Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Li].C[Si](Cl)(C)C.[C:8]1(=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])/[CH2:9][CH2:10][C:11]2[C:16]/1=[CH:15][CH:14]=[CH:13][CH:12]=2.[CH2:23]1C2C(=CC=CC=2)C(CC(OCC)=O)=C1>C(OCC)C.C(Cl)Cl.[Cu](I)I>[CH3:23][C:8]1([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CCOC(=O)CC1=CCc2ccccc21
Reactant: CCOC(=O)/C=C1\CCc2ccccc21
Agent: I[Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Li]C
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CC1(C)CCc2ccccc21
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a suspension of copper iodide (1.9 g, 9.9 mmol) in diethyl ether (10 mL) was added methyl lithium (12.4 mL, 19.8 mmol, 1.6M in diethyl ether) at 0° C. and the mixture was stirred for 10 min. The solvent was removed under reduced pressure at 0° C. and then CH2Cl2 (10 mL) was added. The reaction mixture was stirred for 5 minutes at 0° C., and then the solvent was removed again under reduced pressure at 0° C. To the residue was added pre-cooled CH2Cl2 (75 mL), cooled to −78° C., and then added trimethylsilyl chloride (1.3 mL, 9.9 mmol) and a solution of a mixture of (E)-ethyl 2-(2,3-dihydro-1H-inden-1-ylidene)acetate and ethyl 2-(1H-inden-3-yl)acetate (1:1 mixture, 1 g, 4.9 mmol) in CH2Cl2 (10 mL), successively. The resulted mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by addition of a mixture of aqueous saturated NH4Cl and 28% NH4OH (1:1, 50 mL). The mixture was extracted with diethyl ether (3×50 mL) and the combined extracts were washed with water, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (Hexanes-EtOAc, 0 to 10%) to give 0.47 g of the title compound. Additionally, 0.17 g of unreacted ethyl 2-(1H-inden-3-yl)acetate was recovered. MS (DCI/NH3) m/z 236 (M+NH4)+.
Reaction SMILES: Cl([O-])=O.[Na+].[OH2:5].P([O-])(O)(O)=O.[Na+].[Cl:12][C:13]1[N:14]=[C:15]([CH2:20][CH2:21][CH3:22])[NH:16][C:17]=1[CH:18]=[O:19].CC(=CC)C>O.C1COCC1.C(O)(C)(C)C>[Cl:12][C:13]1[N:14]=[C:15]([CH2:20][CH2:21][CH3:22])[NH:16][C:17]=1[C:18]([OH:5])=[O:19]
Reactant: O
Reactant: CCCc1nc(Cl)c(C=O)[nH]1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CCCc1nc(Cl)c(C(=O)O)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100.4 %

Procedure:
A solution of sodium chlorite (2.9 g, 32.1 mmol) and sodium dihydrogen phosphate monohydrate (2.5 g, 18.1 mmol) in water (7.2 mL) was added to a stirred solution of 4-chloro-2-propyl-1H-imidazole-5-carbaldehyde (0.541 g, 3.1 mmol), 2-methyl-2-butene (19.3 mL of a 2M solution in THF, 38.6 mmol), and tert-butanol (2.3 mL) in THF (10 mL). The reaction mixture was stirred at RT for 6 h. The aqueous phase was separated and extracted with EtOAc (4×40 mL). The combined extracts were dried (Na2SO4), filtered, concentrated and the residue was triturated with diethyl ether to provide the title compound (0.587 g, quant.) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.99 (br. s., 1H), 12.88, (br. s., 1H), 2.55 (t, 2H), 1.63 (sex, 2H), 0.86 (t, 3H). ES-LCMS: m/z 189.0 (M+H).
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[C:5]#[N:6]>[Ni].CO>[NH2:6][CH2:5][CH:4]([N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[CH3:3]
Reactant: CC(C#N)N1CCCC1=O
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(CN)N1CCCC1=O
Yield: 69.1 %

