-1.7 (4H, m), MS(ES+) 337 [M+H]+.
Reaction SMILES: [CH2:1]([Cl:3])[Cl:2].OC1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>N1C=CC=CC=1>[ClH:2].[Cl:3][C:1]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1
Reactant: ClCCl
Reactant: Oc1ncnc2ccccc12
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: c1ccncc1
Product: Cl
Product: Clc1ncnc2ccccc12

Procedure:
The compound of Example 2 was prepared on a larger scale, using a preferred process, as follows: To 54 L of methylene chloride, and 1.8 L of pyridine, 6.5 Kg of 4-hydroxyquinazoline was added, and the mixture was cooled to -5° to 10° C. To this mixture 15.7 Kg of triphenyl phosphite was added. Then 3.67 Kg of chlorine gas was bubbled in over a three hour period while the temperature of the mixture was maintained in the range of 0° to 10° C., to produce 4-chloroquinazoline hydrochloride. After stirring the mixture an additional hour, 105 mL of water was added to quench excess halogenating reagent. Then 9.7 Kg of 4-(t-butyl)benzeneethanol was added over a 15 minute period while the mixture was maintained at 10° to 20° C. The mixture was heated to reflux (40°-45° C.) and held at reflux for three hours. After vacuum distilling the contents of the reaction to minimize volume, 56 L of toluene was added. The contents of the reaction were again vacuum distilled, 56 L of heptane were added, and the mixture was cooled to 30°-35° C. The HCl salt of the desired product was isolated by filtration, and washed with toluene/heptane.
Reaction SMILES: N(C(OC(C)C)=O)=NC([O:5][CH:6]([CH3:8])C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:34]1C=CC=C1CC(O)=O.[CH2:43]([O:45][C:46](=[O:74])[C:47]([CH2:72]O)([CH3:71])[CH2:48][C:49]1[CH:50]=[N:51][C:52]([N:56]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[C:53]([CH3:55])[CH:54]=1)[CH3:44]>C1COCC1>[CH2:43]([O:45][C:46](=[O:74])[C:47]([CH2:72][S:34][C:6](=[O:5])[CH3:8])([CH3:71])[CH2:48][C:49]1[CH:50]=[N:51][C:52]([N:56]([C:64]([O:66][C:67]([CH3:69])([CH3:70])[CH3:68])=[O:65])[C:57]([O:59][C:60]([CH3:61])([CH3:62])[CH3:63])=[O:58])=[C:53]([CH3:55])[CH:54]=1)[CH3:44]
Reactant: CCOC(=O)C(C)(CO)Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: O=C(O)Cc1cccs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(CSC(C)=O)Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1
Reaction time: 0.5 h
Yield: 145.9 %

Procedure:
Diisopropyl azodicarboxylate (755 μL, 3.91 mmol) was added dropwise to a solution of triphenylphosphine (1.026 g, 3.91 mmol) in THF (10 mL) at 0° C. and the reaction was stirred for 30 min. A solution of thiolacetic acid (279 μL, 3.91 mmol) and 3-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-yl)-2-hydroxymethyl-2-methyl-propionic acid ethyl ester (885 mg, 1.96 mmol) in THF (5 mL) was added dropwise during 10 min. The reaction was stirred for 60 min. at 0° C. and then for 16 h at room temperature. Concentration under reduced pressure followed by chromathography (heptane/EtOAc, 10:1→1:3) gave impure 2-acetylsulfanylmethyl-3-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-yl)-2-methyl-propionic acid ethyl ester (1.46 g)
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH:13]2[O:17][CH2:16][CH2:15][O:14]2)[CH:7]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:2][C:3]#[N:4])=[C:8]([CH:13]2[O:14][CH2:15][CH2:16][O:17]2)[CH:7]=1
Reactant: N#CCCl
Reactant: Oc1ccc(Cl)cc1C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCOc1ccc(Cl)cc1C1OCCO1
Temperature: 100 °C

