Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(/[CH:6]=[CH:7]/[CH:8]=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O.C1(C)C=CC=CC=1.[NH:29]1[CH:33]=[C:32]([C:34]2[C:35]3[CH:42]=[CH:41][N:40]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:36]=3[N:37]=[CH:38][N:39]=2)[CH:31]=[N:30]1>>[CH:1]1([C@H:6]([N:29]2[CH:33]=[C:32]([C:34]3[C:35]4[CH:42]=[CH:41][N:40]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:36]=4[N:37]=[CH:38][N:39]=3)[CH:31]=[N:30]2)[CH2:7][CH:8]=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C/C=C/C1CCCC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H](CC=O)C4CCCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.8 %

Procedure:
A solution of (2E)-3-cyclopentylacrylaldehyde (28, 327 mg, 2.50 mmol, 5.0 equiv), (2R)-2-bis[3,5-bis(trifluoromethyl)phenyl][(triethylsilyl)oxy]methylpyrrolidine ((R)-35, 32 mg, 0.050 mmol, 0.10 equiv) and 4-nitrobenzoic acid (8.5 mg, 0.050 mmol, 0.10 equiv) in anhydrous toluene (5.0 mL, 47 mmol) was stirred at room temperature for 10 min before 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (17, 158 mg, 0.50 mmol) was added. The resulting reaction mixture was stirred at room temperature for 24 h. When LCMS showed that the reaction was deemed complete, the reaction mixture was concentrated under reduced pressure. The residue was directly purified by Combiflash (SiO2) with 0-70% EtOAc/hexane gradient elution to give (3R)-3-cyclopentyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal ((R)-38, 184.1 mg, 219.8 mg theoretical, 83.8% yield) as a pale yellow viscous oil. For (R)-38: C23H33N5O2Si (MW, 439.63), LCMS (EI) m/e 440 (M++H).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[CH:54]=[C:53]([C:55]2[CH:56]=[C:57]([NH2:61])[CH:58]=[CH:59][CH:60]=2)[CH:52]=[N:51][CH:50]=1>CN(C=O)C>[N:49]1[CH:54]=[C:53]([C:55]2[CH:56]=[C:57]([NH:61][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=[CH:59][CH:60]=2)[CH:52]=[N:51][CH:50]=1
Reactant: Nc1cccc(-c2cncnc2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cncnc2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 8.6 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-pyrimidin-5-yl-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.002 g of product in 9% yield: LCMS (ESI) m/z 360 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[S:12]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13]1.C([O-])(O)=O.[Na+]>COCCOC.O.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>[S:12]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)=[CH:13]1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(O)Cc1ccc(-c2ccsc2)cc1
Yield: 51.3 %

