Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:13](=[O:31])[NH:14][C:15](=[O:30])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][C:22]([N+:26]([O-:28])=[O:27])=[CH:23][CH:24]=3)[N:19]([CH3:29])[CH:18]=2)=[CH:4]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>O>[CH3:29][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:17]([C:16]2[C:15](=[O:30])[NH:14][C:13](=[O:31])[C:12]=2[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:2][O:1][C:32](=[O:34])[CH3:33])[CH:4]=2)=[CH:18]1
Reactant: Cn1cc(C2=C(c3cn(CO)c4ccccc34)C(=O)NC2=O)c2ccc([N+](=O)[O-])cc21
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)OCn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 2.5 h
Yield: 53 %

Procedure:
A slurry of 3-(1-hydroxymethyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione (120 mg, 0.288 mmol) (prepared as described in U.S. Ser. No. 09/268,887 (Compound II)) in 3 mL of acetic anhydride (Aldrich) was stirred at room temperature for 19 hours, and at 100° C. for 2.5 hours. The resulting solution was cooled, diluted with water, and extracted with EtOAc. The EtOAc layer was washed with water, brine, dried over magnesium sulfate, and evaporated. The residue was purified by flash chromatography using EtOAc/hexanes to give 77.1 mg of acetic acid 3-[4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3yl]-indol-1-ylmethyl ester. (Yield 53%).
Reaction SMILES: [C:1]([C:3]1(O[Si](C)(C)C)[CH2:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1)#[N:2].COCCN(S(F)(F)[F:31])CCOC.[O-][Mn](=O)(=O)=O.[K+]>C(Cl)Cl>[F:31][C:3]1([C:1]#[N:2])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C#N)(O[Si](C)(C)C)C1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#CC1(F)CCCNC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 156.1 %

Procedure:
To a mixture of tert-butyl 3-cyano-3-(trimethylsilyloxy)piperidine-1-carboxylate (300 mg, 1.005 mmol) in DCM (10 mL) was added [bis(2-methoxyethyl)amino]sulfur trifluoride (0.222 mL, 1.206 mmol). The reaction mixture was stirred for 2 hours at room temperature. TLC (1:1 EtAOc/hexanes) shows a new higher Rf spot when stained with KMnO4 and no starting material. The reaction mixture was diluted with DCM (10 mL) and washed with H2O. The organic layer was dried with MgSO4, filtered, and concentrated. Solids were purified on a silica gel cartridge using a 0-100% gradient of EtOAc/hexanes, concentrated, and then treated with TFA/DCM for 1 hour. Solvent was removed in vacuo and the solids were dried to give 201 mg of 3-fluoropiperidine-3-carbonitrile as a TFA salt. 1H NMR (400 MHz, chloroform-d) δ ppm 3.82-4.01 (1H, m), 3.68(1H, br. s.), 3.45-3.61 (1H, m), 3.37(1H, br. s.), 2.06-2.31 (2H, m), 1.79-1.94(1H, m), 1.63-1.76 (1H, m); 19F NMR (400 MHz, chloroform-d) δ ppm −157.4 (alpha-F); −156.5 (TFA).
Reaction SMILES: [CH:1]1([C:7](=O)[C:8](=[N:16]O)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[CH:1]1([C:7]2[NH:26][C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][C:8]=2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)C1CCCCC1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)c1nc(-c2ccccc2)[nH]c1C1CCCCC1
Yield: 27.1 %

Procedure:
tert-Butyl 3-cyclohexyl-2-hydroxyimino-3-oxopropionate (2.6 g) and benzylamine (2.1 g) were dissolved in benzene (50 ml), and the mixture was refluxed under heating for 16 hr. The solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:ethyl acetate=8:1) to give tert-butyl 5-cyclohexyl-2-phenylimidazole-4-carboxylate (0.90 g), melting point 222-223° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)#[N:8].[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20]Br)[CH3:17].O>CN(C=O)C.CCOC(C)=O>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]#[N:8])=[CH:10][CH:11]=1)[CH3:17]
Reactant: CCOC(CBr)OCC
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(COc1ccc(C#N)cc1)OCC
Temperature: 25 °C
Yield: 70.8 %