Procedure:
At room temperature, 2-chloroacetonitrile (12 g, 0.16 mol) was added into a mixture of 4-chloro-2-[1,3]dioxolan-2-yl-phenol (24.6 g, 0.123 mol) and K2CO3 (34 g, 0.246 mol) in DMF (150 mL). After the reaction mixture was heated at 100° C. for 3 h and cooled to room temperature, water was added. The aqueous phase was extracted with EtOAc twice, washed with saturated K2CO3 solution, water, and dried over anhydrous Na2SO4 to give crude (4-Chloro-2-[1,3]dioxolan-2-yl-phenoxy)-acetonitrile. The crude product was used for next step without further purification.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:22][OH:23])[CH:18]=[C:19]([Br:21])[CH:20]=1.[O-2].[Mg+4].[O-2]>O1CCOCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]=[C:19]([Br:21])[CH:20]=1)[CH:22]=[O:23]
Reactant: OCc1cc(Br)cc(OCCCCCCCCC2OCCO2)c1
Agent: [Mg+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: O=Cc1cc(Br)cc(OCCCCCCCCC2OCCO2)c1
Temperature: 100 °C
Yield: 74.4 %

Procedure:
To a stirred solution of (3-((8-(1,3-dioxolan-2-yl)octyl)oxy)-5-bromophenyl)methanol (1.69 g, 4.36 mmol) in 1,4-dioxane (25 mL), was added magnesium (IV) oxide (1.90 g, 21.9 mmol). The reaction mixture was heated to 100° C. for 16 hours. The suspension was filtered, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to afford the title compound (1.25 g, 74%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([I:9])=[C:6]([OH:8])[CH:7]=1.Br[CH2:11][C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+].[ClH:22]>C(#N)C>[Cl:22][C:3]1[CH:2]=[CH:7][C:6]([O:8][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:5]([I:9])[CH:4]=1
Reactant: Oc1cc(Cl)ccc1I
Reactant: COC(=O)CBr
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1ccc(Cl)cc1I

Procedure:
A mixture of 5-chloro-2-iodophenol (4.95 g), methyl bromoacetate (1.85 ml) and potassium carbonate (2.79 g) in acetonitrile (20 ml) was heated under reflux for 2 h. Aq HCl was added and the mixture was extracted with ether (three times). The organic extracts were dried (MgSO4), evaporated and purified by chromatography (silica, petrol ether as eluent) to give the sub-title compound (5.75 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.C=O.[C:35]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:18][CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][N:10]([CH3:35])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2(CCCN3CCN(c4ccccc4)CC3)CNCc3ccccc32)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN1Cc2ccccc2C(CCCN2CCN(c3ccccc3)CC2)(c2ccc(Cl)cc2)C1
Product: Cl

Procedure:
To a solution of 4-(p-chlorophenyl)-4-[3-(4-phenylpiperazin-1-yl)propyl]-1,2,3,4-tetrahydroisoquinoline (0.7 g) in acetonitrile (15 ml) was added formalin (0.64 ml). Then, sodium cyanoborohydride (0.16 g) was added portionwise with stirring. The mixture was stirred for 15 minutes, at the end of which time acetic acid was added dropwise until the solution became neutral. The mixture was further stirred for 2 hours and the reaction mixture was extracted with ethyl acetate-1N aqueous sodium hydroxide solution. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by silica gel column chromatography and treated with hydrochloric acid to provde the title compound (0.6 g) as colorless powder.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1(C)C(CO)=CC=CC=1>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1
Reactant: Brc1cn(-c2ccccc2)cn1
Reactant: OB(O)c1ccco1
Agent: Cc1ccccc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(-n2cnc(-c3ccco3)c2)cc1
Temperature: 80 °C
Yield: 21.1 %

