Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([N:12]1[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[C:14](I)=[CH:13]1)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[Br:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([CH:39]=1)[C:33](N(OC)C)=[O:34]>C1COCC1>[Br:27][C:28]1[CH:39]=[C:32]([C:33]([C:14]2[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[N:12]([C@@H:10]([CH3:11])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:13]=2)=[O:34])[CH:31]=[N:30][CH:29]=1
Reactant: CON(C)C(=O)c1cncc(Br)c1
Reactant: CC(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cnccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(Br)c2)c2cnccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of 1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-3-iodo-1H-pyrrolo[3,2-c]pyridine (Preparation 55, 16 g, 38.6 mmol) in THF (340 mL) was added iPrMgCl (23.2 mL, 46.3 mmol, 2M solution in THF) dropwise at 0° C. After stirring at this temperature for 1 hour, a solution of 5-bromo-N-methoxy-N-methylnicotinamide (11.4 g, 46.3 mmol) in THF (40 mL) was added slowly to the reaction. The reaction was warmed at room temperature and stirred for 18 hours. The reaction was quenched by the addition of water (200 mL) and the solvents removed in vacuo. The residue was diluted with water (400 mL), extracted into DCM:MeOH (95:5, 200 mL)) five times, the organic layers collected, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with a gradient of 10-50% EtOAc in DCM to afford the title compound (18.3 g, 46.5%).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:48]1[CH:55]=[C:54]([NH2:56])[CH:53]=[CH:52][C:49]=1[C:50]#[N:51]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[NH2:56][C:54]1[CH:55]=[C:48]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:49]([C:50]#[N:51])=[CH:52][CH:53]=1
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1ccc(N)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(N)cc1-c1ccccc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
534 mg of phenylboronic acid, 79 mg of palladium(II) acetate, 287 mg of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 1.486 g of potassium phosphate (K3PO4) and 305 mg of 2-chloro-4-aminobenzonitrile were suspended in 7 ml of toluene and stirred at 80° C. under an argon atmosphere for 12 h. The cooled reaction mixture was admixed with water and ethyl acetate and filtered. The filtrate was extracted three times with a mixture of ethyl acetate and toluene. The organic phases were removed, dried over magnesium sulfate, filtered and concentrated under reduced pressure. 1H NMR: 7.52-7.42, m, 6H, 6.63, m, 2H, 6.25, s (broad), 2H.
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][S:3][CH2:2]1.Cl[CH2:19][CH2:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:23].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1>[CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([C:24]5[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=5)=[O:23])[CH2:15][CH2:14][C@@H:11]42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][S:3][CH2:2]1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCSC3)c1ccc(F)cc1
Yield: 67 %

Procedure:
To a solution of (7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole from EXAMPLE 1 (80 mg, 0.32 mmol) in 1,4-dioxane (15 ml) at 25° C. was added 4-chloro-1-(4-fluorophenyl)butan-1-one (96 mg, 0.48 mmol), K2CO3 (100 mg, 0.72 mmol), and KI (32 mg, 0.19 mmol), respectively. The mixture was stirred at ambient temperature for 16 hours before H2O (10 mL) was added and then extracted with EtOAc (2×20 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to give the title compound of EXAMPLE 4 as an oil (88 mg, 67%). 1H NMR(CDCl3, 300 MHz): δ 8.01 (m, 2H), 7.15 (m, 2H), 6.96 (d, 1H, J=6.6 Hz), 6.92 (d, 1H, J=6.6 Hz), 3.82 (m, 2H), 3.25 (m, 2H), 3.19-2.60 (m, 8H), 2.42 (m, 2H), 1.95 (m, 5H). LRMS (ES)+: 411 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:12]([NH:14][S@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Li+].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:12]([N:14]([CH3:22])[S@:15]([C:17]([CH3:19])([CH3:18])[CH3:20])=[O:16])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: C[C@H](N[S@@](=O)C(C)(C)C)c1cc(F)cc(C(F)(F)F)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@@H](c1cc(F)cc(C(F)(F)F)c1)N(C)[S@@](=O)C(C)(C)C