Procedure:
A mixture of 4-bromophenylacetic acid (1.08 g, 5 mmol), 3-thiopheneboronic acid (0.7 g, 5.5 mmol), NaHCO3 (1.68 g, 20 mmol), and dichlorobis(triphenylphosphine)palladium (0.35 g, 0.5 mmol) in DME-water (21 mL-7 mL) was heated at reflux temperature for 2 hours under nitrogen. After cooling, the reaction mixture was partitioned between Et2O (80 mL) and saturated aqueous NaHCO3 (30 mL). The organic layer was washed with saturated aqueous NaHCO3 (30 mL) again. The combined aqueous layer was acidified with 2N HCl solution and the whole extracted with CH2Cl2 (50 mL×3). The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2) eluting with ethyl acetate/hexane (1/1) to give the subtitle compound (0.56 g, 51% yield).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[SH:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].CC1C=CC(S(O[CH2:30][C:31]([F:34])([F:33])[F:32])(=O)=O)=CC=1>O>[F:32][C:31]([F:34])([F:33])[CH2:30][S:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCSCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
1.7 g of sodium hydride was added to 30 ml of dry dimethylformamide, and then 7.5 g of tert-butyl 2-mercaptoethylaminoformate. Upon the end of the addition, the mixture was stirred for 1 h, and then slowly added with 2,2,2-trifluoroethyl (4-methylphenyl)sulfonate. Upon the end of the addition, the mixture was warmed to room temperature, and stirred overnight. The mixture was poured to water, extracted with diethyl ether, washed with 0.5M sodium hydroxide aqueous solution and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, distilled to remove the solvent, and subjected to a column chromatography to obtain 5.4 g of light yellow oily liquid, yield 53.8%.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][O:29][CH:28]([C:32]([OH:34])=O)[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:36]([NH2:38])[CH3:37].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:12][CH2:13][C:14]([F:18])([F:17])[CH2:15][CH2:16]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][O:29][CH:28]([C:32]([NH:38][CH2:36][CH3:37])=[O:34])[CH2:27]3)(=[O:24])=[O:25])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCOC(C(=O)O)C3)ccc2n1CC1CCC(F)(F)CC1
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)C1CN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)CCO1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)morpholine-2-carboxylic acid (500 mg, 1 mmol) (see following steps B and C for preparation) was dissolved in DMF (10 mL). Ethylamine hydrochloride (122 mg, 1.5 mmol) and N,N-diisopropylethylamine (1 mL, 5 mmol) were added and the reaction mixture was cooled down to 0° C. HATU (456 mg, 1.2 mmol) was added portionwise and the reaction was stirred overnight at room temperature. The reaction was concentrated, extracted with EtOAc and washed with sodium bicarbonate, water then brine and dried over anhydrous sodium sulfate. The crude product was purified by LCMS using high pH column 40-70% acetonitrile gradient to give 200 mg (40%) as white solid racemic mixture of the title compound. The two enantiomers were separated on a chiral OD 5 microns column using 20% ethanol/hexane. Example 112 (isomer-1): 1H NMR (400 MHz, METHANOL-D4) δ 1.04 (t, J=7.23 Hz, 3 H), 1.46-1.56 (m, 2 H), 1.57 (s, 9 H), 1.61-1.70 (m, 3 H), 1.70-1.81 (m, 1 H), 1.98-2.08 (m, 2 H), 2.12-2.23 (m, 1 H), 2.39 (m, 1 H), 2.74 (q, J=7.23 Hz, 2 H), 3.17 (dd, J=7.23, 3.91 Hz, 2 H), 3.68 (m, 1 H), 3.87-3.94 (m, 1 H), 4.01 (dd, J=10.45, 2.83 Hz, 2 H), 4.40 (d, J=7.62 Hz, 2 H), 7.64 (dd, J=8.59, 1.56 Hz, 1 H), 7.77 (d, J=8.59 Hz, 1 H), 8.03 (d, J=1.76 Hz, 1 H); MS (APPI) (M+H)+=527.3; Anal. Calc. for C21H29F2N3O3S+4.9C2HO2F3+5.0H2O+2.7 CH3CN: C, 39.47; H, 4.14; N, 6.31. Found: C, 39.48; H, 4.14; N, 6.30.
Reaction SMILES: NCC(N)C.[F:6][C:7]1[CH:8]=[C:9]([CH2:14][CH:15]([NH2:18])[CH2:16][NH2:17])[CH:10]=[C:11]([F:13])[CH:12]=1.[C:19]([NH:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=1)[C:31](O)=O)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[F:6][C:7]1[CH:8]=[C:9]([CH:10]=[C:11]([F:13])[CH:12]=1)[CH2:14][CH:15]1[CH2:16][NH:17][C:31]([C:30]2[CH:34]=[CH:35][N:36]=[C:28]([NH:27][C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:29]=2)=[N:18]1
Reactant: NCC(N)Cc1cc(F)cc(F)c1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Agent: CC(N)CN
Product: O=C(Nc1cc(C2=NC(Cc3cc(F)cc(F)c3)CN2)ccn1)c1ccccc1
Yield: 24 %

