Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:14]2[NH:13][C:12](=[O:15])[N:11](C(OC(C)(C)C)=O)[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27].O>CN(C)C=O>[CH2:27]([N:13]1[C:14]2[C:6]([CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])=[CH:7][CH:8]=[CH:9][C:10]=2[NH:11][C:12]1=[O:15])[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: CCC(CC)c1cccc2c1[nH]c(=O)n2C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)[nH]c2cccc(C(CC)CC)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
To a solution of tert-butyl 4-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (Reference Example 7; 30.4 g, 100 mmol) in N,N-dimethylformamide (300 mL) was added sodium hydride (60% dispersion in mineral oil, 4.80 g, 120 mmol) portionwise at 0° C. After stirring for 30 min, allyl bromide (10.4 mL, 120 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 16 hours. Water was added to the mixture, which was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in ethyl acetate (300 mL) and 4N hydrogen chloride solution in ethyl acetate (300 mL) was added. After stirring for 70 hr, the mixture was concentrated in vacuo to give a solid which was washed with n-hexane to afford the title compound (22.2 g, 90.6 mmol, 91%) as a colorless solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]([F:39])([F:38])[C:14]1[CH:37]=[CH:36][C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([CH2:26][S:27][C:28]3[NH:32][C:31]4=[CH:33][S:34][CH:35]=[C:30]4[N:29]=3)[CH:21]=2)=[CH:16][CH:15]=1>ClCCl>[F:39][C:13]([F:12])([F:38])[C:14]1[CH:37]=[CH:36][C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([CH2:26][S:27]([C:28]3[NH:32][C:31]4=[CH:33][S:34][CH:35]=[C:30]4[N:29]=3)=[O:9])[CH:21]=2)=[CH:16][CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)c1ccc(COc2ccnc(CSc3nc4cscc4[nH]3)c2)cc1
Solvent: ClCCl
Product: O=S(Cc1cc(OCc2ccc(C(F)(F)F)cc2)ccn1)c1nc2cscc2[nH]1

Procedure:
A solution of 0.5 g (2.5 mmol, 85%) of m-chloroperbenzoic acid in 10 ml of dichloromethane is added dropwise with stirring at 0° to 5° C. to 1.0 g (2.37 mmol) of the title compound from Example 6 in a two-phase mixture of 200 ml of dichloromethane and 100 ml of aqueous KH2PO4 /Na2HPO4 buffer solution (pH=7.5). The organic phase is separated off, shaken with saturated aqueous NaHCO3 solution, dried over MgSO4, clarified over activated charcoal and concentrated. The crystalline evaporation residue is treated with ethyl acetate, filtered off with suction and washed twice with a little ethyl acetate. The colorless crystalline product is dried in vacuo, m.p. 149° C. with decomposition.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.[CH3:38][O:39][C:40]1[N:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1>>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:43]4[CH:44]=[N:45][C:40]([O:39][CH3:38])=[CH:41][CH:42]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)s2)cn1

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene 71 obtained in Example 128-(4) and 6-methoxypyridine-3-boronic acid were treated in a manner similar to Example 168 to give the target compound. APCI-Mass m/Z 478/480 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.Cl[C:16]1[NH:20][C:19]2[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:18]=2[N:17]=1.C(N(CC)C(C)C)(C)C>CC#N>[Cl:2][C:3]1[C:4]([N:9]2[CH2:10][CH2:11][N:12]([C:16]3[NH:20][C:19]4[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:18]=4[N:17]=3)[CH2:13][CH2:14]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Clc1cccnc1N1CCNCC1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: FC(F)(F)c1ccc2nc(N3CCN(c4ncccc4Cl)CC3)[nH]c2c1
Reaction time: 0.33 h

Procedure:
A mixture of the hydrochloride salt from step (b) above (0.564 g, 2.4 mmol), 2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.27 g, 1.22 mmol, Example 1c) and N,N-diisopropylethylamine (0.84 mL, 4.8 mmol, Aldrich) in MeCN (1 mL) was subjected to microwave irradiation at 180° C. with stirring for 20 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 30% EtOAc/hexane, to give the title compound as a white solid. M.p. 208-210° C. MS (ESI, pos. ion) m/z: 382 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5](=O)[CH2:6][C:7](=O)[CH3:8])[CH3:2].Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1>C(O)C.O>[CH2:1]([O:3][C:4]([C:5]1[N:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[N:22]=[C:7]([CH3:8])[CH:6]=1)=[O:11])[CH3:2]
Reactant: COc1ccc(NN)cc1
Reactant: CCOC(=O)C(=O)CC(C)=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(C)nn1-c1ccc(OC)cc1
Temperature: 80 °C