Procedure:
Powdered potassium carbonate (5.18 g, 37.7 mmol) is added to a stirred solution of 4-cyanophenol (2.00 g, 16.8 mmol) and bromoacetaldehyde diethyl acetal (4.53 mL, 30.3 mmol) in anhydrous DMF (20 mL). The resultant mixture is stirred at 85° C. under nitrogen for 3 days. The mixture is cooled to ambient temperature; then water (100 mL) and EtOAc (100 mL) are added to the mixture. The organic layer is separated, dried over MgSO4, filtered and concentrated. The oil is chromatographed on silica (gradient 5-20% EtOAc in hexane) to give 2.80 g (11.9 mmol, 71% yield) of the title compound. 1H NMR (CDCl3): δ1.24 (t, J=7.1 Hz, 6H), 3.60-3.68 (m, 2H), 3.73-3.81 (m, 2H), 4.04 (d, J=5.2 Hz, 2H), 4.83 (t, J=5.2 Hz, 1H), 6.97 (br d, J=9.2 Hz, 2H), 7.58 (br d, J=9.2 Hz, 2H); Analysis for C13H17NO3: calcd: C, 66.36; H, 7.28; N, 5.95; found: C, 66.41; H, 7.34; N, 6.01.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][N:16]([C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=1)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]>>[CH3:15][N:16]([C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:26][CH:25]=1)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21]
Reactant: O=[N+]([O-])c1cc(Br)nc2ccccc12
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CN(C(=O)OC(C)(C)C)c1ccc(-c2cc([N+](=O)[O-])c3ccccc3n2)cc1
Yield: 68.5 %

Procedure:
2-Bromo-4-nitroquinoline (50 mg, 0.2 mmol) and tert-butyl methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (66 mg, 0.2 mmol) were reacted using General Procedure (A) to afford tert-butyl methyl(4-(4-nitroquinolin-2-yl)phenyl)carbamate as a yellow oil (52 mg, 68%). 1H NMR (400 MHz, CDCl3): δ 8.43-8.40 (m, 2H), 8.28 (m, 1H), 8.19 (m, 2H), 7.87 (m, 1H), 7.73 (m, 1H), 7.46 (m, 2H), 3.35 (s, 3H), 1.59 (s, 3H), 1.50 (s, 9H); MS (ESI): 380 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([C:17](=[O:21])[CH2:18][CH2:19]Cl)[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[N:9]([CH3:12])[C:10](=[O:11])[C:4]=2[CH:3]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C.CCOCC>O1CCOCC1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([C:17](=[O:21])[CH2:18][CH2:19][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[N:9]([CH3:12])[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: C1CCNC1
Reactant: CN1C(=O)c2cc(Cl)ccc2N(C(=O)CCCl)c2ccccc21
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN1C(=O)c2cc(Cl)ccc2N(C(=O)CCN2CCCC2)c2ccccc21

Procedure:
3.5 gm (0.01 mol) of 2-chloro-5-(3-chloro-propionyl)-5,10-dihydro-10-methyl-11H-dibenzo[b,e][1,4]diazepin-11-one and 3.5 gm (0.05 mol) of pyrrolidine were refluxed in 50 ml of dioxane for 4 hours. After addition of activated charcoal, the reaction mixture was filtered, and the filtrate was evaporated in vacuo. The residue was dissolved in chloroform, the solution was extracted with water, and the organic phase was evaporated in vacuo. The oily residue was obtained as crystals after addition of ether. After recrystallization from cyclohexane 2.6 gm of the crystalline title compound, m.p. 118°-120° C., were obtained.
Reaction SMILES: Br.Br.[C@H:3]12[CH2:9][C@H:6]([NH:7][CH2:8]1)[CH2:5][NH:4]2.Br[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][N:4]2[CH2:5][C@@H:6]3[CH2:9][C@H:3]2[CH2:8][N:7]3[CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: C1N[C@@H]2CN[C@H]1C2
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CCN2C[C@@H]3C[C@H]2CN3CCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 60 °C