Procedure:
4-Bromo-1-phenyl-1H-imidazole (200 mg, 0.9 mmol), furan-2-ylboronic acid (342 mg, 3 mmol), PEPPSI-iPr (18 mg, 0.026 mmol), and K2CO3 (640 mg, 4.64 mmol) were then combined in toluene-methanol (1:1) (4 ml). The reaction mixture was heated under microwave at 80° C. for 20 minutes. It was then filtered and washed with toluene-MeOH (5 ml), and the filtrate was concentrated to yield a crude mixture. The crude mixture was then column purified using 15-20% ethyl acetate/hexanes to afford the desired 4-(furan-2-yl)-1-phenyl-1H-imidazole (50 mg, 0.19 mmol, yield 21.4%) as a brown sticky liquid with an HPLC purity of 95.5%. LC-MS [M+H] 211 (C13H10N2O+H expected 211.08). The 1H-NMR spectra was in accordance with the chemical structure.
Reaction SMILES: [C:1]([N:8]([CH2:10][C:11]([OH:13])=O)[CH3:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:47][C:48]([F:57])([F:56])[C:49]1[CH:50]=[C:51]([CH:53]=[CH:54][CH:55]=1)[NH2:52]>CCOC(C)=O.CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[N:8]([CH3:9])[CH2:10][C:11](=[O:13])[NH:52][C:51]1[CH:53]=[CH:54][CH:55]=[C:49]([C:48]([F:47])([F:56])[F:57])[CH:50]=1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CC(=O)Nc1cccc(C(F)(F)F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a 25 mL round bottomed flask was added Boc-sarcosine (378 mg, 2.0 mmol, 1.0 eq.), DMF (10.0 mL), DIEA (0.35 mL, 2.0 mmol, 2.0 eq.), HATU (836 mg, 2.2 mmol, 2.2 eq.) and 3-trifluoromethylaniline (0.4 mL, 3.0 mmol, 1.5 eq.). The reaction was allowed to stir at RT overnight before quenching with H2O (20 mL) and EtOAc (100 mL). The organic layer was then washed 2× with 10% LiCl, washed with brine, dried with Na2SO4, and concentrated to give an oil. Further drying on high vacuum then gave a solid. Column chromatography on silica gel with 60:40 EtOAc:Hex gave methyl-[(3-trifluoromethyl-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (431 mg, 64%). LC/MSD (HP Series 1100 MSD): Expected MW: 332, Observed M−H: 331, Retention time: 1.6 min. 1H-NMR (d6-DMSO): 10.35 (d, 1H), 8.10 (d, 1H), 7.75 (dd, 1H), 7.55 (t, 1H), 7.40 (d, 1H), 4.00 (d, 2H), 2.88 (d, 3H), 1.40 (d, 9H) ppm.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][NH:5]1)[C:2]#[CH:3].[Cl-:19].[Mn+2:20].[Cl-:21]>CO.C(O)C>[Cl:19][C:4]1([CH2:1][C:2]#[CH:3])[CH2:18][NH:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6][N:5]1[Cl:21].[Mn+2:20]
Reactant: C#CCC1CNCCNCCNCCNCCN1
Reactant: [Cl-]
Agent: [Mn+2]
Solvent: CCO
Solvent: CO
Product: C#CCC1(Cl)CNCCNCCNCCNCCN1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 2-propargyl-1,4,7,10,13-pentaazacyclopentadecane prepared as in Example 29G (310 mg, 1.22 mmol) and anhydrous manganese(II) chloride (154 mg, 1.22 mol) in methanol (50 ml) were refluxed under a dry nitrogen atmosphere for 2 h and then stirred overnight at room temperature. The solution was taken to dryness, redissolved in absolute ethanol (15 ml) and filtered through celite. Concentration and recrystallization from ethanol-ether afforded 370 mg (80% yield) of white microcrystalline product: FAB mass spectrum (NBA) m/z (relative intensity) 378 (M+, 2), 343/345 ((M-Cl)+, 100/30); Anal. calcd. for C13H27Cl2MnN5 : C, 41.14; H, 7.18; N, 18.47. Found: C, 40.49; H, 6.56; N, 18.14.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[CH3:20])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)cc(NCC2CCCC2)c1C
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Cl)cc(N(C)CC2CCCC2)c1C
Temperature: 80 °C
Yield: 96.6 %

Procedure:
To a stirred solution of methyl 5-chloro-3-((cyclopentylmethyl)amino)-2-methylbenzoate (1.0 g, 3.5 mmol) in acetonitrile (10 mL), cesium carbonate (2.3 g, 7.1 mmol) and methyl iodide (5.0 g, 35 mmol) were added. The mixture was heated at 80° C. for 12 h. cooled to room temperature and filtered. The residue was washed with ethyl acetate and the filtrate was concentrated and then purified by column chromatography to afford the title compound (1.0 g, 95%).
Reaction SMILES: O=C1[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])O1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]2[S:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:18]=2)=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1nsc(=O)o1
Product: CCOC(=O)c1nsc(-c2ccc(Cl)cc2)n1
Yield: 61.4 %