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
To a solution of (S)-N-((S)-1-(3-fluoro-5-(trifluoromethyl)phenyl)ethyl)-2-methyl propane-2-sulfinamide (350 mg, 1.12 mmol) in THF (10 mL) under N2 atmosphere, was dropwise added LHMDS (2.24 mL, 1 M in THF, 2.24 mmol) at −60° C. The reaction was stirred for 30 min at −60° C. followed by addition of MeI (240 mg, 1.69 mmol). The mixture was stirred at rt for another 3 h and quenched with water at 0° C. The resulting mixture was extracted with EtOAc (2×40 mL). The organic layers were dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to 2/1) to give the title compound (270 mg, yield: 74%); m/z (ES+): 326 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([Li])CCC.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>O1CCCC1>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])[C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 75.8 %

Procedure:
To a solution of benzothiazole (30.7 g) in tetrahydrofuran (700 ml), which was cooled at −78° C., was added dropwise n-butyllithium (2.5M solution in hexane) (100 ml) under a nitrogen atmosphere, the solution was stirred for 10 minutes at −78° C. Tributyltin chloride (77.9 g) was added dropwise thereto, the solution was stirred for 1.5 hours at −78° C., and then stirred for 2 hours while warming from −78° C. to room temperature. The reaction mixture was concentrated in vacuo, diethyl ether (400 ml) was added thereto, insoluble material was removed by filtration, and then the solvent was evaporated in vacuo. The residue was purified by distillation in vacuo (0.5 mmHg, 170 to 184° C.) to provide the title compound (73.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:33])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:18]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:36](I)[CH3:37].O>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:33])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([O:32][CH2:36][CH3:37])=[CH:31][C:18]3=4)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1ccccc1CO2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-hydroxydibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol (Example 32) (200 mg) in DMF (5 ml) were added sodium hydride (60% in oil, 25 mg), ethyl iodide (0.052 ml) and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:1) to give the titled compound (170 mg).
Reaction SMILES: [CH:1]1([C:7]([N:9]([CH2:20][CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[CH2:10]/[C:11](/[CH3:19])=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].C1(C)C=CC=CC=1>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[CH:1]1([C:7]([N:9]([CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:10]/[C:11](/[CH3:19])=[CH:12]/[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C/C(=C\c1ccccc1)CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C/C(=C\c1ccccc1)CN(CC1CCNCC1)C(=O)C1CCCCC1
Yield: 99.8 %

Procedure:
To a solution of 4-(N-cyclohexylcarbonyl-N-(2-methyl-3-phenyl-2-(E)-propenyl)aminomethyl)-1-t-butoxycarbonylpiperidine (1.55 g, 3.4 mmol) in dichloromethane (15 mL) stirring at room temperature under argon, was added trifluoroacetic acid (3.7 g, 32 mmol). After 1 h toluene (15 mL) was added and the mixture was evaporated under vacuum. The residue was repeatedly dissolved in dichloromethane and evaporated under vacuum to obtain a colorless gum that solidified on standing. This gum contained 4-(N-cyclohexylcarbonyl-N-(2-methyl-3-phenyl-2-(E)-propenyl)aminomethyl)piperidine trifluoroacetic acid salt (1.59 g, quantitative yield) and trace residual trifluoroacetic acid.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(OCC)C.[F:22][C:23]1[C:31]([F:32])=[C:30]([O:33][CH2:34][CH3:35])[CH:29]=[CH:28][C:24]=1[C:25](O)=[O:26]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:34]([O:33][C:30]1[CH:29]=[CH:28][C:24]([C:25]([O:16][C:13]2[CH:14]=[CH:15][C:10]([CH:7]3[CH2:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]3)=[CH:11][CH:12]=2)=[O:26])=[C:23]([F:22])[C:31]=1[F:32])[CH3:35]
