Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[F:32][C:33]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>O1CCCC1>[F:32][C:33]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:34]=1[C:35]([N:21]1[CH2:20][CH2:19][N:18]([C@H:16]([CH3:17])[C@:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:24])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH2:23][CH2:22]1)=[O:36]
Reactant: C[C@@H](N1CCNCC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](N1CCN(C(=O)c2ccc(F)cc2F)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 18 h
Yield: 46.9 %

Procedure:
To a mixture of compound 2 (674 mg, 2 mmol) and triethylamine (0.55 ml, 4 mmol) in tetrahydrofuran (10 ml) was added dropwise 2,4-difluorobezoyl chloride (440 mg, 2.5 mmol) in 5 ml tetrahydrofuran at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes and at room temperature for 18 h. The solvent was removed under reduced pressure, the residue was dissolved in dichloromethane (50 ml). The organic phase was washed with brine, dried over sodium sulphate. The solvent was removed under reduced pressure and the resulting product was purified on a column of silica gel (EtOAc/hexane, 9:1) to give the title compound as colorless prisms (448 mg, 47%).
Reaction SMILES: [OH-].[Na+].[CH3:3][NH2:4].[CH:5]([CH:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:6]>>[CH:5]([CH:7]([N:4]([CH:7]([CH:5]=[CH2:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:6]
Reactant: C=CC(Cl)c1ccccc1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Product: C=CC(c1ccccc1)N(C)C(C=C)c1ccccc1
Reaction time: 1 h

Procedure:
20 grams (0.5 mole) of 98.2% sodium hydroxide pellets are dissolved, with stirring and cooling to a temperature maintained at 10° C., in a saturated solution of monomethylamine (large excess greater than one mole), which is prepared by bubbling gaseous monomethylamine into 200 ml. of distilled water at 10° C. until saturated. Then, 77.8 grams (0.5 mole) of 98% vinylbenzyl chloride are added at a uniform rate over a period of 30 minutes while maintaining the batch temperature below 20° C. Upon removing external cooling, the batch temperature rises to 32° C. in one hour as a result of an exotherm. The batch is then agitated at ambient temperature (26° C.) overnight. On stopping agitation, the phases cleanly separate within a period of one hour. The lower aqueous layer of 250 grams is withdrawn and discarded. The upper product layer of 50 grams is washed with three successive 100 ml. portions of water adjusted to a pH of 8.9, followed by one 100 ml. portion of distilled water (neutral pH). (Without the pH adjustment of the initial three wash portions, some foaming and emulsification occurs.) The washed product layer is then dried over calcium chloride and anhydrous sodium sulfate. Upon removing the drying agent, 38 grams of product is obtained. Analyses showed this material to have the following properties:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([O:15][CH2:16][C@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[C:22](OC(C)(C)C)=O)[CH:11]=[N:12][C:13]=2[Cl:14])=[CH:4][CH:3]=1.C=O>C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([O:15][CH2:16][C@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH3:22])[CH:11]=[N:12][C:13]=2[Cl:14])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Agent: C=O
Solvent: O=CO
Product: CN1CCC[C@@H]1COc1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Temperature: 70 °C
Yield: 94 %