Procedure:
Ethyl-2,4-dioxovalerate (0.555 g, 3.5 mmol) and 4-methoxyphenylhydrazine hydrochloride (0.67 g, 3.8 mmol) were mixed in ethanol and heated to 80° C. overnight. The reaction was cooled, diluted with water and extracted with EtOAc. Organic layers were combined and washed with water, 10% HCl, sat. NaHCO3, dried over MgSO4 and concentrated under reduced pressure. The residue was purified on silica gel (20% EtOAc in hexanes to 30% EtOAc in hexanes). Two regioisomers were isolated, the title regioisomer being the more polar (yield 492 mg). LC-MS (C14H16N2O3 calculated 260) m/z 261 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14](B4OC(C)(C)C(C)(C)O4)[CH:15]=3)[CH:10]=2)[O:3]1.Br[C:30]1[CH:51]=[CH:50][C:33]2[NH:34][C:35]([C@@H:37]3[CH2:42][C@@H:41]4[C@@H:39]([CH2:40]4)[N:38]3[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[N:36][C:32]=2[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:7][C:6]1([CH3:8])[C:2]([CH3:1])([CH3:28])[O:3][B:4]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([C:30]2[CH:51]=[CH:50][C:33]4[N:34]=[C:35]([C@@H:37]5[CH2:42][C@@H:41]6[C@@H:39]([CH2:40]6)[N:38]5[C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[NH:36][C:32]=4[CH:31]=2)[CH:13]=[CH:12]3)[O:5]1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2cc(Br)ccc2[nH]1
Reactant: CC1(C)OB(c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)OC1(C)C
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: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc(-c3ccc4cc(B5OC(C)(C)C(C)(C)O5)ccc4c3)cc2[nH]1
Temperature: 100 °C
Yield: 50 %