Procedure:
A sample of p-chlorobenzonitrile was distilled and then crystallized twice from methylcyclohexane to remove impurities that interfered in the following reaction. A solution of 8.76 g (0.050 mol) of ethyl 2-oxo-1,3,4-oxathiazole-5-carboxylate and 68.8 g (0.50 mol, 10 equiv.) of purified p-chlorobenzonitrile was held at 190° C for 72 hours. The solution, which contained the product in 69% yield, was concentrated under vacuum to 150° C (about 2 torr). The residue was crystallized from heptane (charcoal) to give 8.25 g (61%) of gold crystals, mp 98°-99.5° C. A small sample was crystallized twice from heptane (charcoal) to give a white solid, mp 98°-99.5° C.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.C[O-].[Na+:14].[Na:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>CN(C)C=O>[Na:14][Na:15].[C:17]([CH2:16][C:4]([C:3]1[CH2:7][CH2:8][CH2:9][CH2:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5])(=[O:18])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [Na+]
Reactant: O=C(C[Na])c1ccccc1
Reactant: O=C1OC(=O)C2=C1CCCC2
Agent: C[O-]
Solvent: CN(C)C=O
Product: O=C(O)C1=C(C(=O)CC(=O)c2ccccc2)CCCC1
Product: [Na][Na]
Reaction time: 3 h

Procedure:
To a solution of 30.4 g of 3,4,5,6-tetrahydrophthalic anhydride in 150 ml of dimethylformamide is added 11.0 g of sodium methoxide. After 1/2 hour this mixture is introduced into the sodio-acetophenone solution. The resulting mixture is stirred at 120° for 3 hours; the solid precipitate is filtered off, washed with acetone and ether, and dried to yield the crude disodium salt of 2-benzoylacetyl-1-cyclohexenecarboxylic acid.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([CH2:21]O)[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[NH:28]1[CH2:33][CH2:32]O[CH2:30][CH2:29]1.C(S(C1C=C(C2C=C(CN(C)C)C=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([CH2:21][N:28]3[CH2:33][CH2:32][CH2:30][CH2:29]3)[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(CO)cc3[nH]c4ncc(C)cc4c23)c1
Reactant: C1COCCN1
Agent: CCS(=O)(=O)c1cccc(-c2cc(CN(C)C)cc3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2cc(CN3CCCC3)cc3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was prepared from Compound 133 and morpholine according to the procedure outline for the preparation of Compound 134. 1H NMR (400 MHz, CD3OD) δ 8.36 (br s, 1H), 8.23 (s, 1H), 8.13 (d, 1H, J=7.6 Hz), 8.04 (d, 1H, J=7.6 Hz), 7.96 (s, 1H), 7.91 (t, 1H, J=7.6 Hz), 7.87 (s, 1H), 7.47 (s, 1H), 4.62 (s, 2H), 3.51-3.60 (m, 2H), 3.20-3.36 (m, 4H), 2.39 (s, 3H), 2.15-2.23 (m, 2H), 1.99-2.07 (m, 2H), 1.29 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C25H27N3O2S, 434; found 434.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].CC(C)([O-:14])C.[K+].[CH3:17][O:18][CH2:19]Cl.O>CN(C)C(=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:17][O:18][CH3:19])=[C:6]([CH:9]=1)[CH:7]([OH:14])[OH:8]
Reactant: CC(C)(C)[O-]
Reactant: COCCl
Reactant: OCc1cc(F)ccc1O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COCOc1ccc(F)cc1C(O)O
Reaction time: 0.17 h
Yield: 69 %

Procedure:
4.71 g of 5-fluoro-2-hydroxybenzyl alcohol [prepared as described in step (a) above] were dissolved in 100 ml of N,N-dimethylacetamide, and then 3.72 g of potassium t-butoxide were added to the resulting solution, whilst ice-cooling. The resulting mixture was then stirred at the same temperature for 10 minutes, and then 2.74 ml of methoxymethyl chloride were added at the same temperature. The mixture was then allowed to stand until the temperature returned to room temperature, after which it was stirred for 1 hour. 60 ml of water and 300 ml of ethyl acetate were then added to the reaction solution. The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The concentrated substance was purified by silica gel column chromatography, using a 3:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 4.25 g (yield 69%) of the title compound as an oily substance.
Reaction SMILES: [CH2:1]([CH:4]1[S:9](=[O:11])(=[O:10])[C:8]([CH3:13])([CH3:12])[C:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6][C@@:5]1([C:23]1[C:24]([F:30])=[N:25][CH:26]=[C:27]([Br:29])[CH:28]=1)[CH3:22])[CH:2]=C.C(=O)(O)[O-:32].[Na+].[BH4-].[Na+]>CO.C(Cl)Cl>[Br:29][C:27]1[CH:28]=[C:23]([C@:5]2([CH3:22])[CH:4]([CH2:1][CH2:2][OH:32])[S:9](=[O:11])(=[O:10])[C:8]([CH3:12])([CH3:13])[C:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[N:6]2)[C:24]([F:30])=[N:25][CH:26]=1
Reactant: C=CCC1[C@@](C)(c2cc(Br)cnc2F)N=C(NC(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Reactant: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(Br)cnc2F)C(CCO)S(=O)(=O)C1(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 91.8 %