Procedure:
0.1 g of sodium hydroxide and 1 g of Raney nickel are added to a solution of 13 g (0.094 mole) of alpha-methyl-2-oxo-1-pyrrolidineacetonitrile in 250 ml of methanol and hydrogenated at ambient temperature and pressure until there is no further absorption of hydrogen. The catalyst is then filtered off through a Hyflo-cel filter and the filtrate is evaporated under reduced pressure. 9.2 g (0.065 mole) of 1-(2-amino-1-methylethyl)-2-pyrrolidinone are obtained, this product being used as it is for continuing the synthesis (Yield: 69% of theory). I.R. spectrum (film) in cm-1 : 3380, 2970, 2930, 2870, 1670, 1290.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][OH:7].[H-].[Na+].F[C:11]1[N:16]=[C:15]([CH2:17][N:18]2[C:22]3=[N:23][C:24]([NH:27][C:28]4[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=4)=[N:25][CH:26]=[C:21]3[CH:20]=[N:19]2)[CH:14]=[CH:13][CH:12]=1>CN(C=O)C>[CH3:33][N:31]1[CH:32]=[C:28]([NH:27][C:24]2[N:23]=[C:22]3[N:18]([CH2:17][C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([O:7][CH2:6][C@H:2]5[CH2:3][CH2:4][CH2:5][O:1]5)[N:16]=4)[N:19]=[CH:20][C:21]3=[CH:26][N:25]=2)[CH:29]=[N:30]1
Reactant: Cn1cc(Nc2ncc3cnn(Cc4cccc(F)n4)c3n2)cn1
Reactant: OC[C@H]1CCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(Nc2ncc3cnn(Cc4cccc(OC[C@H]5CCCO5)n4)c3n2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-(Tetrahydrofuran-2-yl)methanol (22 mg, 0.214 mmol) was added to a solution of NaH (10 mg, 0.246 mmol) in dry DMF (1 mL) in a 2-necked flask under Nitrogen. Another portion of NaH (10 mg, 0.246 mmol) was added to a stirring solution of 1-((6-fluoropyridin-2-yl)methyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (Example 170) (50 mg, 0.154 mmol) in DMF (1 ml). This solution was added to the 2-necked flask and stirred for 16 h at rt. The reaction was quenched with NH4Cl (sat. solution, 1 mL) and diluted with Ethyl Acetate (20 mL). The organics were separated and washed with NaHCO3 (sat. solution, 20 mL). The aqueous phase was re-extracted with Ethyl Acetate (2×10 mL). The combined organics were dried over Na2SO4, filtered and the solvent evaporated to give a crude product that was purified by prep HPLC. (R)—N-(1-methyl-1H-pyrazol-4-yl)-1-((6-((tetrahydrofuran-2-yl)methoxy)pyridin-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine was obtained as a white solid (24 mg, 38% yield). 1H NMR (d6-Acetone) δ 8.87 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.61 (s and t, 2H), 6.70 (d, 1H), 6.64 (d, 1H), 5.54 (s, 2H), 4.07 (m, 3H), 3.82 (s, 3H), 3.75 (m, 1H), 3.61 (m, 1H), 1.84 (m, 3H), 1.54 (m, 1H); LC-MS method B, (ES+) 407.1, RT=7.65 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[S:24][C:25]([CH2:28]Cl)=[CH:26][CH:27]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:28][C:25]2[S:24][C:23]([Cl:22])=[CH:27][CH:26]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: ClCc1ccc(Cl)s1
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCc2ccc(Cl)s2)c1C(=O)OC
Yield: 99.3 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.4 g, 6.8 mmol) in acetone (70 mL) and potassium carbonate (2.8 g, 20 mmol) was added 2-chloro-5-chloromethyl-thiophene (0.83 mL, 7.1 mmol) and refluxed for two hours. The solvent was evaporated and the residue was partitioned between water (100 mL) and ethyl acetate (150 mL) and washed with water (2×100 mL). The combined organic phases was dried, concentrated and purified by flash column chromatography (EtOAc/Hexane) to give 3-(5-chloro-thiophen-2-ylmethoxy)-phthalic acid dimethyl ester (2.3 g, 100% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:27]=[CH:26][C:7]([CH2:8][NH:9][C:10](=[O:25])[C:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=2[O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:6]([F:28])[CH:5]=1)#[N:2].[N-:29]=[N+:30]=[N-:31].[Na+].Cl.C(N(CC)CC)C.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:12]2[N:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:9][CH2:8][C:7]2[CH:26]=[CH:27][C:4]([CH2:3][C:1]3[NH:31][N:30]=[N:29][N:2]=3)=[CH:5][C:6]=2[F:28])=[O:25])=[CH:19][CH:20]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)c(F)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(Cc2nnn[nH]2)cc1F)c1cccnc1Oc1ccc(F)cc1
Temperature: 116 °C
Yield: 296.4 %