Procedure:
To 5-(4-chlorophenyl)-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from step 76aa (340 mg, 0.8 mmol) was added formalin (37%, 10 mL) and formic acid (5 mL), and the mixture was heated at 70° C. for 2.5 hours. The solvent was concentrated, and solid NaHCO3 was added to the residue. At pH 8 the mixture was extracted with methylene chloride, which was dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with methylene chloride:methanol 100:5-100:10 to afford to give the free base of the title compound (255 mg, 94% yield). MS (DCI/NH3) m/z 337 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.80-2.40 (m, 4H), 2.52 (m, 1H), 2.65 (s, 3H), 2.98 (m, 1H), 3.38 (m, 1H), 4.08 (m, 1H), 4.28 (m, 1H), 7.23 (m, 1H), 7.42 (m, 4H), 8.10 (m, 1H). The base was converted to the salt by treatment with hydrogen chloride in ether/THF to give the title compound. mp 176°-178° C. MS (DCI/NH3) m/z 337 (M+H)+. 1 H NMR (D2O, 300 MHz) δ: 2.06-2.16 (m, 2H), 2.19-2.23 (m, 1H), 2.38-2.41 (m, 1H), 3.03 (s, 3H), 3.24 (m, 1H), 3.74 (m, 1H), 3.91 (m, 1H), 4.36 (dd, J=6.1, 11.2 Hz, 1H), 4.54 (dd, J=3.1, 11.2 Hz, 1H), 7.49-7.57 (m, 5H), 8.14 (d, J=3.0 Hz, 1H). Anal. Calcd for C17H18N2OCl2 ·1.3 HCl: C, 53.08; H, 5.06; N, 7.28. Found: C, 52.93; H, 5.17; N, 7.33. [α]25D =+7.33° (c 2.25, MeOH).
Reaction SMILES: C(=N[OH:9])C1C=CC=CC=1.[H-].[Na+].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:26]([C:33]#[N:34])([CH3:32])[C:27]([O:29]CC)=O)=[C:17]([C:19]#[C:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:18]=1>CN(C=O)C.O1CCOCC1>[Cl:12][C:13]1[CH:18]=[C:17]2[C:16](=[CH:15][CH:14]=1)[C:26]([C:33]#[N:34])([CH3:32])[C:27](=[O:29])[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]2[OH:9]
Reactant: ON=Cc1ccccc1
Reactant: CCOC(=O)C#Cc1cc(Cl)ccc1C(C)(C#N)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C#N)C1=O
Reaction time: 0.5 h

Procedure:
A solution of benzaldehyde oxime (0.16 g, 1.3 mmol) in DMF (3 mL) was added dropwise to a stirred suspension of 60% NaH (0.033 mL, 1.3 mmol) in dry 1,4-dioxane (5 mL) under a nitrogen atmosphere at room temperature. After 30 minutes, a solution of ethyl 3-(5-chloro-2-(2-cyano-1-ethoxy-1-oxopropan-2-yl)phenyl)propiolate (0.445 g, 1.3 mmol) in DMF (3 mL) was added dropwise. The reaction was monitored by LC-MS and, when complete, the solvent was removed. The residual brown oil was dissolved in DCM (50 mL), water (30 mL), and AcOH (2 mL). The layers were separated, and the aqueous layer was extracted with DCM (3×30 mL). The combined organic layers were dried with MgSO4 and concentrated in vacuo. The crude residue was purified using silica flash chromatography with a gradient of 10-50% EtOAc/hexanes. MS m/e=306 (M+H)+.
Reaction SMILES: [CH:1]([N:4](C(C)C)CC)(C)C.ClC(OCC)=O.[C:16]([S:19][CH:20]([CH:25]([C:30]([NH:32][C@H:33]([C:43]([NH:45][CH3:46])=[O:44])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)=[O:31])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:21][C:22]([OH:24])=O)(=[O:18])[CH3:17].CN>C1COCC1>[C:16]([S:19][CH:20]([CH2:21][C:22]([NH:4][CH3:1])=[O:24])[CH:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:30]([NH:32][C@H:33]([C:43]([NH:45][CH3:46])=[O:44])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)=[O:31])(=[O:18])[CH3:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)O)SC(C)=O
Agent: CCOC(=O)Cl
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)CC(SC(C)=O)C(CC(C)C)C(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)NC
Reaction time: 3 h