Procedure:
Pd(Ph3P)4 (0.382 g, 0.330 mmol) was added to a degassed solution of 2,6-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene (2.51 g, 6.61 mmol), (1R,3S,5R)-tert-butyl 3-(5-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (2.5 g, 6.6 mmol) and sodium carbonate (2.78 g, 33.0 mmol) in DME (52.9 mL) and water (13.2 mL) at 80° C. The reaction was backfilled with nitrogen, sealed and heated at 100° C. overnight. The volatiles were removed under vacuum and the residue was taken in EtOAc, washed with water, and the water layer was extracted with EtOAc. The combined organic layers were filtered through a pad of diatomaceous earth (CELITE®) and dried over Na2SO4, concentrated and purified on a BIOTAGE® (dry loaded on silica gel, charged to a 90 g silica gel cartridge and eluted with a gradient of 0 to 70% ethyl acetate in hexanes, then flushed with 10% MeOH/DCM) to yield (1R,3S,5R)-tert-butyl 3-(6-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (1.8 g, 3.3 mmol, 49% yield) as yellowish solid. LC-MS retention time 1.905 min; m/z 552.47 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% MeOH/90% H2O/0.1% TFA and Solvent B was 10% H2O/90% MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S(=O)(=O)(O)O>C(#N)C>[C:10]1([NH:9][C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)CCC(=O)Cl
Reactant: Nc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: O=C(O)CCC(=O)Nc1ccccc1
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
100 mg of succinic acid monochloride are dissolved in 2 ml of anhydrous acetonitrile. 1.5 equivalents of aniline (102 mg) are added at room temperature and the reaction mixture is kept stirred for 30 minutes. 100 ml of 0.005M sulfuric acid are then added and the solution is extracted with ethyl ether (3×3 ml). The ether phases are combined and washed with water to neutrality and then dried over anhydrous MgSO4. The ether is then filtered and evaporated under reduced pressure to give 90 mg of N-phenylsuccinamic acid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH2:27]([OH:31])[CH2:28][CH2:29][CH3:30]>>[CH2:27]([O:31][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCO
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CCCCOc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.19 mmol), intermediate 42.1, and butan-1-ol (74 μl; 0.773 mmol), example 44 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=[O:20])[C:8]#[C:9][C:10]2([O:15][Si](C)(C)C)[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:3][CH:2]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[OH:15][C:10]1([C:9]#[C:8][C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[O:20])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C[Si](C)(C)OC1(C#CC(=O)c2ccncc2)CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: O=C(C#CC1(O)CCCC1)c1ccncc1
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a stirred solution of 1-(pyridin-4-yl)-3-(1-(trimethylsilyloxy)cyclopentyl)prop-2-yn-1-one (1.1 g, 3.8 mmol) in DCM (15 mL) was added PTSA (0.87 g, 4.6 mmol) at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water (2 mL), the organic layer was washed with a saturated NaHCO3 solution, water, dried over Na2SO4, filtered and then concentrated in vacuo to afford 3-(1-hydroxycyclopentyl)-1-(pyridin-4-yl)prop-2-yn-1-one (0.42 g, 51%) as an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:18])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[BrH:19].BrBr>C(O)(=O)C>[Br:19][CH:10]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[C:9]([C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=1)=[O:18]
Reactant: Br
Reactant: CSc1ccc(C(=O)Cc2ccc(F)cc2)cc1
Agent: BrBr
Solvent: CC(=O)O
Product: CSc1ccc(C(=O)C(Br)c2ccc(F)cc2)cc1
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a stirred slurry of 2-(4-fluorophenyl)-1-(4-methylthiophenyl)ethanone from Step 1 (5.04 g, 19.36 mmol) in acetic acid (100 mL) was added HBr in acetic acid (45 mL, 48% by wt.) and bromine (1.0 mL, 3.09 g, 19.36 mmol). The resulting green slurry became homogeneous within 30 minutes. After 4 hours, the reaction was concentrated in vacuo, the residue diluted with toluene, and reconcentrated in vacuo. The crude haloketone was purified by flash chromatography (2:1 hexane:methylene chloride) and recrystallized from ethyl acetate and isooctane yielding 2-bromo-2-(4-fluorophenyl)-1-(4-methylthiophenyl)ethanone as an off-white solid (4.51 g, 69%): mp 108°-111° C. 1H NMR (CDCl3) 300 mHz δ7.94 (d, J=8.79 Hz, 2H), 7.60-7.50 (m, 2H), 7.25 (d, J=8.79 Hz, 2H), 7.10 (t, J=8.67 Hz, 2H), 6.34 (s, 1H), 2.56 (s, 3 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=3)[C:10]([C:20]([CH:22]3[C:24]([CH3:26])([CH3:25])[C:23]3([CH3:28])[CH3:27])=[O:21])=[CH:9]2)[CH2:3][CH2:2]1.C(N1C=CN=C1)([N:31]1C=CN=C1)=O.[NH4+].[OH-]>CCOC(C)=O.C1COCC1>[O:1]1[CH2:2][CH2:3][CH:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([NH2:31])=[O:18])=[CH:14][CH:15]=3)[C:10]([C:20]([CH:22]3[C:23]([CH3:27])([CH3:28])[C:24]3([CH3:25])[CH3:26])=[O:21])=[CH:9]2)[CH2:5][CH2:6]1
Reactant: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(=O)O)cc23)C1(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(N)=O)cc23)C1(C)C
Yield: 20 %

