Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][CH2:37][OH:38]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][CH2:37][OH:38])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CCO)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 2-bromoethanol (0.40 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.26 g, 23%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].Cl.[CH3:9][O:10][C:11](=[O:18])[CH2:12][CH2:13][C@H:14]([NH2:17])[CH2:15][F:16].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(N(CC)CC)C>[F:1][C:2]([F:7])([F:6])[C:3]([NH:17][C@H:14]([CH2:15][F:16])[CH2:13][CH2:12][C:11]([O:10][CH3:9])=[O:18])=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)CC[C@H](N)CF
Agent: Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@@H](CF)NC(=O)C(F)(F)F
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
0.28 g of triethylamine and 0.96 ml of trifluoroacetic acid were added to 0.28 g of 4, and the mixture was cooled to -10° C. 0.25 ml of trifluoroacetic anhydride was added drop-by-drop. The resulting mixture was allowed to warm to room temperature and stirred for 90 minutes. Volatile materials were evaporated under reduced pressure, and the residue, an oil, was eluted through a column of florisil, using ethyl acetate as eluent. After evaporation of the solvent, the resulting oil was stripped under reduced pressure to give 8, as a brown solid.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][O:6][C:7]([C:9]1[S:13][CH:12]=[N:11][C:10]=1[NH2:14])=[O:8].[Sn](Cl)Cl>Cl>[CH3:5][O:6][C:7]([C:9]1[S:13][CH:12]=[N:11][C:10]=1[NH:14][NH2:1])=[O:8]
Reactant: COC(=O)c1scnc1N
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: COC(=O)c1scnc1NN
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
An aqueous solution (10 ml) of sodium nitrite (7.32 g) was added dropwise to a concentrated hydrochloric acid solution (90 ml) of 4-aminothiazole-5-carboxylic acid methyl ester (15.3 g) at 0-10° C. The mixture was then stirred at 0° C. for 30 minutes. To this mixture there was added dropwise a concentrated hydrochloric acid solution (100 ml) containing tin(II) chloride (73.2 g) at 0-10° C., and the mixture was stirred at the same temperature for 2 hours. The mixture was filtered and the filtrate was carefully added to a suspension of potassium carbonate and Celite in ethyl acetate (3 l) while stirring, with regular addition of potassium carbonate to prevent solution acidity. After adding the filtered substance to this ethyl acetate suspension, it was rendered basic with a 5N aqueous sodium hydroxide solution. The mixture was allowed to stand, and then most of the supernatant (organic layer A) was separated off. The remaining suspension was filtered through Celite and the filtrate was separated into organic layer B and aqueous layer A. Ethyl acetate (500 ml) and anhydrous magnesium sulfate were added to the filtered substance, and the mixture was stirred and then filtered. Aqueous layer A was re-extracted with the resulting filtrate. Washing of the filtered substance and re-extraction of aqueous layer A were repeated 4 times in the same manner. Organic layer A and organic layer B were combined with the obtained organic layer, and the mixture was dried over anhydrous magnesium sulfate. The desiccant was filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-methanol system) to obtain the target compound (11.6 g) as an off-white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCI
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1

Procedure:
Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 10.7 mg, 0.025 mmol) in DMF (1.0 ml) was reacted with K2CO3 (10.0 mg, 0.074 mmol) and 1-iodohexane (18.0 μl, 0.12 mmol) to yield the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[C:7]([NH:14][C@H:15]([C:23](O)=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>>[C:10]([O:9][C:7](=[O:8])[NH:14][C@@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23](=[O:24])[N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C1CSCCN1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCSCC1

Procedure:
Thiomorpholine (38 mmol) and Boc-L-phenylalanine (19 mmol) were coupled according to Procedure A (0-25° C. reaction temperature) with the following work up: the reaction mixture was concentrated, diluted with ethyl acetate, then washed first with 1 N HCl three times, then with 2 N NaOH, the organic layer dried over MgSO4 and concentrated. The resulting foam was used without further purification. Yield 6.3 g, 95%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[CH2:14][CH:15]([CH:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:12])([F:13])[F:11])=[CH:6][C:5]=1[CH2:14][CH:15]([CH:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1
Reactant: COC(=O)C(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1[N+](=O)[O-])c1ccc(OC)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1N)c1ccc(OC)cc1
Yield: 91 %