Procedure:
Diisopropylethylamine (0.13 ml, 0.7 mmol) and ethyl chloroformate (0.07 ml, 0.7 mmol) were added to a solution of 3-acetylmercapto-6-methyl-4-[[[1-(S)-[(methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoic acid (E5, Isomer A; 300 mg, 0.66 mmol) in dry THF (10 ml), at -20° C. After 15 min a solution of methylamine (20 mg) in THF (0.8 ml) was added dropwise and the mixture was stirred in an ice bath for 3 h. The solvent was evaporated in vacuo, and a solution of the residue in dichloromethane was washed successively with water, 1M hydrochloric acid, water, saturated sodium hydrogen carbonate and brine. The solution was dried (MgSO4) and evaporated in vacuo. Column chromatography on silica (10 g), eluting with 5% methanol/ethyl acetate gave the title compound, mp 195°-199° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[C:35]([F:36])=[CH:34][C:31]([C:32]#[N:33])=[C:30]([F:37])[CH:29]=1.O1C=NC(C2C=CC(CN([C@@H]3CCCC[C@H]3CO)S(C3C=CC(Cl)=CC=3)(=O)=O)=CC=2)=N1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:27][C:28]2[CH:29]=[C:30]([F:37])[C:31]([C:32]#[N:33])=[CH:34][C:35]=2[F:36])[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)cc1
Reactant: N#Cc1cc(F)c(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncon2)cc1)[C@@H]1CCCC[C@H]1CO
Agent: [Cs+]
Product: N#Cc1cc(F)c(CN([C@@H]2CCCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1F
Yield: 43.3 %

Procedure:
The title compound was synthesized from 4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (200 mg, 0.66 mmol), cesium carbonate (257 mg, 0.79 mmol), and 4-(bromomethyl)-2,5-difluorobenzonitrile (183 mg, 0.79 mmol) according to the procedure described for N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 11) to give 4-chloro-N-(4-cyano-2,5-difluorobenzyl)-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (130 mg, 43%). 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (m, 2H), 7.59 (dd, J=8.81, 5.79 Hz, 1H), 7.51 (m, 2H), 7.28 (dd, J=8.56, 5.04 Hz, 1H), 4.48 (d, J=13.00 Hz, 1H), 4.39 (d, J=14.00 Hz, 1H), 3.64 (td, J=11.58, 3.02 Hz, 1H), 3.55 (ddd, J=11.77, 4.72, 3.40 Hz, 1H), 3.15 (ddd, J=11.58, 9.19, 2.14 Hz, 1H), 2.41 (t, J=6.00 Hz, 1H), 1.68 (d, J=10.58 Hz, 3H), 1.30-1.52 (m, 2H), 0.98-1.19 (m, 4H). Analytical HPLC R.T.=23.37 min. MS [M+H]+=455; [M+Na]+=477.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=[O:18].[Na+].O>Cl.CO>[OH:18][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=N[O-]
Reactant: Nc1cc(C(=O)O)cc(N2CCCC2=O)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(O)cc(N2CCCC2=O)c1
Temperature: 90 °C