Procedure:
A mixture of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane dihydrobromide (60 mg, 0.23 mmol), 1-(2-bromoethyl)-4-nitrobenzene (210 mg, 0.92 mmol), tetrabutylammonium iodide (8.5 mg, 0.023 mmol), and K2CO3 (128 mg, 0.92 mmol) in DMF (2 mL) was heated to 60° C. for 16 hours. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 397 [M+1]+. (0.11 μM)
Reaction SMILES: BrC1C=CC(O)=C([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[S:45][C:46](C(=O)C)=[C:47]([CH3:49])[N:48]=2)=[CH:40][CH:39]=1.[OH-].[K+]>C(O)C>[Cl:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]2[S:45][C:46]([C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:18]5[N:22]([CH:23]6[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]6)[C:21]6[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=6[N:19]=5)[CH:14]=4)[N:9]=3)=[C:47]([CH3:49])[N:48]=2)=[CH:42][CH:43]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1sc(-c2ccc(Cl)cc2)nc1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(-c2ccc(Cl)cc2)sc1-c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1
Yield: 19 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-[2-(4-chloro-phenyl)-4-methyl-thiazol-5-yl]-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (27 mg, 19% yield). MS: 580.19 (M+H+); HPLC Procedure B, retention time=9.18 min.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH2:13]O)[CH:10]=[CH:11][CH:12]=2)=[N:4][CH:3]=1.P(Br)(Br)([Br:17])=O.C([O-])(O)=O.[Na+]>C1COCC1>[Br:17][CH2:13][C:9]1[CH:8]=[C:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][N:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cnc(-c2cccc(CO)c2)o1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cnc(-c2cccc(CBr)c2)o1
Temperature: 25 °C
Yield: 84.5 %