Procedure:
N-(4-Cyanomethyl-2-fluoro-benzyl )-2-(4-fluoro-phenoxy)-nicotinamide (0.100 g) was combined with sodium azide (0.653 g) and triethylamine hydrochloride (0.334 g) in anhydrous toluene (4 mL). The reaction mixture was heated under nitrogen in a sealable tube in an oil bath (116° C.) overnight. The reaction mixture was then allowed to cool to ambient temperature. Water (10 mL) and ethyl acetate (10 mL) were added, and the organic layer was separated. The pH of the aqueous layer was adjusted to 3 with 3N hydrochloric acid. The aqueous layer was subsequently extracted with ethyl acetate (5×15 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (acetic acid:methanol:dichloromethane=1:5:94) to yield the title compound (0.33 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:18][NH2:19])[N:13]=[N:14][C:15]=1[O:16][CH3:17].[N:20]#[C:21]Br>C(O)C.O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:17][O:16][C:15]1[C:10]([O:9][CH3:8])=[CH:11][C:12]2[N:13]([C:21]([NH2:20])=[N:19][CH:18]=2)[N:14]=1
Reactant: N#CBr
Reactant: COc1cc(CN)nnc1OC
Solvent: CCO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2cnc(N)n2nc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
C-(5,6-Dimethoxypyridazin-3-yl)methylamine trifluoroacetic acid salt (37 mg) was initially charged in a mixture of ethanol and water (3.75/0.75 ml) while stirring at RT. Thereafter, cyanogen bromide solution (0.1 ml; 5M in ACN) was cautiously added dropwise and the mixture was stirred at RT for 3 h. Then further cyanogen bromide solution (0.1 ml) was added and the mixture was left to stand overnight. After again adding cyanogen bromide solution (0.1 ml), the mixture was stirred for 4 h, left to stand over the weekend and then heated to 40° C. for 2 h. Subsequently, the solvent was drawn off and the residue was purified by means of preparative HPLC. The product-containing fractions were combined, freed of the acetonitrile and freeze-dried. 18 mg of the desired compound were obtained.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][N:9]2[C:13](=[O:14])[N:12]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([N:31]5[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]5)=[CH:27][CH:26]=4)(=[O:23])=[O:22])=[CH:17][CH:16]=3)[N:11]=[N:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:38][C@@H:39]([CH2:52][NH2:53])[CH2:40][O:41][C:42]1[C:50]2[NH:49][C:48](=[O:51])[NH:47][C:46]=2[CH:45]=[CH:44][CH:43]=1>>[CH:1]1([CH2:6][CH2:7][CH2:8][N:9]2[C:13](=[O:14])[N:12]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([N:31]5[CH2:32][CH2:33][CH:34]([NH:53][CH2:52][C@H:39]([OH:38])[CH2:40][O:41][C:42]6[C:50]7[NH:49][C:48](=[O:51])[NH:47][C:46]=7[CH:45]=[CH:44][CH:43]=6)[CH2:35][CH2:36]5)=[CH:27][CH:26]=4)(=[O:23])=[O:22])=[CH:17][CH:16]=3)[N:11]=[N:10]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(-n4nnn(CCCC5CCCC5)c4=O)cc3)cc2)CC1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: O=c1[nH]c2cccc(OC[C@@H](O)CNC3CCN(c4ccc(NS(=O)(=O)c5ccc(-n6nnn(CCCC7CCCC7)c6=O)cc5)cc4)CC3)c2[nH]1