Procedure:
This amine (1.10 g, 5.0 mmol) in 2N HCl (10 ml) and methanol (approx 15 ml, to aid solubility) was cooled in an ice bath and treated portionwise with sodium nitrite (0.76 g, 11.0 mmol) at such a rate to keep the temperature below 5° C. After completion of the addition, water (20 ml) was added and the mixture was heated at approx 90° C. for 1 hr. After cooling the product was extracted into ethyl acetate and the combined extracts were washed with brine and then dried over sodium sulfate and evaporated to give the title compound, 0.93 g.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:16]([C:26](=[O:29])[NH:27][CH3:28])[C:15]=3[CH:30]=2)=[C:9]([CH3:31])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1([NH2:41])[CH2:40][CH2:39]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[C:3]([C:4](=[O:5])[NH:41][C:38]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)[CH2:40][CH2:39]2)=[CH:7][CH:8]=[C:9]([CH3:31])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[C:16]([C:26]([NH:27][CH3:28])=[O:29])[C:15]=2[CH:30]=1
Reactant: NC1(c2ccccn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3c(C)ccc(C(=O)O)c3F)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3c(C)ccc(C(=O)NC4(c5ccccn5)CC4)c3F)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the solution of 2-fluoro-3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.1 g, 0.273 mmol, 1.0 eq) in DMF (5.0 ml), 1-(pyridin-2-yl)cyclopropanamine (0.038 g, 0.285 mmol, 1.2 eq), TBTU (0.130 g, 0.403 mmol, 1.7 eq) and DIPEA (0.154 g, 1.187 mmol, 5.0 eq) were added. Mixture was stirred at ambient temperature for 12 h under nitrogen atmosphere. DMF was concentrated and to this residue water was added and extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate and ethyl acetate was evaporated. The crude was purified by preparative TLC eluted with hexane/EtOAc (5:5). The product was further purified by recrystallization with DCM and hexane. Yield: 0.045 g (39%). 1H NMR (400 MHz, DMSO-d6): δ 1.23-1.25 (m, 2H), 1.51-1.54 (m, 2H), 2.18 (s, 3H), 2.81-2.82 (d, 3H, J=4.0 Hz), 7.13-7.15 (t, 1H, J=3.78 Hz), 7.27-7.29 (d, 1H, J=8.00 Hz), 7.33-7.35 (d, 1H, J=4.26 Hz), 7.39-7.44 (m, 3H, J=5.26 Hz), 7.56-7.60 (t, 2H, J=7.56 Hz), 7.68-7.72 (m, 1H), 7.80-7.82 (d, 1H, J=8.44 Hz), 7.96-8.00 (m, 2H), 8.43-8.49 (m, 2H), 9.12 (s, 1H). LCMS: (ES+) m/z=538.0 (M+H). Method: Column: Chromolith SpeedRod C18 (4.6×30) mm, 5 micron Mphase A: 10% MeOH-90% H2O-0.1% TFA Mphase B: 90% MeOH-10% H2O-0.1% TFA Flow: 5 ml/min
Reaction SMILES: [Cl:1][C:2]([C:30]([F:33])([F:32])[F:31])([CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[CH:9][C:8]=1[N+:27]([O-])=O)[C:3](O)=[O:4].O>C(O)(=O)C.[Fe]>[Cl:1][C:2]1([C:30]([F:33])([F:32])[F:31])[CH2:6][C:7]2[C:8](=[CH:9][C:10]([N:14]3[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[N:16]([CH3:25])[C:15]3=[O:26])=[C:11]([F:13])[CH:12]=2)[NH:27][C:3]1=[O:4]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc([N+](=O)[O-])c(CC(Cl)(C(=O)O)C(F)(F)F)cc2F)c1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3c(cc2F)CC(Cl)(C(F)(F)F)C(=O)N3)c1=O
Yield: 53.5 %

Procedure:
This compound was prepared in a manner analogous to that of Step D of Example 1, using 6.8 grams (0.013 mole) of 2-chloro-2-trifluoromethyl-3-[5-fluoro-2-nitro-4-(1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl)phenyl]propanoic acid, 7.0 grams (0.130 g-atom) of iron powder, and 20 mL of water in 100 mL of acetic acid, yielding 3.2 grams of 3-(3-chloro-6-fluoro-3,4-dihydro-3-trifluoromethylquinolin-2-on-7-yl)-1-methyl-6-trifluoromethyluracil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:27])[C@@H:7]1[CH2:11][C@@H:10]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][N:8]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CO>O.O1CCCC1>[C:23]([O:22][C:20]([N:8]1[CH2:9][C@H:10]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][C@H:7]1[C:6]([OH:27])=[O:5])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)[C@@H]1C[C@@H](NC(=O)OC(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.3 %