Procedure:
To a stirred solution of (3-(5-methyloxazol-2-yl)phenyl)methanol (0.79 g, 4.13 mmol) in THF (15 mL), POBr3 (1.93 g, 6.61 mmol) was added in portions at 5° C. The reaction mixture was allowed to warm to rt and then heated at 60° C. for 4 h. The mixture was cooled to rt, poured into saturated aqueous NaHCO3 solution and extracted with TBME (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash-column chromatography over silicagel (eluent: gradient 5%-40% ethyl acetate/heptane) to yield the title compound (0.88 g, 84%). [1H NMR (400 MHz, CHLOROFORM-d) ♀ ppm 8.01-8.07 (m, 1H), 7.93 (ddd, J=6.7, 2.1, 1.9 Hz, 1H), 7.39-7.47 (m, 2H), 6.85 (d, J=1.3 Hz, 1H), 4.53 (s, 2H), 2.41 (d, J=1.3 Hz, 3H); LCMS RtA=1.10, [M+H]+=252.1/254.1].
Reaction SMILES: O1CCCC1.Br[C:7]1[CH:16]=[N:15][C:10]2[O:11][CH2:12][CH2:13][NH:14][C:9]=2[CH:8]=1.[C:17]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)(=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>O>[NH:14]1[CH2:13][CH2:12][O:11][C:10]2[N:15]=[CH:16][C:7]([C:23]3[CH:24]=[CH:25][C:20]([C:17](=[O:19])[CH3:18])=[CH:21][CH:22]=3)=[CH:8][C:9]1=2
Reactant: Brc1cnc2c(c1)NCCO2
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(-c2cnc3c(c2)NCCO3)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
To 3 ml of tetrahydrofuran/0.5 ml of distilled water, 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (80.0 mg, 0.37 mmol), 4-acetylphenyl boronic acid (71 mg, 0.55 mmol), potassium carbonate (103 mg, 0.74 mmol) and tetrakis triphenylphosphine palladium (21 mg, 0.02 mmol) were added and stirred at 80° C. for 2 hours. After completion of the reaction, the mixture was extracted ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The resulting solid was recrystallized from n-hexane and diethyl ether to obtain 1-[4-(2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-phenyl]-ethanone as yellow solid (59 mg, 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[N:8]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1.O>C(Cl)Cl>[CH:31]1([C:34]([NH:1][C:2]2[CH:23]=[CH:22][C:5]([O:6][C:7]3[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:8]=3)=[CH:4][CH:3]=2)=[O:35])[CH2:33][CH2:32]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc(Oc2nc(-c3cccnc3)ncc2C(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1cnc(-c2cccnc2)nc1Oc1ccc(NC(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a solution of Compound 17c (0.5 g; 1.6 mmol) in CH2Cl2 (6 mL) was added Et3N (0.72 mL; 6.4 mmol) and cyclopropylcarbonyl chloride (0.19 mL; 2.1 mmol). The solution was stirred at room temperature for 1 h, then poured the reaction mixture into water. Filtered to collect the solid and dried to afford Compound 17d (410 mg; 68% yield). MS: m/z 376.1 (M+H)+.
Reaction SMILES: CC([N:5]([C@@H:9]([CH3:16])[CH2:10][CH2:11][NH:12][CH:13]1[CH2:15][CH2:14]1)[C:6](=[O:8])[O-:7])(C)C.[CH3:17][C:18](N([C@@H](C)CC=O)C(=O)[O-])([CH3:20])[CH3:19].C1(N)CC1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:13]1([NH:12][CH2:11][CH2:10][C@@H:9]([NH:5][C:6](=[O:8])[O:7][C:18]([CH3:20])([CH3:19])[CH3:17])[CH3:16])[CH2:14][CH2:15]1
Reactant: C[C@@H](CC=O)N(C(=O)[O-])C(C)(C)C
Reactant: C[C@@H](CCNC1CC1)N(C(=O)[O-])C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: NC1CC1
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: C[C@@H](CCNC1CC1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
1,1-Dimethylethyl[(1S)-1-methyl-3-oxopropyl]carbamate. To a stirred solution of 1,1-dimethylethyl[(1S)-2-cyano-1-methylethyl]carbamate (0.656 g, 3.56 mmol) in anhydrous ether cooled to −40° C. was added dropwise a 1.0 M solution of diisobutylaluminum hydride in hexanes (14.2 mL, 14.2 mmol) over 20 minutes. Stirring was continued at this temperature for an additional 20 minutes. The yellow solution was quenched with Rochelle's salt and the resultant stirred at room temperature for 1 hour. The solids were filtered off through celite and rinsed with EtOAc. The organics were washed with brine, concentrated, and flash chromatographed (10-100% EtOAc/hexanes) to give 1,1-dimethylethyl [(1S)-1-methyl-3-oxopropyl]carbamate (0.193 g, 30%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 1.22 (d, J=6.8 Hz, 3H), 1.41 (s, 9H), 2.53-2.65 (m, 2H), 4.08-4.13 (m, 1H), 4.63 (m, 1H), 9.74-9.75 (m, 1H). b) 1,1-Dimethylethyl[(1S)-3-(cyclopropylamino)-1-methylpropyl]carbamate. The protected diamine was prepared using a modified procedure as described in example Z-32. A solution of 1,1-dimethylethyl[(1S)-1-methyl-3-oxopropyl]carbamate (0.178 g, 0.95 mmol) and cyclopropylamine (197 μL, 2.85 mmol) in anhydrous dichloroethane (10 mL) was treated with acetic acid (272 μL, 4.8 mmol) and stirred for 30 minutes. Sodium triacetoxyborohydride (0.444 g, 2.1 mmol) was added and the solution was stirred for 20 hours. The resultant was subjected to a workup and purification procedure as described in example Z-32 to give 1,1-dimethylethyl [(1S)-3-(cyclopropylamino)-1-methylpropyl]carbamate (0.136 g, 63%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 0.32-0.42 (m, 4H), 1.12 (d, J=6.8 Hz, 3H), 1.39-1.51 (m, 10H), 1.58-1.92 (m, 2H), 2.05-2.10 (m, 1H), 2.67-2.80 (m, 2H), 3.71 (m, 1H), 4.78 (m, 1H). c) [(3S)-3-Aminobutyl]cyclopropylamine dihydrochloride was prepared in a similar manner as described in example Z-29. 1H NMR (400 MHz, CDCl3/CD3OD) δ 0.70-0.75 (m, 2H), 0.90-0.94 (m, 2H), 1.18 (d, J=6.8 Hz, 3H), 1.84-1.94 (m, 1H), 1.97-2.05 (m, 1H), 2.49-2.54 (m, 1H), 2.99-3.04 (m, 2H), 3.23-3.28 (m, 1H), d)
Reaction SMILES: [CH:1]1([O:7][C:8]2[N:13]=[C:12]([C@H:14]([OH:18])[CH2:15][C:16]#[N:17])[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N.CO.C(Cl)Cl>>[NH2:17][CH2:16][CH2:15][C@H:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:13]=1)[OH:18]
Reactant: N#CC[C@@H](O)c1cccc(OC2CCCCC2)n1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: NCC[C@@H](O)c1cccc(OC2CCCCC2)n1