Procedure:
The title compound was prepared from 4-[4-(3-cyclopentyl-propyl)-5-oxo-4,5-dihydro-tetrazol-1-yl]-N-[4-(4-oxo-piperidine-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 226) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.90-4.00 (m, 29H), 5.10-5.30 (m, 1H), 6.58 (d, J=7.9 Hz, 1H), 6.61 (d, J=7.9 Hz, 1H), 6.81 (d, J=8.9 Hz, 2H), 6.89 (d, J=8.9 Hz, 2H), 6.90 (dd, J=7.9, 7.9 Hz, 1H), 7.86 (d, J=8.5 Hz, 2H), 8.07 (d, J=8.5 Hz, 2H), 10.70 (s, 1H), 10.80 (s, 1H); MS (ES) m/z: 732.3 (MH+); HRMS Calcd. for C36H46N9O6S(MH+): 732.3292. Found: 732.3294.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][C@H:14]1[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15]1)[CH:8]=O)(=O)C.[Cl-].[C:23]([C:25]1[CH:26]=[CH:27][C:28]2[O:32][C:31]([CH2:33][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:30][C:29]=2[CH:53]=1)#[N:24].C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(O)C.O>[C:19]([N:16]1[CH2:17][CH2:18][C@H:14]([O:13][C:12]2[CH:11]=[CH:10][C:7]([CH:8]=[CH:33][C:31]3[O:32][C:28]4[CH:27]=[CH:26][C:25]([C:23]#[N:24])=[CH:53][C:29]=4[CH:30]=3)=[CH:6][C:5]=2[OH:4])[CH2:15]1)(=[O:21])[CH3:20]
Reactant: N#Cc1ccc2oc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1
Reactant: CC(=O)Oc1cc(C=O)ccc1O[C@H]1CCN(C(C)=O)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Solvent: O
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)N1CC[C@H](Oc2ccc(C=Cc3cc4cc(C#N)ccc4o3)cc2O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.8 %

Procedure:
1.3 g of 3-acetyloxy-4-[((3S)-1-acetyl-3-pyrrolidinyl)oxy]benzaldehyde and 2.22 g of (5-cyano-2-benzofuranyl)methyltriphenylphosphonium chloride were dissolved in a solvent mixture of 10 ml of tetrahydrofuran and 10 ml of ethanol, followed by the addition of 0.943 g of 1,8-diazabicyclo[5.4.0]-7-undecene and by subsequent stirring at room temperature for 2 hours. To the mixture obtained were further added 1.88 g of 1,8-diazabicyclo[5.4.0]-7-undecene and 3 ml of water, followed by stirring at room temperature for 2 hours. The thus prepared reaction solution was adjusted to pH 4-5 with 10% citric acid aqueous solution and concentrated under a reduced pressure, and the resulting residue was extracted with chloroform, and then dried. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a chloroform/ethanol mixture as an elution solvent, thereby obtaining 1.8 g of 2-[2-[4-[((3S)-1-acetyl-3-pyrrolidinyl)oxy]-3-hydroxyphenyl]vinyl]-5-benzofurancarbonitrile as a powdery mixture of E and Z forms.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][S:10]2(=[O:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][C:21](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:22]>N1C=CC=CC=1>[C:21]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][S:10]2(=[O:19])=[O:18])=[CH:4][CH:3]=1)(=[O:22])[CH3:20]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: O=S1(=O)Nc2ccccc2C1=Cc1ccc(O)cc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C=C2c3ccccc3NS2(=O)=O)cc1
Yield: 80 %