Procedure:
Following the procedure as described in Example 9, making variations as required to replace 1,2-diaminopropane with 3-(3,5-difluorophenyl)propane-1,2-diamine to react with 2-benzamidoisonicotinic acid, N-(4-(4-(3,5-difluorobenzyl)-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl)benzamide was obtained in 24% yield: MS (ES+) m/z 393.2 (M+1).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][CH:22]=[N:21][C:20]=2[C:24]#[N:25])=[CH:15][CH:14]=1.[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O>[Cl:28][C:22]1[O:23][C:19]([C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:11])([F:26])[F:27])=[CH:18][CH:17]=2)=[C:20]([C:24]#[N:25])[N:21]=1
Reactant: N#Cc1ncoc1-c1ccc(C(F)(F)F)cc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1nc(Cl)oc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
LiHMDS (1.0 M in THF, 4.5 mL, 4.5 mmol) was added dropwise to a solution of Example 56C (0.980 g, 4.11 mmol) in THF (13 mL) at −78° C. After 30 min solid hexachloroethane (0.974 g, 4.11 mmol) was added in one portion. The reaction was allowed to warm to room temperature while stirring overnight during which a solid formed. The mixture was diluted with hexanes and water, and filtered. The filtrate was diluted with EtOAc, and the phases separated. The organic phase was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was dissolved in toluene, loaded on silica gel, and eluted with 1 column length of hexanes and then 0% to 30% EtOAc:hexanes to afford 0.51 g (46%) of the title compound as a yellow milky oil. 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=8.2, 2H), 7.81 (d, J=8.3, 2H).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[N:13]=[C:12]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:11]=2[N:10]=[C:9]1[CH2:36][CH2:37][CH2:38][CH3:39])(=O)=O.[C:40]1([SH:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:36]([C:9]1[N:8]([CH2:7][CH2:6][S:46][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:20]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[N:13]=[C:12]([N:21]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[C:11]=2[N:10]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCc1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2n1CCOS(C)(=O)=O)CCCC3
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2n1CCSc1ccccc1)CCCC3
Temperature: 80 °C
Yield: 86.1 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, 2-{4[bis(tert-butoxycarbonyl)amino]-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl}ethyl methanesulfonate (0.61 g, 1.08 mmol), benzenethiol (0.21 g, 1.88 mmol), triethylamine (0.25 g, 2.43 mmol) and anhydrous dimethyl formamide (11 mL) under a nitrogen atmosphere. The reaction mixture was heated to 80° C. to give a dark yellow, homogeneous solution that was maintained at 80° C. for 2.5 hours at which time the reaction was judged to be complete. The solution was cooled and then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a yellow oil. The material was purified by chromatography over silica gel (95/5 dichloromethane/methanol) to provide di(tert-butyl) 2-butyl-1-[2-(phenylthio)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-ylimidodicarbonate (0.54 g, 0.93 mmol) as a light yellow oil. MS (CI) for C32H44N4O4S m/z 581 (MH+), 481, 381, 245.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:12]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Yield: 69 %

Procedure:
28 g (0.2 mole) of 3-fluoro-4-nitrophenol was dissolved in 200 mL of acetone. 56 g (0.4 mole) of K2CO3 was added, and the contents heated to 40 C for 10 min. Contents were cooled to 0 C, 25 mL (0.4 mole) of methyl iodide added, and again heated to 40 C for 3 hrs. Reaction cooled to rt, roto-evaporated to approx. 100 mL, and 200 mL of methylene chloride was added. Contents were filtered, and the filtrant was rotary-evaporated to dryness. The crystalline solid was recrystallized from 4:1 EtOH/H2O to give 23.6 g (46%) of desired product. 1H NMR (CDCl3, 400 MHz) 8.12 (m, 1H), 6.78 (m, 2H), 3.93 (s, 3H); LCMS (M+H)+ 172 found.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1I.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:11])[C:17]=1[Cl:18]
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: Nc1cc(Cl)c(I)cc1N
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: C1COCCO1
Solvent: O
Product: Nc1cc(Cl)c(-c2cccc(Cl)c2Cl)cc1N
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-5-iodobenzene-1,2-diamine (100 mg, 0.37 mmol) in dioxane (15 ml) and water (5 ml) was added (2,3-dichlorophenyl)boronic acid (141.3 mg, 0.74 mmol), sodium carbonate (118.2 mg, 1.10 mmol) and Pd(PPh3)4 (42.9 mg, 0.04 mmol). The resulting solution was stirred overnight at 100° C. within an inert atmosphere of nitrogen. The resulting solution was concentrated under vacuum and dissolved in water (100 ml) and extracted with ethyl acetate (4×30 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with between 5% to 25% ethyl acetate in petroleum ether to afford 4-chloro-5-(2,3-dichlorophenyl)benzene-1,2-diamine as a brown solid (92 mg, crude). Finally, the solution of 4-chloro-5-(2,3-dichlorophenyl)benzene-1,2-diamine (100 mg, 0.35 mmol) in pentafluoropropionic acid (35 ml) and hydrochloric acid (conc, 7 ml) was stirred overnight at 100° C. and then concentrated under vacuum. The residue was dissolved in water (100 ml) and extracted with ethyl acetate (4×30 ml), dried over anhydrous sodium sulfate and concentrated. The crude product (500 mg) was purified by Prep-HPLC to afford 5-chloro-6-(2,3-dichlorophenyl)-2-(pentafluoroethyl)-1H-1,3-benzodiazole. TFA salt as a white solid (42 mg).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[CH3:19][C:20]1[N:24]([CH3:25])[C:23]([SH:26])=[N:22][N:21]=1.Cl>O.CC(C)=O.C([O-])(O)=O.[Na+]>[CH3:19][C:20]1[N:24]([CH3:25])[C:23]([S:26][CH2:5][C:6]2[CH2:15][S:14][C@@H:9]3[CH:10]([NH2:13])[C:11](=[O:12])[N:8]3[C:7]=2[C:16]([OH:18])=[O:17])=[N:22][N:21]=1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1nnc(S)n1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n1C
Yield: 60 %