Reactant: CCCC1CCC(c2ccc(O)cc2)CC1
Reactant: CCOc1ccc(C(=O)O)c(F)c1F
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCC1CCC(c2ccc(OC(=O)c3ccc(OCC)c(F)c3F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
In a 1 L three-neck flask, 6.60 g of 2,3-difluoro-4-ethoxybenzoic acid (a) and 7.06 g of 4-(4-propyl-1-cyclohexyl)phenol (b) were dissolved in 450 mL of methylene chloride. 4.09 g of 4-dimethylaminopyridine was added thereto and stirred for 1 hour at room temperature. A solution of 7.60 g of N,N-dicyclohexylcarbodiimide dissolved in 195 mL of methylene chloride was added thereto and stirred overnight. Then diethyl ether was added and the precipitated urea was filtered off, saturated aqueous solution of sodium chloride was added and was stirred for 1 hour. The organic layer separated was washed with 3N hydrochloric acid and saturated aqueous solution of sodium bicarbonate, and was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 13.1 g of 4-(4-propylcyclohexyl)phenyl 4-ethoxy-2,3-difluorobenzoate (c).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C(O[C:12](=[O:27])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:16][CH:15]=1)C>C1COCC1.C1CCCCC1>[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:12](=[O:27])[CH2:2][C:1]#[N:3])=[CH:19][CH:18]=1
Reactant: CC#N
Reactant: CCOC(=O)Cc1ccc(OCCCN(C)C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CN(C)CCCOc1ccc(CC(=O)CC#N)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
The [4-(3-Dimethylamino-propxy)-phenyl]-acetic acid ethyl ester is then condensed with the lithium anion of acetonitrile by the following method: A solution of dry acetonitrile (0.627 mL) in 20 mL of THF, that had been cooled in a dry ice-acetone bath for 2 h under Ar(g), is treated dropwise with 6 mL of a 2M solution of n-butyl lithium in cyclohexane. This mixture is allowed to stir at −78° C. for an additional 1.5 h, and is subsequently treated with 2.45 gms. of [4-(3-dimethylamino-propoxy)-phenyl]-acetic acid ethyl ester in dropwise fashion. The resulting solution is allowed to stir at −78° C. for an additional 30 minutes, and is then allowed to warm to room temperature overnight. The reaction mixture is then vacuum filtered affording the desired nitrile, 4-[4-(3-dimethylamino-propoxy)-phenyl]-3-oxo-butyronitrile, as a white solid (20–28% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N+:11]([O-])=O)=[CH:10][C:5]=2[CH2:4][S:3]1(=[O:15])=[O:14].CCOC(C)=O.[O:22]1[CH2:24][C@@H:23]1[CH2:25][NH:26][C:27](=[O:29])[CH3:28].FC(F)(F)S([O-])(=O)=O.[Mg+2].FC(F)(F)S([O-])(=O)=O>[Pd].CC#N>[OH:22][C@H:23]([CH2:24][NH:11][C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[S:3](=[O:15])(=[O:14])[CH2:4][C:5]=2[CH:10]=1)[CH2:25][NH:26][C:27](=[O:29])[CH3:28]
Reactant: CC(=O)NC[C@H]1CO1
Reactant: CN1c2ccc([N+](=O)[O-])cc2CS1(=O)=O
Agent: [Pd]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)NC[C@H](O)CNc1ccc2c(c1)CS(=O)(=O)N2C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
