Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([C:18]#[C:19][C:20]([C:22]3[N:23](C(OC(C)(C)C)=O)[CH:24]=[CH:25][CH:26]=3)=O)[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:34]C(OC(C)(C)C)=O)=O)(C)(C)C.[OH:42][CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[F:17][C:13]1[C:12]2[C:11]3[C:16](=[CH:15][CH:14]=1)[NH:8][C:9](=[O:34])[C:10]=3[C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)=[CH:19][C:18]=2[N:46]1[CH2:47][CH2:48][CH:43]([OH:42])[CH2:44][CH2:45]1
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)Oc1cc2c(C#CC(=O)c3cccn3C(=O)OC(C)(C)C)c(F)ccc2n1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1Nc2ccc(F)c3c(N4CCC(O)CC4)cc(-c4ccc[nH]4)c1c23
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 2-tert-butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-oxo-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester (from Example 4 above) (392 mg, 0.69 mmol) and 4-hydroxy-piperidine (Aldrich, 2.12 g, 20.94 mmol) in DMF(6 mL) was treated with NaH. (Aldrich, 250 mg, 10.42 mmol). The mixture was stirred for 30 minutes at room temperature and overnight at 120° C. The reaction mixture was poured in a mixture of ethyl acetate and water. The aqueous layer was extracted a few more times with ethyl acetate and the combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, with 0-50% ethyl acetate in hexanes gradient), and further purified by HPLC (silica gel, 50% ethyl acetate in hexanes) and precipitation out of THF with excess of pentane to give 6-fluoro-5-(4-hydroxy-piperidin-1-yl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 85 mg, 38%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OS(C(F)(F)F)(=O)=O)[CH:10]=2)[C:5](=[O:20])[CH2:4][CH2:3]1.[CH3:22][Si:23](C#C)([CH3:25])[CH3:24].[CH2:28](N(CC)CC)[CH3:29]>C(OCC)C.[Cu]I.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>[CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Si:23]([CH3:25])([CH3:24])[CH3:22])[CH:10]=2)[C:5](=[O:20])[CH:4]([C:28]#[CH:29])[CH2:3]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CCC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Product: C#CC1CC(C)(C)c2cc([Si](C)(C)C)ccc2C1=O
Temperature: 70 °C
Yield: 72 %

Procedure:
A solution of 4,4-dimethyl-6-trifluoromethylsulfonyloxy-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate 11, 0.46 g, 1.43 mmol) in triethyl amine (3 mL) and anhydrous tetrahydrofiran (8 mL) was treated with copper(I)iodide (0.1 g, 0.53 mmol) and sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.85 mL, 6 mmol) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (0.25 g, 0.36 mmol). The resulting reaction mixture was heated at 70° C. for 17 h. It was then cooled to ambient temperature, diluted with diethyl ether and filtered over a bed of celite. The filtrate was evaporated vacuo to an oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title compound (0.28 g, 72%).
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=2)(=O)=O)=CC=1.[C:29](O)(=[O:34])[CH2:30][C:31]([OH:33])=[O:32].[CH2:36]([CH:38]([CH2:42][CH3:43])[C:39]([NH2:41])=[O:40])[CH3:37].CC[O-].[Na+]>C(O)C>[CH2:36]([CH:38]([CH2:42][CH3:43])[C:39]([NH2:41])=[O:40])[CH3:37].[C:29]([O:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:17][CH:18]=1)(=[O:34])[CH2:30][C:31]([O-:33])=[O:32]
Reactant: O=C(O)CC(=O)O
Reactant: CCCCCCCC(=O)c1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: CCC(CC)C(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCC(=O)c1ccc(CCOC(=O)CC(=O)[O-])cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2-(4-Octanoyl phenyl)ethyl p-toluene sulfonate prepared in the step D-1 (500 mg), diethyl acetamide malonate (810 mg) and sodium ethylate (313 mg) were dissolved in anhydrous ethanol (1.5 ml)—anhydrous N,N-dimethylformamide (6 ml) to obtain a solution. The solution was stirred under atmosphere of nitrogen at 60° C. overnight. The reaction solution was poured into ice water, extracted with ether, and washed with saturated saline solution. The extracted solution was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography using hexane-ethyl acetate (1:0→3:1) as an eluate to obtain diethyl acetamide-2-(4-octanoyl phenyl)ethyl malonate (417 mg) in the form of colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:25]1[O:27][CH2:26]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]3[CH2:25][CH2:26][O:27][C:7]3([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1