Procedure:
A solution of lithium hydroxide monohydrate (86 mg) in water (7 mL) was added to a cold (0° C.) stirred solution of N-tert-butoxycarbonyl-trans-4-(tert-butoxycarbonylamino)-L-proline methyl ester (N, 589 mg) in tetrahydrofuran (21 mL)-methanol (7 mL). The mixture was stirred at room temperature for 5 hr and evaporated in vacuo. The residue was diluted with water and washed with ether. The aqueous layer was acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give the title compound (222 mg) as a colorless foam: 1H NMR (400 MHz, CDCl3) δ 1.35-1.57 (m, 18H), 2.05-2.52 (m, 2H), 3.19-3.37 (m, 1H), 3.66-3.81 (m, 1H, 4.17-4.45 (m, 2H), and 4.63-4.87 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([C@H:24]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)O)[CH2:9][C@:10]([CH3:23])([CH2:20][CH:21]=[CH2:22])[C:11]([NH:13][C@@H:14]([CH:17]([CH3:19])[CH3:18])[CH2:15][OH:16])=[O:12])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.O>C1C=CC=CC=1.C(OCC)(=O)C.O1CCOCC1>[CH2:20]([C@@:10]1([CH3:23])[CH2:9][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:24]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[N:13]([C@@H:14]([CH:17]([CH3:18])[CH3:19])[CH2:15][OH:16])[C:11]1=[O:12])[CH:21]=[CH2:22]
Reactant: C=CC[C@@](C)(C[C@H](c1cccc(Cl)c1)[C@@H](O)c1ccc(Cl)cc1)C(=O)N[C@H](CO)C(C)C
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: CS(=O)(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO)C(C)C)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(S)-2-((2R,3R)-2-(3-Chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N-((S)-1-hydroxy-3-methylbutan-2-yl)-2-methylpent-4-enamide (example 261, step G) was transferred as a solution in anhydrous benzene to a pre-weighed, oven-dried 50 mL round bottom flask and stripped to dryness. Azeotropic distillation of benzene/water was performed twice more, and the residue was dried under high vacuum for 2 h, after which it weighed 550 mg. An oven-dried stir bar was added to the flask. The vessel was sealed and purged with nitrogen and then anhydrous dichloromethane (23 mL) was added, followed by triethylamine (1.3 mL, 9.33 mmol). The resulting stirred solution was cooled to 0° C. Methanesulfonyl chloride (0.270 mL, 3.49 mmol) was added dropwise by microsyringe. After 1 h, the reaction was quenched by addition of HCl (1.2M, 12 mL) and diluted in ethyl acetate. The organic layer was washed with 1.2 M HCl (30 mL), saturated sodium bicarbonate (2×25 mL), and sat. aq. NaCl solution. After drying over magnesium sulfate and concentration in vacuo an intermediate was obtained as an off-white foam (0.64 g,). 1,8-Bis(dimethylamino)naphthalene, 314 mg, 1.465 mmol) and water (0.104 mL, 5.75 mmol) were added to the intermediate, followed by dioxane (23 mL). The mixture was heated under nitrogen at 110° C. overnight. After cooling, the mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution. The aqueous phase was back-extracted with ethyl acetate. The combined organic layers were washed with sat. aq. NaCl solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica, eluting with ethyl acetate in hexanes. Chromatography fractions containing predominantly the desired product were combined. The product was re-purified by chromatography on a 40 g silica column, eluting with a gradient of 0 to 50% ethyl acetate in hexanes to give the title compound.
Reaction SMILES: [CH:1]([SiH:4]([CH:11]([CH3:13])[CH3:12])[C:5]#[C:6][Si:7]([CH3:10])([CH3:9])[CH3:8])([CH3:3])[CH3:2].[Br:14]N1C(=O)CCC1=O>ClC(Cl)C>[CH:11]([Si:4]([Br:14])([CH:1]([CH3:3])[CH3:2])[C:5]#[C:6][Si:7]([CH3:9])([CH3:8])[CH3:10])([CH3:13])[CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)[SiH](C#C[Si](C)(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: CC(C)[Si](Br)(C#C[Si](C)(C)C)C(C)C
Yield: 87.9 %