Procedure:
A mixture 1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxylic acid (0.10 g, 0.26 mmol, the minor product of Example 114 B), 1,1′-carbonyldimidazole (55 mg, 0.34 mmol) and concentrated aqueous NH4OH (2 mL) in 5 mL of EtOAc and 3 mL of THF was processed as described in Example 93 to provide the title compound (20 mg, 0.052 mmol, 20% yield). 1H NMR (CDCl3, 300 MHz) δ ppm 1.32 (s, 6H), 1.36 (s, 6H), 1.39-1.58 (m, 4H), 1.92 (s, 1H), 2.08-2.23 (m, 1H), 3.34 (dt, J=11.4, 2.5 Hz, 2H), 3.94-4.04 (m, 2H), 4.08 (d, J=7.1 Hz, 2H), 7.41 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.98 (dd, J=8.5, 1.4 Hz, 1H), 8.84 (d, J=1.0 Hz, 1H); MS (DCI/NH3) m/z 383 (M+H)+; Anal. Calculated for C23H30N2O3.0.4H2O: C, 70.89; H, 7.97; N, 7.19. Found: C, 70.77; H, 7.91; N, 7.32.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[O:7][CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=1)[CH2:2][CH2:3][CH3:4].[C:14](Cl)(=[O:18])[CH:15]([CH3:17])[CH3:16]>>[CH2:1]([N:5]([C:6]1[O:7][CH:8]=[C:9]([CH:11]([CH3:12])[CH3:13])[N:10]=1)[C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nc(C(C)C)co1
Reactant: CC(C)C(=O)Cl
Product: CCCCN(C(=O)C(C)C)c1nc(C(C)C)co1

Procedure:
2-(N-Butylamino)-4-isopropyloxazole was acylated with isobutyryl chloride as described in Example 9.
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](S(C)(=O)=O)[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.C[Si](C)(C)[O-:41].[K+]>>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([OH:41])[N:30]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: C[C@@H]1CN2c3c(cc4c(-c5ccnc(S(C)(=O)=O)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Reactant: C[Si](C)(C)[O-]
Agent: [K+]
Product: C[C@@H]1CN2c3c(cc4c(-c5ccnc(O)n5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1

Procedure:
Starting materials: (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(2-(methylsulfonyl)pyrimidin-4-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione (Example 169) and potassium trimethylsilanolate.
Reaction SMILES: C[O:2][C:3](=[O:36])[C@@H:4]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([O:22][CH2:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:18]=1)=[O:16])[CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[OH-].[Na+].Cl>C1COCC1>[C:10]([O:9][C:7](=[O:8])[CH2:6][CH2:5][C@H:4]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([O:22][CH2:23][C:24](=[O:29])[C:25]([CH3:26])([CH3:27])[CH3:28])[N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:18]=1)=[O:16])[C:3]([OH:36])=[O:2])([CH3:11])([CH3:12])[CH3:13]
Reactant: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(OCC(=O)C(C)(C)C)n(-c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)C(C)(C)C)n(-c2ccccc2)n1)C(=O)O
Temperature: 25 °C

Procedure:
To a solution of 3.4 g of (S)-2-{[5-(3,3-Dimethyl-2-oxo-butoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-pentanedioic acid 5-tert-butyl ester 1-methyl ester in 15 ml of THF, 6.5 ml of a 1 M aqueous NaOH solution was added. After stirring at RT upon completion of the reaction the mixture was acidified to pH 2 with diluted aqueous hydrochloric acid and extracted with DCM (3×100 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure to yield a crystalline solid. Yield: 3.4 g
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10](=O)[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.P(Cl)(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][C:10]1[N:11]=[N:12][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][N:9]=1
Reactant: O=c1ncc(-c2ccccc2)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Clc1ncc(-c2ccccc2)nn1
Yield: 81.4 %