Procedure:
Reduction of (R)-3-(6-(cyclohexyloxy)pyridin-2-yl)-3-hydroxypropanenitrile following the method described in Example 6 gave after flash chromatography purification (15%-25% 7N NH3/MeOH—CH2Cl2 gradient) Example 26 as a colorless oil. Yield (0.4 g, 33%); 1H NMR (400 MHz, CD3OD) δ 7.61 (t, J=7.8 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.58 (d, J=8.4 Hz, 1H), 5.05-4.96 (m, 1H), 4.40-4.28 (m, 1H), 2.84 (t, J=6.8 Hz, 2H), 2.08-1.74 (m, 6H), 1.62-1.32 (m, 6H); RP-HPLC tR=7.04 min; ESI-MS m/z 251.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]3[C:13]([O:20][CH3:21])=[CH:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:10]=3[CH:9]=2)[C:5]([Cl:22])=[CH:4][N:3]=1.C([N:26]([CH:29]([CH3:31])[CH3:30])CC)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C1(N)CC1>ClCCl>[CH:29]1([NH:26][C:17]([C:16]2[C:10]3[CH:9]=[C:8]([C:6]4[C:5]([Cl:22])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=4)[S:12][C:11]=3[C:13]([O:20][CH3:21])=[CH:14][CH:15]=2)=[O:19])[CH2:31][CH2:30]1
Reactant: COc1ccc(C(=O)O)c2cc(-c3nc(Cl)ncc3Cl)sc12
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Solvent: ClCCl
Product: COc1ccc(C(=O)NC2CC2)c2cc(-c3nc(Cl)ncc3Cl)sc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.7 %

Procedure:
To a stirred suspension of 2-(2,5-dichloropyrimidin-4-yl)-7-methoxybenzo[b]thiophene-4-carboxylic acid (2.50 g, 3.07 mmol) is added diisopropylethylamine (1.12 mL, 6.44 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (617 mg, 3.22 mmol) and 1-hydroxybenzotriazole (435 mg, 3.22 mmol) at room temperature under nitrogen atmosphere. The mixture is treated with cyclopropylamine (184 mg, 3.22 mmol) and stirred at room temperature for 1 day. The mixture is diluted with dichloromethane (60 mL) and washed with water (3×30 mL). The organic phase suspension is filtered off to give a yellow solid which is washed with dichloromethane and water to give the title compound as a yellow solid (880 mg, 72% yield).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[CH:20]=[C:19]([O:21][CH2:22][O:23][CH3:24])[CH:18]=[CH:17][C:16]=1[C:25](=[O:28])[CH2:26]I)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC(C)=O>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:1][OH:4])=[C:19]([CH:20]=1)[O:21][CH2:26][C:25]([C:16]1[CH:17]=[CH:18][C:19]([O:21][CH2:22][O:23][CH3:24])=[CH:20][C:15]=1[O:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:28])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COCOc1ccc(C(=O)CI)c(OCc2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1ccc(C(=O)COc2cc(OCc3ccccc3)ccc2CO)c(OCc2ccccc2)c1
Yield: 144.2 %