Reactant: O=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reactant: C1CO1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C1CN2CCOC2(c2ccccc2F)c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 15 g. (51.9 mmole) of 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 150 ml. of dry benzene, 9 g. (67.7 mmole) of aluminum chloride was added and stirring was continued 15 minutes. The reaction mixture was cooled in an ice bath and 8.8 g. (0.2 mole) of ethylene oxide was added dropwise. After 18 hours of stirring at room temperature, the reaction mixture was heated to 40° for 1 hour and then cooled to room temperature and treated with 5 g. (37.6 mmole) of aluminum chloride, followed by 4.4 g. (0.1 mole) of ethylene oxide. The reaction mixture was heated 4 hours at 45°-50° and then evaporated to dryness. ethylene chloride, ice and ammonium hydroxide were added and the solid removed by filtration. The filtrate was separated and the organic phase reduced to dryness in vacuo. The residue was dissolved in dilute hydrochloric acid and the pH of the solution adjusted to 5 with ammonium hydroxide. The acidic solution was washed with ether, made basic and extracted with methylene chloride. The organic phase was washed with brine, dried and evaporated to dryness. Recrystallization from methylene chloride-hexane gave the above-titled product as colorless rods, m.p. 183°-184°.
Reaction SMILES: [CH3:1][C:2]([OH:33])([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>ClCCl>[OH:33][C:2]([CH3:1])([CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:26][CH:27]=3)[CH2:18][CH2:19]2)=[CH:12][CH:13]=1)[CH2:3][CH2:4][O:5][S:47]([C:44]1[CH:45]=[CH:46][C:41]([CH3:51])=[CH:42][CH:43]=1)(=[O:49])=[O:48]
Reactant: CC(O)(CCO)COc1ccc(N2CCC(CCc3ccc(OC(F)(F)F)cc3)CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCC(C)(O)COc2ccc(N3CCC(CCc4ccc(OC(F)(F)F)cc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
3-Methyl-4-(4-{4-[2-(4-trifluoromethoxyphenyl)ethyl]piperidin-1-yl}phenoxy)butane-1,3-diol (1.68 g, 3.6 mmol), dichloromethane (17 ml), triethylamine (1.00 ml, 7.2 mmol) and p-toluenesulfonyl chloride (0.82 g, 4.3 mmol) were mixed and ice-cooled. 1,1,3,3,-Tetramethylpropanediamine (0.12 ml, 0.7 mmol) was added thereto and stirred at room temperature for 1 hour. The reaction mixture was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0, 50:50) to afford the title compound as a colorless powder (2.03 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][CH:13]2[CH2:15][CH2:14]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:16][C:17]1[CH:18]=[C:19]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[CH3:39])=[O:30])[C:20]2[N:24]=[C:23]([N:25]([CH3:27])[CH3:26])[NH:22][C:21]=2[CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][CH:13]2[CH2:15][CH2:14]2)=[CH:7][C:3]=1[C:4]([NH:16][C:17]1[CH:18]=[C:19]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[CH3:39])=[O:30])[C:20]2[N:24]=[C:23]([N:25]([CH3:26])[CH3:27])[NH:22][C:21]=2[CH:28]=1)=[O:6]
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(N)cc2[nH]c(N(C)C)nc12
Reactant: O=C(O)c1cc(C#CC2CC2)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2cc(C#CC3CC3)ccc2Cl)cc2[nH]c(N(C)C)nc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 93.1 %

Procedure:
To a solution of 2-chloro-5-(cyclopropylethynyl)benzoic acid (33 mg, Reference Example 3), 6-amino-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (50 mg) and HATU (72 mg) in DMF (1 mL), was added N,N-diisopropylethylamine (66 μL), and the mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with ethyl acetate, and washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on column chromatography to obtain 6-({[2-chloro-5-(cyclopropylethynyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (74 mg). This was suspended in MeOH (1 mL), 2N hydrogen chloride/EtOH solution (1 Eq) was added to obtain a homogeneous solution, and the solvent was removed under reduced pressure. The residue was triturated in ethyl acetate, and the precipitate was collected by filtration and dried under reduced pressure to obtain the titled compound (58 mg) as pale yellow powder.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:5]=1[O:6][CH2:7]C(O)=O)(=O)[CH3:2].C(OC(=O)C)(=O)C.C(O)(=O)C>O>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][C:5]2[O:6][CH:7]=[C:1]([CH3:2])[C:4]=2[CH:14]=1
Reactant: COc1ccc(OCC(=O)O)c(C(C)=O)c1
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2occ(C)c2c1
Temperature: 110 °C
Reaction time: 5 h
Yield: 81.1 %

Procedure:
A mixture of (2-acetyl-4-methoxyphenoxy)acetic acid (10.0 g) synthesized above, acetic anhydride (18.3 g) and acetic acid (100 mL) was stirred at 110° C. for 5 hr, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate/hexane) to give the title object compound (5.87 g, 81%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][NH:3]1.Cl.O1CCOC[CH2:17]1>CO>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:17])=[O:13])[CH:10]=2)[N:5]=[CH:4][NH:3]1
Reactant: O=C(O)c1ccc2nc[nH]c(=O)c2c1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc2nc[nH]c(=O)c2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a sealed tube was added 4-oxo-3,4-dihydroquinazoline-6-carboxylic acid (0.88 g, 4.6 mmol), methanol (70 mL) and 4.0 M hydrochloric acid in 1,4-dioxane (4.63 mL, 18.5 mmol). The reaction mixture was heated to 90° C. and stirred overnight. The mixture was then cooled to rt, and concentrated to yield methyl 4-oxo-3,4-dihydroquinazoline-6-carboxylate (0.94 g, quant). LC-MS: (FA) ES+ 205; 1H NMR (400 MHz, DMSO) δ 8.65 (d, J=2.1 Hz, 1H), 8.30 (dd, J=8.5, 2.1 Hz, 1H), 8.22 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 3.88 (s, 3H).
Reaction SMILES: C[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:16]C1C=CC(C(O)=O)=C(I)C=1.N1C=CN=N1>>[CH3:16][C:3]1[CH:2]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N:11]2[N:12]=[CH:13][CH:14]=[N:15]2)[CH:4]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: Cc1ccc(C(=O)O)c(I)c1
Agent: c1c[nH]nn1
Product: Cc1ccc(C(=O)O)c(-n2nccn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A11 using 4-methyl-2-iodobenzoic acid and 1,2,3-triazole. ESI-MS (m/z): 204 [M+1]+.
Reaction SMILES: Cl[Si](C)(C)C.Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[N:15]1([CH2:24]NC2CCCCC2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2N=N1>O1CCCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[C:7]([F:14])([F:13])[CH2:24][NH:15][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:18]1)[CH3:12]
Reactant: c1ccc2c(c1)nnn2CNC1CCCCC1
Reactant: CCOC(=O)C(F)(F)Br
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CNC1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 35.1 %

Procedure:
To a mixture of 13.7 g (0.21 g-atom) of zinc powder (325 mesh) and 200 mL of anhydrous tetrahydrofuran was added 20 mL (0.156 mole) of chlorotrimethylsilane in one portion. After stirring for 5 minutes, a solution of 20.4 mL (0.156 mole) of ethyl bromodifluoroacetate in 50 mL of tetrahydrofuran was added dropwise at a rate to maintain the internal temperature below 35 degrees. The mixture was stirred for 30 minutes and then cooled to −10 to 0 degrees. A solution of 40 g (0.174 mole) of benzotriazol-1-ylmethyl-cyclohexylamine in 400 mL of tetrahydrofuran was added dropwise at a rate to maintain the internal temperature at −10 to 0 degrees. After 10 minutes, the reaction mixture was warmed to room temperature, stirred for another 3 hours and then cooled to −10 to 0 degrees. The reaction was quenched by the addition of 200 mL of saturated aqueous sodium bicarbonate, added at a rate to maintain the internal temperature at −10 to 0. The mixture was stirred at room temperature for 10 minutes, then filtered through Celite, washing with 200 mL of ether. The filtrate was extracted twice with 200 mL of ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 200 mL of hexanes-ether (80:20) was added to the residue, the resulting solid was removed by filtration and the filtrated concentrated under reduced pressure. The residue was distilled under vacuum to give 12.9 g of 3-cyclohexylamino-2,2-difluoropropionic acid ethyl ester as a colorless oil. bp. 85-90 degrees at 1 mm Hg.