Procedure:
To a cooled solution of 3-(4'-hydroxyphenyl)methylene-2,1-benzisothiazoline-2,2-dioxide (273 mg, 1 mmol) in dry pyridine (0.5 ml) is added acetic arthydride (204 mg, 2 mmol) and the mixture maintained at 0°-5° C. overnight. Thereupon the mixture is concentrated under vacuum, the residue dissolved in dichloromethane, the organic layer washed with water and then evaporated under reduced pressure. The crude product is crystallized from chloroformmethanol to yield pure 3-(4'-acetoxyphenyl)methylene-2,1-benzisothiazoline-2,2-dioxide (80% yield).
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH2:14][C:15]([N:17]([CH:27]1[CH2:29][CH2:28]1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[Cl:26])=[O:16])[CH2:12][OH:13])C1C=CC=CC=1.C[Si](I)(C)C>C(#N)C>[NH2:10][C@H:11]([CH2:12][OH:13])[CH2:14][C:15]([N:17]([CH:27]1[CH2:29][CH2:28]1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[Cl:26])=[O:16]
Reactant: O=C(N[C@H](CO)CC(=O)N(Cc1cccc(Cl)c1Cl)C1CC1)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: N[C@H](CO)CC(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Reaction time: 0.25 h
Yield: 82.3 %

Procedure:
Into a 1L round bottom flask fitted with a nitrogen inlet was added 4A (18.3 g, 40.6 mmol) and acetonitrile (450 mL). Trimethylsilyliodide (TMSI) (17.4 mL, 121.7 mmol, 3 eq) was added quickly at room temperature. After stirring for 15 minutes, the reaction was quenched with 50 mL of methanol. The solvent was removed under vacuum. The residue was partitioned between ethyl acetate (100 mL) and saturated sodium bicarbonate (50 mL). The organic layer was separated and the aqueous layer was extracted further with ethyl acetate (2×50 mL). The organic layers were combined and washed once with brine (50 mL). The organic phase was dried over sodium sulfate and filtered. Solvent was removed under vacuum and the residue was purified by column chromatography (5% methanol/1% triethylamine/DCM) to give 10.6 g of 4B (69%). ESI-MS:m/z 317.3 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[CH:24]=2)[NH:19][N:18]=1
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)c1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.7 %

Procedure:
TFA (0.5 mL, 6.490 mmol) was added to a solution of N-(3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-3-fluorobenz amide (9 mg, 0.019 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound as an off-white solid (4 mg). 1H NMR (400 MHz, CD3OD): δ 8.77 (bs, 1H), 7.85 (m, 3H), 7.76 (m, 3H), 7.58 (m, 3H), 7.39-7.35 (m, 1H); ESI-MS [M+H]+: 372.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:9])=[N:6][CH:7]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH:27]=[O:28])=[C:22](B(O)O)[CH:23]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCOC(C)=O.O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:27]=[O:28])=[C:20]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:9])=[N:6][CH:7]=2)[CH:19]=1
Reactant: O=Cc1ccc(Cl)cc1B(O)O
Reactant: COC(=O)CCNC(=O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C=O)cn1

Procedure:
Methyl 3-(5-bromopicolinamido)propanoate (2.0 g, 7.0 mmol), (5-chloro-2-formylphenyl)boronic acid (1.4 g, 7.7 mmol), Pd(dppf)Cl2 (572 mg, 0.7 mmol), and K2CO3 (2.1 g, 15.4 mmol) were dissolved in 1,4-dioxane (24 mL) and water (6 mL) and heated to 90° C. After 3 h the resulting mixture was poured into EtOAc/H2O (30 mL/30 mL) and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:37])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH:33]([OH:36])[CH2:34][OH:35])[C:5]2=[CH:4][CH:3]=1.[CH3:38][Si:39]([C:42]#[CH:43])([CH3:41])[CH3:40].CCN(CC)CC>CN(C=O)C.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.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:37])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:43]#[C:42][Si:39]([CH3:41])([CH3:40])[CH3:38])[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH:33]([OH:36])[CH2:34][OH:35])[C:5]2=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OCC(O)CO)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(OCC(O)CO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 75 °C