The product of Step 1 (0.20 g, 0.88 mmol) is dissolved into EtOAc (30 mL) in a Parr bottle and 10% Pd/C (100 mg) added under nitrogen. The mixture is hydrogenated on a Parr apparatus for 2 hrs at 30 psi. Filtration and evaporation of solvent gave a white solid. This material is added to a mixture of N-[(2S)oxiranylmethyl] acetamide (0.81 g, 7.0 mmol) and magnesium trifluoromethanesulfonate (0.42 g, 1.3 mmol) in dry CH3CN (10 mL) at room temperature. After 20 hrs solvent is evaporated and the residue purified by chromatography (4%MeOH/CH2Cl2) to give a foamy solid (0.23 g, 79%). HRMS (FAB) calcd for C13H19N3O4S +H1 314.1174, found 314.1174.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:19]3[C:10](=[C:11]4[C:16](=[CH:17][CH:18]=3)[NH:15][C:14]([CH3:21])([CH3:20])[CH:13]=[C:12]4[CH3:22])[C:9](=[O:23])[O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1.CC([O-])(C)C.[K+].[CH3:30][C:31]([Si:34](Cl)([CH3:36])[CH3:35])([CH3:33])[CH3:32].CCOC(C)=O.CCCCCCC>C1COCC1.CC#N.O>[Si:34]([O:1][C:2]1[C:3]2[C:19]3[C:10](=[C:11]4[C:16](=[CH:17][CH:18]=3)[NH:15][C:14]([CH3:20])([CH3:21])[CH:13]=[C:12]4[CH3:22])[C:9](=[O:23])[O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1)([C:31]([CH3:33])([CH3:32])[CH3:30])([CH3:36])[CH3:35]
Reactant: CC1=CC(C)(C)Nc2ccc3c(c21)c(=O)oc1cccc(O)c13
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: CC1=CC(C)(C)Nc2ccc3c(c21)c(=O)oc1cccc(O[Si](C)(C)C(C)(C)C)c13
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
10-hydroxy-2,2,4-trimethyl-1,2-dihydro-5H-chromeno[3,4-f]quinolin-5-one (HCl salt) (131.6 g), prepared as described in WO99/41256, in THF (2.6L) in a 5L 4-necked flask fitted with N2 inlet, temperature probe and overhead stirrer was treated with t-BuOK in approximately 20 g portions over 15 minutes (103.4 g total) at 0° C. under a N2 atmosphere. The cooled reaction mixture was stirred for 30 minutes. The mixture was treated with TBSCl in approximately 20 g portions over 15 minutes. The reaction was monitored by TLC, EtOAc:heptane (2:3), and/or HPLC, Zorbax Rx-C8 4.6 mm×25 cm column; mobile phase 90% H2O (0.1% H3PO4): 10% CH3CN (0.1% H3PO4) to 30:70 over 15 minutes, then to 10:90 over 20 minutes before ramping back to 10:90 over 2 minutes; 45 minute run; flow rate of 1 mL/minute; UV detection at 225 nm. Retention times: starting material—17.6 minutes; product—29.9 minutes, until starting material was consumed, about 30 minutes. The reaction mixture was quenched with 50% NH4Cl solution (1L) and extracted with EtOAc (1L). The organic layer was washed with brine (500 mL) before concentrating to a crude solid (180.8 g). The crude solid was slurried in CH3CN (900 mL) with heating until an even suspension was obtained. The suspension was then cooled to approximately 0° C., filtered and washed with cold CH3CN. The wet cake was dried at 40° C. in a vacuum oven to yield 82.2 g of the title compound as a yellow solid. The mother liquors were concentrated to a solid (69 g) and re-slurried in CH3CN (250 mL). A second crop was collected and dried to yield an additional 11.8 g (81% combined yield). A small sample was crystallized from CH3CN. Anal. calcd for C25H31NO3Si: C, 71.22; H, 7.41; N, 3.32. Found: C, 68.38; H, 7.45; N, 3.16; 1H NMR (CDCl3) δ0.32 (6H, s), 1.05 (9H, s), 1.33 (6H, s), 2.12 (3H, s), 4.26 (1H, br), 6.75 (1H, d), 6.94˜6.97 (2H, m), 7.17 (1H, t), 8.75 (1H, d); 13C NMR (CDCl3)δ−3.9, 18.4, 21.2, 25.9, 28.3, 50.4, 77.2, 110.1, 111.3, 115.4, 118.2, 120.0, 124.2, 126.9, 126.9, 127.3, 131.7, 132.0, 144.9, 151.9, 153.2, 160.1 with 3 peaks overlapping; HRMS-FAB: calcd m/z 422.2151, found 422.2137.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][N+:10]([O-:12])=[O:11]
Reactant: Cc1ccc(N)c(C)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(N[N+](=O)[O-])c(C)c1
Temperature: 4 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
In a solution that consists of 2,4-dimethylaniline (12.4 ml, 100 mmol) in 80 ml of concentrated sulfuric acid, it is mixed at 0° C. with 5.0 ml of fuming nitric acid and stirred for 20 minutes at 4° C., and then for 30 minutes at room temperature. The reaction mixture is poured into 600 ml of ice water, and set at a pH of 10 with 5N sodium hydroxide solution. The precipitate is suctioned off, washed with water and dried. 15.72 g (95% of theory) of 2,4-dimethylnitrophenylamine is obtained as a mixture of regioisomers.