Procedure:
A suspension of 25.0 g (0.055 mol) of [2-(2-nitro-5-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (see Example 4A) in 200 ml of methanol was treated with a cold suspension of 2.5 g of 5% palladium on charcoal in 50 ml of methanol (under nitrogen) and placed on the Parr apparatus at 58 lbs. of hydrogen. The theoretical amount of hydrogen was consumed in about 30 minutes and this mixture was then heated at 50°-55° C. for one hour to assure that all of the nitro compound had dissolved. The mixture was removed from the Parr and allowed to stand at room temperature overni-ght. The flask was heated to dissolve the crystallized product, and the hot solution was filtered through Celite (under nitrogen) and washed with hot methanol. The colorless filtrate was concentrated on a rotary evaporator to give 22.2 g of a nearly colorless solid. The latter was triturated with 100 ml of hexane and then with 50 ml of hexane. The solvent was decanted and the entrained solvent removed on a rotary evaporator to give 21.3 g of product, melting point 124°-127° C. A sample of this material, after crystallization from methanol, melted at 125°-127° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]=[C:4]([N:17]2[CH2:23][CH:22]3[CH2:24][CH2:25][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[N:3]=1.[C:26](N)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]=[C:4]([N:17]2[CH2:23][CH:22]3[CH2:24][CH2:25][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[N:3]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)CC(C)(C)Nc1nc(Cl)nc(N2CC3CCC(CC3)C2)n1
Product: CC(C)(C)CC(C)(C)Nc1nc(N2CC3CCC(CC3)C2)nc(C(C)(C)C)n1

Procedure:
Eight grams (0.022 mole) of 3-[4-chloro-6-(1,1,3,3-tetramethylbutylamino)-s-triazin-2-yl]-3-azabicyclo[3.2.2]nonane and 23 ml. (0.22 mole) of t-butylamine is placed in a glass liner in a bomb and then heated in an oil bath maintained at 185°-200° C. for about 40 hours. After cooling, the contents of the bomb are rinsed with chloroform and water into a flask and 50 ml. of 10 N NaOH is added. The solution is then evaporated in vacuo and the aqueous solution remaining is extracted with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulfate, filtered through Magnesol® and the Magnesol® washed with chloroform. Removal of solvent in vacuo and recrystallization from acetone gives 5.8 g. of colorless crystals, m.p. 163.5°-167.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH:11]=[C:10](I)[CH:9]1[CH2:8][N:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6]2)=[O:4].[Br:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO.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>[CH3:1][O:2][C:3]([C:5]12[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH:11]=[C:10]([C:32]3[CH:33]=[CH:34][C:29]([Br:28])=[CH:30][CH:31]=3)[CH:9]1[CH2:8][N:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6]2)=[O:4]
Reactant: OB(O)c1ccc(Br)cc1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(c1ccc(Br)cc1)=CCC2c1ccccc1
Yield: 72.5 %

Procedure:
By carrying out the reaction as in Stage C of Example 45, but from 1 g of methyl(3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate in 20 cm3 of toluene, from 120 mg of tetrakis(triphenylphosphine)palladium, from 0.46 g of 4-bromophenylboronic acid in 10 cm3 of methanol and from 15 cm3 of a 2N aqueous sodium carbonate solution at reflux for eighteen hours, 0.77 g (73%) of methyl(3aRS,4SR,7aRS)-2-benzyl-7-(4-bromophenyl)-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate was obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution was carried out with a mixture of cyclohexane and of ethyl acetate (90/10 by volume), in the form of a white foam, the characteristic of which was as follows:
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH:3]=O.Cl[CH:7]([C:13]([CH3:15])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C([O-])(=O)C.[Na+]>C(O)(=O)C>[OH:14][C:13]1[CH:15]=[CH:3][C:2]([CH3:5])=[CH:1][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C=C(C)C=O
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)ccc1O
Temperature: 25 °C
Yield: 70.6 %

Procedure:
A stirred mixture of 2-methylacrolein (22.8 g, 92%, 0.30 mol), ethyl 2-chloroacetoacetate (41.1 g, 95%, 0.25 mol) and anhydrous sodium acetate (24.6 g, 0.30 mol) in acetic acid is heated at reflux temperature under N2 for 16 hr., cooled to room temperature and concentrated in vacuo to give a residue. The residue is partitioned between ethyl acetate and water. The organic phase is concentrated in vacuo to give the title product as an oil, 44.2 g, 71.9% purity (70.6% yield), characterized by NMR analysis).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Cu][C:12]#[N:13].Cl.O>CN(C=O)C>[C:12]([C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8])#[N:13]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(F)c(C=O)c1
Temperature: 190 °C
Reaction time: 5 h