Procedure:
To a solution of tert-butyl ((5R)-6-allyl-5-(5-bromo-2-fluoropyridin-3-yl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (0.988 g, 1.96 mmol) in MeOH (5 mL) and DCM (15 mL) at room temperature was added sodium bicarbonate (0.333 g, 3.96 mmol). The reaction mixture was cooled to −78° C. and ozone was bubbled through the solution. After 15 min, the solution turned blue and oxygen was bubbled through the mixture for 5 min. Sodium borohydride (0.154 g, 4.07 mmol) was added and the reaction mixture was removed from the −78° C. bath. The solution was warmed to room temperature, stirred for 1 h, and quenched with saturated NH4Cl, and diluted with EtOAc water. The aqueous phase was extracted with EtOAc (2×). The combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, concentrated. Purification by flash column chromatography on silica gel (40 g, 20% to 60% EtOAc in hexanes) gave tert-butyl ((5R)-5-(5-bromo-2-fluoropyridin-3-yl)-6-(2-hydroxyethyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (0.913 g, 1.80 mmol, 92% yield) as a mixture of isomers that was used in the next step without separation. LC/MS (ESI+) m/z=508 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=C[C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:23])[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=2)=[O:13])=[CH:4][CH:3]=1.[Br:24]C1C=CC(CCNC)=CC=1.N(C1C=C(C=CC=1)C#N)=C=O>>[Br:24][C:3]1[CH:2]=[CH:7][C:8]([CH2:9][CH2:10][N:11]([CH3:23])[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[N:22])[CH:16]=2)=[O:13])=[CH:5][CH:4]=1
Reactant: CN(CCCc1ccc(Br)cc1)C(=O)Nc1cccc(C#N)c1
Reactant: CNCCc1ccc(Br)cc1
Agent: N#Cc1cccc(N=C=O)c1
Product: CN(CCc1ccc(Br)cc1)C(=O)Nc1cccc(C#N)c1
Yield: 81 %

Procedure:
Using a procedure analogous to that used to prepare 22C, 23B (300 mg, 1.4 mmol) was reacted with 3-isocyanatobenzonitrile to yield 23C (406 g, 81%) as a clear oil. MS (ESI) m/z 358.31/360.29 (M+H)+.
Reaction SMILES: [C:1]([NH:6][C:7]([NH2:9])=[S:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].Br[CH2:11][C:12](=O)[C:13]([OH:15])=[O:14].[CH3:17][CH2:18]O>>[CH2:17]([O:15][C:13]([C:12]1[N:9]=[C:7]([NH:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[S:8][CH:11]=1)=[O:14])[CH3:18]
Reactant: CCO
Reactant: O=C(O)C(=O)CBr
Reactant: CC(C)C(=O)NC(N)=S
Product: CCOC(=O)c1csc(NC(=O)C(C)C)n1
Temperature: 25 °C
Yield: 100 %

Procedure:
11A (29.6 g, 0.2 mol) was dissolved in anhydrous EtOH (300 mL). To the solution was added 3-bromo-2-oxo-propionic acid (34 g, 0.17 mol). The mixture was refluxed for 2 hours, then cooled to room temperature, concentrated to dryness, dissolved with ethyl acetate, washed with saturated aqueous of NaHCO3. The organic layer was dried and concentrated to give a crude product 11B (48 g, 100% yield).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([OH:13])=O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1>>[NH:16]1[C:15]([NH:14][C:11]([C:7]2[CH:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:10]=[CH:9][N:8]=2)=[O:13])=[N:19][N:18]=[N:17]1
Reactant: CCCCc1ccnc(C(=O)O)c1
Reactant: Nc1nnn[nH]1
Product: CCCCc1ccnc(C(=O)Nc2nnn[nH]2)c1
Yield: 63 %

Procedure:
0.52 g of 4-n-butyl-2-pyridinecarboxylic acid, 0.48 g of N,N'-carbonyldiimidazole and 0.27 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide, water and ethanol, whereby 0.45 g of N-(5-tetrazolyl)-4-n-butyl-2-pyridinecarboxamide is obtained.