Reaction SMILES: [NH2:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10](S(O)(=O)=O)=[CH:9][CH:8]=1.C(O)C1C=CC=CC=1.O>C1(C)C=CC=CC=1.ClCCl>[CH2:17]([O:4][C:3](=[O:5])[CH:2]([NH2:1])[CH3:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(N)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: OCc1ccccc1
Solvent: Cc1ccccc1
Product: CC(N)C(=O)OCc1ccccc1

Procedure:
4.45 g (50 mMol) 2-Amino propanoic acid were added to 9.7 (51 mMol) p-toluenesulphonic acid and 20 ml (193 mMol) Benzyl alcohol in 10 ml toluene. The reaction mixture was heated under reflux for 2 h using a water separator. 30 ml dichloromethane was added to the cooled reaction mixture. The product was purified by flash chromatography using CH2Cl2:CH3OH 50:1.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:7][CH:8]=1.CN(CCN(C)C)C.[Li]CCCC.[I:31]I>C1COCC1>[I:31][C:5]1[C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:13])[CH3:14])=[N:7][CH:8]=[C:3]([C:2]([F:16])([F:1])[F:17])[CH:4]=1
Reactant: II
Reactant: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cn1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncc(C(F)(F)F)cc1I
Temperature: -75 °C
Reaction time: 2 h

Procedure:
N-(5-(trifluoromethyl)pyridin-2-yl)pivalamide (22 g, 89.4 mmole) and TMEDA (33.3 ml, 223.4 mmole) were dissolved in THF (400 ml) under nitrogen and n-BuLi (139.6 ml, 223.4 mmole; 1.6 M solution in n-hexane) was added dropwise at −75° C. The mixture was stirred for 2 hours at −75° C. While maintaining this temperature a solution of iodine (56.7 g, 223.4 mmole) in THF (280 ml) was added dropwise and the reaction mixture was stirred for 2 hours. The reaction mixture was heated to 0° C. and quenched with saturated aqueous sodium thiosulfate solution. The aqueous phase was extracted with DCM (2×150 ml) and the combined organic phases were dried over MgSO4. After filtering off the drying agent and removing the solvent on a rotary evaporator the residue was purified by means of column chromatography (ether: cyclohexane=1:1) and N-(3-iodo-5-(trifluoromethyl)pyridin-2-yl)pivalamide (13 g, 39.1%) was thereby obtained.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:11][C@H:12]([C:14]([NH:16][CH:17]1[C:23](=[O:24])[N:22]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[N:19]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:18]1=[O:37])=[O:15])[CH3:13]>>[CH:1]1([CH2:6][C:7]([NH:11][C@H:12]([C:14]([NH:16][CH:17]2[C:18](=[O:37])[N:19]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:20]3[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=3[N:22]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:23]2=[O:24])=[O:15])[CH3:13])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)CN1C(=O)C(NC(=O)[C@H](C)N)C(=O)N(CC(C)C)c2ccccc21
Reactant: O=C(O)CC1CCCC1
Agent: Cl
Product: CC(C)CN1C(=O)C(NC(=O)[C@H](C)NC(=O)CC2CCCC2)C(=O)N(CC(C)C)c2ccccc21

Procedure:
Following General Procedure I above using cyclopentylacetic acid (Aldrich) and 3-(L-alaninyl)amino-2,4-dioxo-1,5-bis-(2-methylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-S), the title compound was prepared as an amorphous white solid. Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1). Rf=0.31 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: C([N:8]([C@H:10]([C:20]#[CH:21])[CH2:11][O:12][Si](C(C)(C)C)(C)C)[CH3:9])(OC(C)(C)C)=O.[F:22][C:23]1[C:24](I)=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:33]\[C:34]1[NH:35][CH:36]=[CH:37][C:38]=1[O:39][CH3:40].O>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.FC(F)(F)C(O)=O.C(Cl)Cl.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>[F:22][C:23]1[C:24]([C:21]#[C:20][C@@H:10]([NH:8][CH3:9])[CH2:11][OH:12])=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:33]\[C:34]1[NH:35][CH:36]=[CH:37][C:38]=1[O:39][CH3:40]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#C[C@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN[C@H](C#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2)CO
Reaction time: 2.5 h

Procedure:
Using Method C above, (R)-2-(N-Boc-N-methylamino)-1-(tert-butyldimethylsilyloxy)-but-3-yne (130 mg, 0.42 mmol) (Example 104C) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P)4Pd (24 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80 IC for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated, and the residue was chromatographed on a silica gel column with a 40-100% EtOAc in hexanes gradient. The intermediate that resulted from this operation was dissolved directly in 10 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.5 mL of H2O at 0 °C. and stirred for 2.5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (R)-(Z)-1,3-Dihydro-5-fluoro-4-[4-hydroxy-3-methylamino-1-butynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-10% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 28 mg, 38%).