Procedure:
Potassium carbonate (0.165 g, 1.2 mmol) was added to a solution of 1-[2-benzyloxy-4-(methoxymethyloxy)phenyl]-2-iodo-ethanone (0.412 g, 1 mmol) and 4-benzyloxy-salicylalchohol (0.254 g, 1.1 mmol) in 10 mL of acetone and the mixture refluxed for 10 hours. After completion of the reaction (TLC), the solvent was evaporated and the residue extracted with EtOAc:water (2×20 mL:20 mL). The organic layers were combined, dried over sodium sulfate and evaporated. The residue was chromatographed over silica using hexanes:EtOAc (2:1). The organic fractions were evaporated to provide 0.371 g (72%) of white solid: mp 115-118° C.; TLC Rf0.16 in hexanes:EtOAc (2:1); 1H NMR (600 MHz, CDCl3) δ 7.88-7.86 (d, 1H, J=9 Hz, Ar—H5), 7.64-7.25 (m. 10H, 2×C6H5), 7.21-7.20 (d, 1H, J=8.4 Hz, Ar—H6′), 6.92 (d, 1H, J=2.4 Hz, Ar—H8), 6.78-6.76 (dd, 1H, 2J=9 Hz, 3J=2.4 Hz, Ar—H6), 6.56-6.54 (dd, 1H, 2J=8.4 Hz, 3J=2.4 Hz, Ar—H5′), 6.26-6.25 (d, 1H, J=2.4 Hz, Ar—H3′), 5.30 (s, 4H, PhCH2), 5.21 (s, 2H, O—CH2—O), 4.98 (s, 2H, H-2), 4.57-4.56 (d, 2H, J=6 Hz, CH2OH), 4.13-4.11 (t, 1H, CH2OH), 3.44 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3) δ 194.6, 164.4, 162.2, 160.7, 158.6, 138.9, 137.6, 133.6, 130.2, 129.9, 129.8, 129.2, 125.1, 120.4, 110, 106.8, 102.5, 101.7, 95.6, 75.3, 72.4, 71.2, 61.5, 56.9; analysis calcd. for C31H30O7. C, 72.36; H, 5.88. found: C, 72.1; H, 5.85.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([N:14]1[CH2:31][CH:30]([CH2:32]O)[O:29][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:15]1)[C:11]#[C:12][CH3:13].CO.ClCCl>ClCCl>[CH2:10]([N:14]1[CH2:31][CH:30]([CH2:32][F:7])[O:29][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:15]1)[C:11]#[C:12][CH3:13]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC#CCN1CC(CO)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Solvent: CO
Solvent: ClCCl
Product: CC#CCN1CC(CF)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 45.6 %

Procedure:
To a solution of diethylaminosulfur trifluoride (19.5 μL, 0.148 mmol) in dichloromethane (1.0 mL) at −78° C. was added dropwise a solution of tert-butyl 8-but-2-ynyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (50.0 mg, 0.148 mmol) in dichloromethane (1 mL). The reaction was stirred for 10 min at −78° C. then allowed to warm to room temperature and stirred for 16 h. Silica gel chromatography (4 g silica, 0-15% methanol/dichloromethane) provided tert-butyl 8-but-2-ynyl-10-(fluoromethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (23.0 mg, 46%). ESI-MS m/z calc. 340.2. Found 341.3 (M+1)+; Retention time: 1.16 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 4.52-4.40 (m, 1H), 4.39-4.28 (m, 1H), 4.06-3.91 (m, 1H), 3.71 (br s, 2H), 3.35-3.14 (m, 3H), 3.08 (t, J=11.4 Hz, 1H), 2.78 (d, J=10.3 Hz, 1H), 2.58 (d, J=11.1 Hz, 1H), 2.31 (d, J=13.5 Hz, 1H), 2.06 (t, J=12.5 Hz, 2H), 1.84 (t, J=2.3 Hz, 3H), 1.57-1.44 (m, 12H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[CH:7][C:8]=1[CH3:9].C([Mg]Cl)(C)C.[CH:16]([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](=[O:38])[C:30]1=[O:39])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[C:23]1([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([OH:38])([C:6]3[CH:7]=[C:8]([CH3:9])[C:3]([O:2][CH3:1])=[CH:4][C:5]=3[OH:10])[C:30]2=[O:39])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: COc1cc(O)ccc1C
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Product: COc1cc(O)c(C2(O)C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 116.5 %

Procedure:
To a stirred solution of 3-methoxy-4-methylphenol (Jorgensen, E. C., et al., J. Med. Chem. (1971), 14:1199-202) (7.5 g, 54.3 mmol) in dichloromethane (160 mL) was added isopropylmagnesium chloride (29.0 mL, 2 M in tetrahydrofuran, 58 mmol) at 0° C. The resultant mixture was stirred at 0° C. for 30 min followed by the addition of 1-benzhydrylindoline-2,3-dione (10.4 g, 36.3 mmol). The reaction mixture was stirred at ambient temperature for 10 min and concentrated in vacuo to dryness. The residue was dissolved in ethyl acetate (300 mL) and washed with saturated ammonium chloride solution (2×200 mL). The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford 1-(diphenylmethyl)-3-hydroxy-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one (19.10 g) as a crude brown oil: MS (ES−) m/z 450.3 (M−1).