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (1.93 g, 9.51 mmol) in DMF (4 mL) was added copper(I) cyanide (0.98 g, 10.93 mmol). The mixture was heated to 190° C. and stirred for 5 h. The dark brown reaction mixture was poured into a solution containing ferric chloride (3.0 g), conc. HCl (0.93 mL) and water (6 mL) and warmed to 65° C. for 20 min. The mixture was partitioned between toluene (20 mL) and water (20 mL). The organic was washed with diluted HCl (25 mL), water (20 mL), 10% sodium hydroxide (25 mL), dried over magnesium sulfate, and concentrated to provide a solid product:
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31]1[CH:36]=[CH:35][NH:34][C:33](=[O:37])[C:32]=1[C:38]1[NH:42][C:41]2[CH:43]=[C:44](Br)[CH:45]=[C:46]([CH3:47])[C:40]=2[N:39]=1)[CH2:9][O:10]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49]1(B(O)O)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(Cl)Cl.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>[CH2:1]([C@H:8]([NH:30][C:31]1[CH:36]=[CH:35][NH:34][C:33](=[O:37])[C:32]=1[C:38]1[NH:42][C:41]2[CH:43]=[C:44]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:45]=[C:46]([CH3:47])[C:40]=2[N:39]=1)[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Br)cc2[nH]c(-c3c(N[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)Cc4ccccc4)cc[nH]c3=O)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(-c2ccccc2)cc2[nH]c(-c3c(N[C@H](CO)Cc4ccccc4)cc[nH]c3=O)nc12
Yield: 52.4 %

Procedure:
To a solution of (S)-4-(1-benzyl-2-trityloxy-ethylamino)-3-[6-bromo-4-methyl-1H-benzimidazole-2-yl]-1H-pyridin-2-one (50 mg, 0.072 mmol), phenylboronic acid (13 mg, 0.11 mmol), and 2 M K2CO3 (0.108 mL, 0.22 mmol) in THF (5 mL) was added Pd(PPh3)4 (8.3 mg, 0.007 mmol). The mixture was heated to reflux 14 h. Upon cooling, the reaction mixture was diluted with CH2Cl2, washed with saturated NaHCO3, dried over Na2SO4, and concentrated in vacuo. The residue was used for the next step without purification. LCMS (M+H)+ m/z 693 (t=2.82 min.). The crude product was treated with 4 N HCl dioxane solution (5 mL) at room temperature for 6 h. After concentration in vacuo, the residue was purified by prep. HPLC to yield the title compound (17 mg, 34%) as a white solid. 1H NMR (300 MHz, CD3OD) δ7.13–7.67 (13H, m), 6.15 (1H, d, J=7.4 Hz), 3.99–4.11 (1H, m), 3.74–3.77 (2H, m), 3.16 (1H, dd, J=5.4, 13.6 Hz), 2.97 (1H, dd, J=7.8, 13.6 Hz), 2.69 (3H, s). LCMS (M+H)+ m/z 451 (t=2.04 min.).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:22]/[OH:23])/[C:8]([O:10][CH2:11][CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[O:9])[N:6]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:22]/[O:23][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])/[C:8]([O:10][CH2:11][CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:15])=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/O)C(=O)OCCS(=O)(=O)c2ccccc2)cs1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)OCCS(=O)(=O)c1ccccc1)c1csc(N)n1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 61.9 %

Procedure:
In 100 ml of acetone was suspended 5 g (0.0141 mole) of phenylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 11. After a serial addition of 4.0 g (0.0205 mole) of t-butyl bromoacetate, 0.3 ml of water and 7.7 g of anhydrous potassium carbonate, the mixture was stirred at 40° C. for 1.5 hours. After completion of the reaction, the insoluble matter was filtered off and 100 ml of water and 100 ml of ethyl acetate were added to extract the reaction product. The aqueous layer was further extracted with ethyl acetate and the organic layers were combined, washed twice with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and ethyl acetate-isopropyl ether (1:5, v/v) was added to the residue, whereupon white crystals separated out. After cooling, the crystals were collected by filtration to give 4.1 g (yield, 62%) of phenylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:31])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:23][CH:24]([CH2:27][C:28]([OH:30])=O)[CH2:25][N:26]=1)=[CH:18]2)(=[O:11])=[O:10].[NH2:32][C:33]1[NH:37][N:36]=[N:35][N:34]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:31])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:23][CH:24]([CH2:27][C:28]([NH:32][C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[O:30])[CH2:25][N:26]=1)=[CH:18]2)(=[O:11])=[O:10]
Reactant: Nc1nnn[nH]1
Reactant: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(=O)Nc4nnn[nH]4)S3)[nH]c12
Temperature: 25 °C
Yield: 56.6 %