Procedure:
To a stirred solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2,3-dihydroxy-propoxy)-5-iodo-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione (120 mg, 0.183 mmol) in DMF (2 mL) were added PdCl2(PPh3)2 (15 mg), CuI (2 mg), trimethylsilyl acetylene (Aldrich, 2 mL) and Et3N (Aldrich, 2 mL) and the mixture was purged with nitrogen and then heated at 75° C. for 3 hrs. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried, and concentrated. The residue was purified by chromatography (0-4% MeOH in EtOAc). Yield 8 mg. MS (H+), 623
Reaction SMILES: NC1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:27].[H-].[Na+].IC.[CH3:38][N:39]([CH:41]=O)[CH3:40]>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[C:10]3[C:41]([N:39]([CH3:38])[CH3:40])=[C:3]([C:26]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[O:27])[O:4][C:5]3=[N:6][C:7]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:16][CH:15]=1
Reactant: CN(C)C=O
Reactant: Nc1c(C(=O)c2cccnc2)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(C)c1c(C(=O)c2cccnc2)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 0.050 g (0.101 mmol) of the product from Example 26 in DMF (1 mL) at 0° C. was treated with sodium hydride (0.008 g; 60% dispersion; 0.213 mmol). After the addition, the reaction mixture was stirred for 20 minutes at 0° C., and then treated with iodomethane (19 μL; 0.303 mmol). The reaction was warmed to room temperature and stirred for 1 h. The reaction was quenched with saturated NaHCO3 solution. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 50% ethyl acetate-hexane gradient) gave the title compound. HPLC/MS: 521.9 (M+1), 523.9 (M+3); Rt=3.96 min.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C@@H:7]([CH:12]1[CH2:14][CH2:13]1)[CH2:8]/[CH:9]=[CH:10]/[CH3:11])C.C(OC[C@H](OCC=[N:34][OH:35])CC=C)C1C=CC=CC=1.C(OC(OCC)CO[C@H](CC=C)COCC1C=CC=CC=1)C.C(OC[C@@H]1OCC2=NOC[C@@H]2C1)C1C=CC=CC=1>>[CH:12]1([C@H:7]([O:6][CH2:5][CH:4]=[N:34][OH:35])[CH2:8]/[CH:9]=[CH:10]/[CH3:11])[CH2:14][CH2:13]1
Reactant: C=CC[C@H](COCc1ccccc1)OCC=NO
Reactant: C/C=C/C[C@@H](OCC(OCC)OCC)C1CC1
Agent: C=CC[C@H](COCc1ccccc1)OCC(OCC)OCC
Agent: c1ccc(COC[C@H]2C[C@H]3CON=C3CO2)cc1
Product: C/C=C/C[C@@H](OCC=NO)C1CC1

Procedure:
[(1R,3E)-1-(2,2-Diethoxyethoxyl)pent-3-en-1-yl]cyclopropane (C25) was converted to the product using the method described for synthesis of 2-{[(2R)-1-(benzyloxy)pent-4-en-2-yl]oxy}-N-hydroxyethanimine (C3) in the section “Alternate conversion of C2 to C4.” In this case, purification was carried out using silica gel chromatography (Gradient: 0% to 80% ethyl acetate in heptane) to provide the product as a colorless oil. By 1H NMR, this was assigned as a roughly 1:1 mixture of oxime isomers. Yield: 200 mg, 1.09 mmol, 48%. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ [7.50 (dd, J=5.8, 5.6 Hz) and 6.93 (dd, J=3.6, 3.6 Hz), total 1H], 7.46 and 7.21 (2 br s, total 1H), 5.45-5.63 (m, 2H), {[4.50 (dd, half of ABX pattern, J=16.3, 3.6 Hz) and 4.40 (dd, half of ABX pattern, J=16.3, 3.7 Hz)] and [4.25 (dd, half of ABX pattern, J=12.8, 5.6 Hz) and 4.15 (dd, half of ABX pattern, J=12.9, 5.8 Hz)], total 2H}, 2.59-2.68 (m, 1H), 1.66-1.72 (m, 3H), 0.45-0.54 (m, 1H), 0.29-0.43 (m, 1H), 0.18-0.24 and 0.06-0.14 (2 m, total 1H).