Procedure:
To a solution of NaHCO3 (4.2 g., 0.05 mol.) in water (50 ml.) was added 7-ACA (6.8 g., 0.025 mol.), water (50 ml.) and acetone (25 ml.). The resulting solution was warmed to 45° and then a solution of 3,4-dimethyl-5-mercapto-1,2,4-triazole (5.0 g., 0.038 mol.) in acetone (50 ml.) and 5% NaHCO3 (10 ml.) was added. The reaction was refluxed until the reaction was completed as determined by the disappearance of the acetoxy carbonyl band in the infrared absorption spectrum. During this time the pH was maintained at ca. 7.6. The solution was cooled to 10° and adjusted to pH 3.5 with 3N HCl. The precipitated product was collected, washed with acetone, and dried to give a 60% yield of 3-(3,4-dimethyl-1,2,4-triazol-5-ylthiomethyl)-7-amino-3-cephem-4-carboxylic acid.
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH2:4][F:5].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH2:41][CH2:42][O:43][CH3:44])[N:36]=[CH:35][N:34]=[C:33]2[S:45][C:46]1[CH:47]=[C:48]([CH:50]=[CH:51][CH:52]=1)[NH2:49].C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13]([NH:49][C:48]2[CH:50]=[CH:51][CH:52]=[C:46]([S:45][C:33]3[C:32]4[C:37](=[CH:38][C:39]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[C:30]([O:29][CH3:28])[CH:31]=4)[N:36]=[CH:35][N:34]=3)[CH:47]=2)=[O:21])[N:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:8]=1)([CH3:6])[CH2:4][F:5]
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)nn4-c4ccccc4)c3)c2cc1OC
Yield: 28 %

Procedure:
Using the procedure described in Example 159B, phenyl 3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate described in Example 167B (0.186 g, 0.5 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (0.143 g, 0.4 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) at 50° C. for 6 hours, which was purified by silica gel chromatography with EtOAc/hexane as eluants and preparative HPLC(C18 column and 55-70% MeCN/H2O with 0.05% AcOH) to afford 1-[3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}urea as solid (0.072 g, 28%). 1H NMR (300 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.68 (s, 1H), 8.56 (s, 1H), 7.80 (s, 1H), 7.56 (m, 4H), 7.33-7.47 (m, 5H), 7.24 (d, 1H), 6.51 (s, 1H), 4.71 (m, 2H), 4.55 (m, 2H), 4.33 (m, 2H), 3.99 (s, 3H), 3.77 (m, 2H), 3.34 (s, 3H), 1.31 (s, 3H); LC-MS (ESI) m/z 635 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23](F)[CH:22]=1)[C@@H:3]([C@H:5]1[CH2:10][O:9][C@@H:8]([O:11][CH2:12][C:13]([CH2:17][F:18])([CH2:15][F:16])[CH3:14])[C@H:7]([CH3:19])[NH:6]1)[OH:4].[CH3:29][CH:30]([S-:32])[CH3:31].[Na+].[Cl-].[NH4+]>CN1CCCC1=O.CO>[NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([S:32][CH:30]([CH3:31])[CH3:29])[CH:22]=1)[C@@H:3]([C@H:5]1[CH2:10][O:9][C@@H:8]([O:11][CH2:12][C:13]([CH2:17][F:18])([CH2:15][F:16])[CH3:14])[C@H:7]([CH3:19])[NH:6]1)[OH:4]
Reactant: CC(C)[S-]
Reactant: C[C@@H]1N[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO[C@H]1OCC(C)(CF)CF
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: CC(C)Sc1cc(F)cc(C[C@H](N)[C@H](O)[C@H]2CO[C@@H](OCC(C)(CF)CF)[C@H](C)N2)c1
Temperature: 25 °C
Yield: 3.9 %