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.[Br:12][C:13]1[C:14]([NH:20][C:21]2[CH:25]=[C:24]([O:26][CH3:27])[NH:23][N:22]=2)=[N:15][C:16](Cl)=[N:17][CH:18]=1.CCN(C(C)C)C(C)C>CCCCO>[Br:12][C:13]1[C:14]([NH:20][C:21]2[CH:25]=[C:24]([O:26][CH3:27])[NH:23][N:22]=2)=[N:15][C:16]([NH:11][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=2)[CH3:10])=[N:17][CH:18]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: COc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2Br)n[nH]1
Temperature: 165 °C
Yield: 33.1 %

Procedure:
To a microwave vial was added (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 155 mg, 0.77 mmol), 5-bromo-2-chloro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 39, 180 mg, 0.59 mmol), and DIEA (181 mg, 1.48 mmol). Anhydrous n-BuOH (2.5 mL) was added, and the vial was heated in microwave oven at 165° C. for 5 hours. The reaction mixture was concentrated. The resulting residue was separated by silica gel column to afford desired product (80 mg, 33%). LC-MS, 409 (M+1). 1H NMR δ 12.03 (s, 1H), 9.38 (s, 1H), 8.82 (s, 2H), 7.97-8.12 (m, 2H), 5.60 (s, 1H), 5.13 (s, 1H), 3.75 (m, 3H), 1.49 (m, 3H).
Reaction SMILES: [O:1]=[S:2](Cl)Cl.[Br:5][C:6]1[CH:7]=[C:8]([C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:15])[CH2:13][OH:14])[CH:9]=[CH:10][CH:11]=1.N1C=CC=CC=1>CC#N>[C:19]([O:18][C:17]([N:16]1[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([Br:5])[CH:7]=2)([CH3:15])[CH2:13][O:14][S:2]1=[O:1])=[O:23])([CH3:20])([CH3:21])[CH3:22]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC(C)(CO)c1cccc(Br)c1
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1S(=O)OCC1(C)c1cccc(Br)c1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of SOCl2 (5.7 mL, 2.5 eq) in dry CH3CN (37 mL) under argon was cooled to −40° C. was added tert-butyl 2-(3-bromophenyl)-1-hydroxypropan-2-ylcarbamate (DC3; R4=Me) (10.3 g, 31 mmol) in dry CH3CN (27 mL) was added dropwise, followed by the addition of dry pyridine (12.4 mL, 160 mmol, 5 eq). The mixture was then allowed to warm to RT in 1 h. The mixture was concentrated to about 30 mL. EtOAc (30 mL) was added and the precipitate was filtered off. The filtrate was concentrated in vacuo to give 10.4 g (89%) of 3-(tert-butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2-oxide as a colorless oil. 1H NMR (CDCl3) 7.64 (t, J=2.0 Hz, 1H), 7.36-7.53 (m, 2H), 7.24 (m, 1H), 4.52 (q, J=9.5 Hz, 2H), 1.86 (s, 3H), 1.42 (br s, 9H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([OH:15])[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5]1.I[CH2:23][CH2:24][CH3:25]>CCOCC>[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([O:15][CH2:23][CH2:24][CH3:25])[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5]1
Reactant: Cn1nc(-c2ccccc2)c(O)c1-c1ccccc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCOc1c(-c2ccccc2)nn(C)c1-c1ccccc1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
Sodium hydride (57%, 0.92 g, 0.022 mole) is added slowly to a suspension of 1-methyl-3,5-diphenyl-4-pyrazolol (5 g, 0.02 mole) in anhydrous ether (100 ml). An off-white precipitate forms. After stirring for 45 minutes, the solid is removed by filtration, added to dry DMF (30 ml) and treated with 1-iodopropane (5 ml. 0.05 mole). The reaction mixture is stirred, heated at 60° C for 14 hours and then poured into ice water (600 ml). After standing for 24 hours in the refrigerator, a tacky yellow solid is formed. Recrystallization from hexane at -20° C affords an off-white solid, melting point 56°-57° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[S:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)(=[O:9])=[O:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C(Cl)Cl.[C:64]([C:68]1[CH:75]=[CH:74][C:71]([CH2:72][NH2:73])=[CH:70][CH:69]=1)([CH3:67])([CH3:66])[CH3:65]>>[C:64]([C:68]1[CH:69]=[CH:70][C:71]([CH2:72][NH:73][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([S:7]([NH:6][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)(=[O:8])=[O:9])=[CH:18][CH:17]=2)=[CH:74][CH:75]=1)([CH3:67])([CH3:65])[CH3:66]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(C(=O)O)cc2)c(OC)c1