Procedure:
Diisopropyl(trimethylsilylethynyl)silane (6.9 g, 33 mmol) was dissolved in dichloroethane (20 mL) in a round-bottom flask equipped with a stir bar and placed in an ice bath. N-Bromosuccinimide (36 mmol, 6.5 g) was added scoopwise over 30 minutes, and stirring was continued for 15 more minutes or until the solution began to turn bright orange. Solvent was removed using rotary evaporation, pentane was added to the resulting solid, and the remaining solid succinimide residues were removed by filtration. The pentane solution was again evaporated, the process repeated, and the pentane was removed to yield 8.6 g (29 mmol, 89%) of a product as a pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[N:21](C3CCCCO3)[N:20]=[C:19](I)[C:16]2=[N:17][CH:18]=1.[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.C(Cl)(=O)C>O1CCOCC1.O.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>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:14]=[C:15]2[NH:21][N:20]=[C:19]([C:33]3[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=3)[C:16]2=[N:17][CH:18]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cnc3c(I)nn(C4CCCCO4)c3c2)c1Cl
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)Cl
Product: COc1cc(OC)c(Cl)c(-c2cnc3c(-c4cnn(C)c4)n[nH]c3c2)c1Cl
Temperature: 85 °C
Reaction time: 3 h
Yield: 20.5 %

Procedure:
A mixture of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine (25 mg, 0.047 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (12 mg, 0.056 mmol), tetrakis(triphenylphosphine)palladium(0) (3 mg, 0.002 mmol), and cesium carbonate (46 mg, 0.14 mmol) in 1,4-dioxane (0.5 mL) and water (0.07 mL) in a reaction vial was degassed, sealed, and stirred at 85° C. for 3 h. After cooling the mixture was concentrated and the residue was dissolved in methanol (0.4 mL, 10 mmol). To the solution was added HCl solution previously prepared from acetyl chloride (0.3 mL) in methanol (0.3 mL). The mixture was stirred at r.t. for 1 h then concentrated, diluted with methanol, and purified by RP-HPLC (pH=2) to afford the desired product (3.9 mg) as a TFA salt. LCMS (M+H)+=404.1.
Reaction SMILES: [F:1]/[CH:2]=[C:3](\[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])/[CH2:4][N:5]1[C:9](=[O:10])C2=CC=CC=C2C1=O.[OH2:26].NN>C(O)C>[C:3]([O:26][C:9]([NH:5][CH2:4]/[C:3](/[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[CH:2]/[F:1])=[O:10])([CH3:16])([CH3:4])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1C/C(=C/F)COc1ccc(Cl)cc1Cl
Reactant: O
Agent: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)NC/C(=C/F)COc1ccc(Cl)cc1Cl

Procedure:
A solution of (Z)-1-fluoro-2-(2',4'-dichlorophenoxy) methyl-3-phthalimidopropene (0.67 g) and hydrazine hydrate (0.13 g) in ethanol (20 ml) is refluxed for 3 hours. The ethanol is evaporated, the residue extracted with ether and the ether solution washed with dilute aqueous sodium hydroxide, then with water, dried and evaporated. The residue is treated with di-tert-butyl dicarbonate (0.44 g), chloroform (20 ml) and water (6 ml), with added sodium chloride (1 g), for 1.5 hours at reflux to give (Z)-N-t-butyloxycarbonyl-2-(2',4'-dichlorophenoxy)methyl-3-fluoroallylamine. Pure colorless needles (0.43 g) are obtained by silica chromatography using 15% EtOAC in light petroleum as eluant. Cleavage of the butyloxycarbonyl group (HCl/ether) gave (Z)-2-(2',4'-dichlorophenoxy)methyl-3-fluoroallylamine as its hydrochloride salt; colorless needles (0.30 g; 59% yield); mp 135°-136° C.