Procedure:
Heat a mixture of (1S,2S)-2-Amino-3-(3,5-difluorophenyl)-1-[(3R,5S,6R)-6-(2,2-di-(fluoromethyl)propoxy)-5-methylmorpholin-3-yl]-propan-1-ol (91 mg, 0.22 mol) and sodium 2-propanethiolate (328 mg, 3.34 mmol) in N-methylpyrrolidin-2-one (2.0 mL) at 90° C. in a sealed tube for 1 hour. Cool the reaction mixture to room temperature, dilute with methanol, add ammonium chloride (192 mg, 3.34 mmol), and mix well. Load mixture on SCX™ column and elute with 2.0 M ammonia in methanol to provide the desired compound (60 mg, 58%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:22])[C:11](=[O:21])[N:12]2[CH2:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+:23]([O-])([O-:25])=[O:24].[K+]>S(=O)(=O)(O)O>[C:1]([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([NH:9][C:10](=[O:22])[C:11](=[O:21])[N:12]2[CH2:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CCC(CC)Cn1c(=O)c(=O)[nH]c2ccc(NC(C)=O)cc21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCC(CC)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(NC(C)=O)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
21.0 g (69.2 mmol) of 7-acetamido-1-(2-ethylbutyl)-2,3(1H,4H)-quinoxalinedione were dissolved in 250 ml of concentrated sulfuric acid and, at 0°-5° C., 7.0 g (69.2 mmol) of potassium nitrate were added a little at a time. The mixture was stirred for 1 h and a further 3.5 g (34.6 mmol) of potassium nitrate were added, and the mixture was stirred at room temperature for 16 h. It was then poured into ice-water, and the precipitate was filtered off with suction and dried to yield 18.0 g (75%) of the product, which was immediately processed further.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:19][C:20]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[O:22][N:21]=1>CN(C=O)C>[F:33][C:31]([F:32])([F:34])[C:27]1[CH:26]=[C:25]([C:23]2[O:22][N:21]=[C:20]([CH2:19][N:1]3[C:9]4[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)[N:24]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 90 °C
Yield: 77.6 %

Procedure:
To a solution of 1H-indole-5-carbonitrile (0.05 g, 0.35 mmol) in anhydrous DMF (2 mL) was added Cs2CO3 (0.18 g, 0.55 mmol) and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (0.14 g, 0.55 mmol). The mixture was heated at 90° C., under N2, for 30 min. Upon cooling, the mixture was partitioned between Et2O and H2O. The aqueous phase was extracted with Et2O (×2). The combined organic phases were washed with sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (2-20% EtOAc-hexanes gradient) and the product crystallized from CH2Cl2-hexanes to afford the title compound as a white solid (0.1 g, 78% yield): MS (ES) m/z 369 (M+1).
Reaction SMILES: [CH2:1]([OH:10])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[CH2:11]([NH:15][C:16]#[N:17])[CH2:12][CH2:13][CH3:14]>>[CH2:11]([NH:15][C:16]1[O:10][CH:1]=[C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:17]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCNC#N
Reactant: O=C(CO)c1ccccc1
Product: CCCCNc1nc(-c2ccccc2)co1

Procedure:
The procedure as described in Example 1 was followed using phenacyl alcohol and butylcyanamide. A colourless oil was obtained after distillation of the product.