Procedure:
A mixture of 6-phenyl-1,2,4-triazin-3(2H)-one (2.45 g, 0.0141 mol) and DMF (0.5 mL) in phosphoryl chloride (20.0 mL, 0.214 mol) and chloroform (20.0 mL) was heated under reflux overnight. After cooling, the volatiles were removed under reduced pressure. The residue was dissolved in DCM (60 mL) and was poured into ice with stirring. The mixture was neutralized with NaOH (1N), and filtered through a pad of celite to remove a small amount of insoluble residue. The organic layer was separated. The aqueous layer was extracted with DCM (3×20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was flash chromatographed on a silica gel column to give the desired product (2.20 g, 81.1%). Analytical LCMS: (M+H)+=192.1/194.1.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])(=O)[CH3:2].P(Cl)(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[Cl:13][C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1[NH:5][N:4]=[C:1]([Cl:16])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)NNc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: CC(Cl)=NNc1ccc(Cl)cc1Cl
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
A solution of 25.0 grams (0.1142 mole) of 1-acetyl-2-(2,4-dichlorophenyl)-hydrazine (2) in 120 grams of toluene was stirred, and 17.7 grams (0.1142 mole) of phosphorus oxychloride was added portionwise. Upon completion of addition the reaction mixture was warmed to about 110° C. where it stirred for about 30 minutes. GC analysis of the reaction mixture after this time indicated the reaction was complete. An additional 100 grams of toluene was added to the reaction mixture, and the solution was decanted into a separatory funnel. A residue in the reaction vessel was washed with about 40 grams of toluene, and the wash was also decanted into the separatory funnel. The toluene solution was then washed with an aqueous solution of 10% potassium carbonate. The aqueous layer was back-washed with two 75 gram portions of toluene. The combined toluene layer and washes was dried with magnesium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure, yielding 21.3 grams (78.5% yield) of N-(2,4-dichlorophenyl)-ethanehydrazonoyl chloride (A).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][C:9]([C:13]#[N:14])=[N:10]2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>C1COCC1.CO>[OH:2][CH2:1][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][C:9]([C:13]#[N:14])=[N:10]2)=[CH:5][CH:4]=1
Reactant: N#Cc1cc(-c2ccccc2)c2ccc(C=O)cc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc(-c2ccccc2)c2ccc(CO)cc2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 7-formyl-4-phenylquinoline-2-carbonitrile (516 mg, 2.0 mmol) in THF (6 mL) and MeOH (2 mL) was added at 0° C. sodium borohydride (91 mg, 2.4 mmol). The mixture was stirred 1 h at 0° C., quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The compound was used as such for the next step. MS (+ESI): 262 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:7]=[C:8]([OH:16])[C:9]([CH3:15])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].[CH3:17]O>>[Cl:5][C:6]1[CH:7]=[C:8]([OH:16])[C:9]([CH3:15])=[C:10]([CH:14]=1)[C:11]([O:13][CH3:17])=[O:12]
Reactant: CO
Reactant: Cc1c(O)cc(Cl)cc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)cc(O)c1C
Temperature: 25 °C
Yield: 64.7 %

Procedure:
To cold (0° C. ice bath) methanol (200 mL) with stirring was added drop-wise thionyl chloride (12 mL, 164 mmol). The reaction was maintained for 15 minutes, at which time 5-chloro-3-hydroxy-2-methylbenzoic acid (6.5 g, 34.8 mmol) was added. The reaction was allowed to warm to room temperature and maintained overnight. The reaction was evaporated to dryness under vacuum and the residue was purified by silica gel chromatography (Analogix, SF40-150 g, 50 to 100% CH2Cl2 in hexanes). An overlap fraction containing a close faster running impurity was combined and repurified to give more pure product. The combined pure fractions were evaporated to dryness to give methyl 5-chloro-3-hydroxy-2-methylbenzoate (4.52 g, 22.53 mmol, 64.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 7.18 (d, J=2.02 Hz, 1H), 7.01 (d, J=2.27 Hz, 1H), 3.82 (s, 3H), 2.25 (s, 3H). MS(ES) [M+H]+ 201.0.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(O[CH2:17][CH3:18])=O>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:17]([O:11][C:10]([C@@H:8]1[CH2:9][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:12])[CH3:18]
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of 1.62 g of (1R, 2R)-2-phenyl-cyclopropane carboxylic acid (from racemic trans-2-phenyl-cyclopropane carboxylic acid by resolution on a chiral HPLC column) and 2.0 mL of triethylamine and 0.12 g of 4-dimethylaminopyridine was added 1.2 mL of ethyl chloroformate The mixture was allowed to warm and stir for 1 h, then washed with 25 mL of 3N HCl, 25 mL of water, 25 mL of saturated sodium carbonate and dried over magnesium sulfate. Removal of solvents under reduced pressure gave 1.9 g of product as an oil: MS (m+1)=191.1; 1H NMR (400 MHz, CDCl3) 7.3 (dd, 2H), 7.2 (t, 1H), 7.1 (d, 2H), 4.18 (q, 2H), 2.5 (m, 1H), 1.9 (m, 1H), 1.6 (m, 1H), 1.3 (overlapping m and t, 4H).