Procedure:
To a mixture of (2-{7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (165 mg), 5-amino-tetrazole (37 mg), 1H-1,2,3-benzotriazol-1-ol (68 mg) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (96 mg) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 2 days. The reaction solution was diluted with ethyl acetate, washed with water, aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound (107 mg, yield 56%) as a pale-yellow amorphous solid. MS:527(MH+).
Reaction SMILES: Br[C:2]1[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C([Mg]Cl)(C)C.[CH2:20]([N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH:29]=[C:30](OS(C(F)(F)F)(=O)=O)[CH2:31]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.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>[CH2:20]([N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH:29]=[C:30]([C:2]1[C:3]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])[CH2:31]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)Oc1c(Br)cccc1C#N
Reactant: O=S(=O)(OC1=CC2CCC(C1)N2Cc1ccccc1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)Oc1c(C#N)cccc1C1=CC2CCC(C1)N2Cc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 104.2 %

Procedure:
To a solution of 3-bromo-2-tert-butoxy-benzonitrile (30.73 g, 0.121 mol) in THF (100 mL) at 0° C. was added 2 M isopropylmagnesium chloride in THF (60 mL) dropwise. The reaction mixture was stirred for 1 h and then tetrakis(triphenylphosphine)palladium(0) (2.33 g, 0.002 mol) was added followed by trifluoro-methanesulfonic acid 8-benzyl-8-aza-bicyclo[3.2.1]oct-2-en-3-yl ester (35.00 g, 0.101 mol) in THF (23 mL). The reaction mixture was refluxed at 80° C. for 1 h, cooled to RT, washed with brine, and extracted with EtOAc (2×). The organic layer was dried over sodium sulfate and the solvent was evaporated to provide the title compound (39.2 g) which was used without further purification. (m/z): [M+H]+ calcd for C25H28N2O 373.22; found 373.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18](O)=[O:19])[CH:5]=[CH:6][C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1.[Si:21]([O:28][CH2:29][C:30]([CH3:44])([CH3:43])[CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][C:33]=1[C:39]([F:42])([F:41])[F:40])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].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>C(Cl)Cl>[Si:21]([O:28][CH2:29][C:30]([CH3:44])([CH3:43])[CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36][C:18](=[O:19])[CH2:17][C:4]2[CH:5]=[CH:6][C:7]([B:8]3[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]3)=[C:2]([F:1])[CH:3]=2)=[CH:34][C:33]=1[C:39]([F:40])([F:41])[F:42])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Cc1ccc(N)cc1C(F)(F)F
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2F)OC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)Cc1ccc(NC(=O)Cc2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
To a solution of 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (5 g, 17.85 mmol) in DCM (100 mL) was added 4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)aniline (7.10 g, 19.64 mmol), DIEA (6.24 mL, 35.7 mmol) and HATU (8.14 g, 21.42 mmol). The solution was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated to give the crude product, which was purified by silica column chromatography (PE/EA=8:1). All fractions found to contain product by TLC (PE/EA=8:1, Rf=0.6) were combined and concentrated to yield a white solid of N-(4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (10 g, 12.83 mmol, 72% yield): 1H NMR (400 MHz, CD3OD) δ 7.83 (d, J=2.0 Hz, 2H), 7.35 (d, J=8.8 Hz, 2H), 6.99 (dd, J=4.8, 10.0 Hz, 2H), 3.63 (s, 2H), 3.26 (s, 2H), 2.69 (s, 2H), 1.11 (s, 12H), 0.86 (s, 9H), 0.73 (s, 6H), 0.00 (s, 6H); ES-LCMS m/z 624.2 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:22][CH2:21][CH2:20][N:5]2[C:6]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:7]=3O[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1.[C:23]1(C)C=CC=CC=1.C(O)C>>[CH3:1][N:2]1[CH2:22][CH2:21][CH2:20][N:5]2[C:6]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:7]=3[CH2:23][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:4]2[CH2:3]1
Reactant: Cc1ccccc1
Reactant: Cc1ccc2c(c1)N1CCCN(C)CC1c1ccccc1O2
Solvent: CCO
Product: Cc1ccc2c(c1)N1CCCN(C)CC1c1ccccc1C2

Procedure:
1,2,3,4,5,15b-hexahydro-2,8-dimethyl-1,4-diazepino[1,2-d]dibenz[b,f](1,4)oxazepine, (oil) Rf in toluene:ethanol (8:2)=0.42 on SiO2 ;