Reactant: CC(C)(C)c1ccc(CN)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CNC(=O)c2ccc(S(=O)(=O)Nc3nccs3)cc2)cc1
Reaction time: 8 h
Yield: 45.8 %

Procedure:
4-{[(2,4-Dimethoxybenzyl)(1,3-thiazol-2-yl)amino]sulfonyl}benzoic acid (Preparation 99, 1.30E3 mg, 0.00300 mol), HBTU (1400.8 mg, 0.0031671 mol) and Et3N (1.07 mL, 0.00766 mol) were mixed in methylene chloride (10 mL, 0.2 mol). 4-tert-butylbenzylamine (424.1 mg, 0.002598 mol) was added and the reaction stirred overnight. The reaction was washed with saturated sodium bicarbonate (aq) followed by 0.5N HCl. The organic phase was separated and dried over magnesium sulfate, then treated with activated carbon and filtered through a Celite pad. The solvent was removed in vacuo to give an oily residue. The residue was triturated with DCM and the solid collected by filtration. LCMS analysis of the solid revealed cleavage of the dimethoxybenzyl protection group had occurred. The gray solid was saved. The filtrate was purified by column chromatography, chloroform to 10% MeOH in chloroform gradient eluent. Product fractions were combined and evaporated to an oily residue. The residue was triturated with methylene chloride and beige solid collected. The solid products from steps 4 and 5 were combined and dissolved in 1N NaOH (aq). The solution was washed 3× with diethyl ether. The basic aqueous phase was treated with activated carbon and filtered through a Celite pad. The pale yellow filtrate was slowly acidified to pH 2-3 with 6N HCl (aq). The resultant precipitate was collected by filtration. Vacuum drying yielded 511 mg of product as a white powder.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(C(C)C)C(C)C.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:21]([NH:28][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: NCc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(F)cc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Difluoro-1-nitrobenzene (2.00 g, 12.57 mmol) was dissolved in acetonitrile (20 mL) and DIPEA (2.2 mL, 12.57 mmol) added, followed by the dropwise addition of benzylamine (1.35 g, 12.57 mmol). The reaction mixture was stirred at RT, under an atmosphere of nitrogen overnight. The mixture was concentrated in vacuo to afford the title compound as a yellow oil, which solidified on standing (3.8 g, 100%). The crude material was used without purification in the next step. 1H NMR (CDCl3, 400 MHz): δ 8.55 (1H, s), 8.25 (1H, dd, J=9.46, 6.08 Hz), 7.43-7.29 (5H, m), 6.47 (1H, dd, J=11.35, 2.60 Hz), 6.39 (1H, ddd, J=9.46, 7.28, 2.61 Hz), 4.51 (2H, d, J=5.60 Hz)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([NH:14][C:15]([NH2:17])=N)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[ClH:18].[NH2:19][OH:20].C(=O)([O-])[O-].[Na+].[Na+].C[N:28](C)C=O>>[ClH:18].[ClH:18].[NH2:28][N:17]=[CH:15][NH:14][C:11]1[S:12][CH:13]=[C:9]([C:5]2[CH:4]=[C:3]([C:1](=[NH:2])[NH:19][OH:20])[CH:8]=[CH:7][CH:6]=2)[N:10]=1
Reactant: NO
Reactant: CN(C)C=O
Reactant: N#Cc1cccc(-c2csc(NC(=N)N)n2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N=C(NO)c1cccc(-c2csc(NC=NN)n2)c1

Procedure:
A stirred mixture of 3.4 g. (0.01 mole) of [4-(3-cyanophenyl)-2-thiazolyl]guanidine of Example 3, 1.38 g. (0.02 mole) of hydroxylamine hydrochloride and 4.24 g. (0.04 mole) of sodium carbonate in 60 ml. of dry N,N-dimethylformamide is heated under reflux for 6 hours. The mixture is filtered and the filtrate is diluted with a little water. The precipitate which forms is collected and is recrystallized from N,N-dimethylformamide. This solid is added to 150 ml. of a saturated ethanolic hydrochloric acid solution and the mixture is quickly filtered. The filtrate is cooled in ice to precipitate 0.4 g. of product, m.p. 246° (dec.).