Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:13](=[O:15])[CH3:14])[CH:8]=[C:9]([Cl:12])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].CI.[CH3:18]N(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([C:13](=[O:15])[CH3:14])[CH:8]=[C:9]([Cl:12])[C:10]=1[O:11][CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(=O)c1cc(Cl)c(O)c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: Cc1ccccc1
Product: COc1c(Cl)cc(C(C)=O)cc1C(C)(C)C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
1-(3-tert-Butyl-5-chloro-4-hydroxyphenyl)ethanone (1.65 g, 7.28 mmol) and methyl iodide (2.07 g, 14.56 mmol) were added to N,N-dimethylformamide (2.5 mL), followed by stirring on ice, and addition of potassium carbonate (1.51 g, 10.92 mmol). After 3 hours of stirring, toluene (30 mL) and water (20 mL) were added, and the solution was separated. The organic layer was washed with water (15 mL), dried, and then concentrated under reduced pressure (50° C.) to obtain 1.37 g of the subject compound as a yellowish oily substance (yield: 78.2%, HPLC purity: 99.4%)
Reaction SMILES: [CH3:1][C@H:2]1[C@H:15](/[CH:16]=[CH:17]/[C:18]([CH3:31])([O:24]C2CCCCO2)[CH2:19][CH2:20][C:21]#[C:22][CH3:23])[C@@H:5]([CH2:6]/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:4](=[O:32])[CH2:3]1>C(O)(=O)C.O.C1COCC1>[CH3:1][C@H:2]1[C@H:15](/[CH:16]=[CH:17]/[C:18]([CH3:31])([OH:24])[CH2:19][CH2:20][C:21]#[C:22][CH3:23])[C@@H:5]([CH2:6]/[CH:7]=[CH:8]\[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:4](=[O:32])[CH2:3]1
Reactant: CC#CCCC(C)(/C=C/[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)O)OC1CCCCO1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC#CCCC(C)(O)/C=C/[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Reaction time: 16 h

Procedure:
A solution of 450 mg. of (5Z,13E)-(11R,15RS)-11,15-dimethyl-9-oxo-15-(tetrahydropyran-2-yloxy)-5,13-prostadien-18-ynoic acid in 15 ml. of a mixture of glacial acetic acid/water/THF (65/35/10) is agitated for 16 hours at 25°. After evaporating the solvent under vacuum, the remainder is purified by chromatography on silica gel. By elution with methylene chloride containing 1-5% methanol, 305 mg. of the title compound is isolated in the form of an oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:35]5[NH:39][C:38](=[O:40])[O:37][N:36]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:41][CH2:42][CH3:43])[N:17]=[C:16]3[CH3:44])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH3:44][C:16]1[N:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH:5]3[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]3)=[CH:14][CH:13]=2)[C:20](=[O:21])[C:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][C:38](=[O:40])[O:37][N:36]=3)=[CH:25][CH:24]=2)=[C:18]([CH2:41][CH2:42][CH3:43])[N:17]=1
Reactant: CCCc1nc(C)n(-c2ccc(OC3CCC(O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC3CCC(=O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 2 h
Yield: 77.8 %

Procedure:
To a solution of 3-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.49 g) in methylene chloride (4 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.52 g), and the mixture was stirred for 2 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.38 g, 79%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[C:27]5[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][C:28]=5[N:29]=[CH:30][N:31]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:43]([NH2:46])([CH3:45])[CH3:44].[Na+].[I-]>>[CH:43]([NH:46][CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[C:27]5[CH2:35][CH2:34][NH:33][CH2:32][C:28]=5[N:29]=[CH:30][N:31]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1)([CH3:45])[CH3:44]
Reactant: CC(C)N
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(CCl)cc(C(F)(F)F)c3)c2)C1
Agent: [I-]
Agent: [Na+]
Product: CC(C)NCc1cc(NC(=O)n2ccc3cc(Oc4ncnc5c4CCNC5)ccc32)cc(C(F)(F)F)c1
Temperature: 45 °C

Procedure:
To a solution of the above mixture (0.15 g, 0.227 mmol) in 3 mL of DCM, isopropyl amine (0.06 mL, 0.680 mmol) is added followed by sodium iodide (0.1 g, 0.68 mmol). After 45 min, LC-MS shows that tert-butyl 4-(1-(3-((methylsulfonyloxy)methyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate is converted to desired product and the tert-butyl 4-(1-(3-(chloromethyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate left over. To the reaction 3 mL (0.227 mmol) of isopropyl amine is added followed by NaI (0.1 g, 0.68 mmol) and the mixture is heated to 45° C. for 2 h. The solvent is then removed and the residue diluted with EtOAc, washed with H2O, brine and the organic layer dried over Na2SO4. Following concentration the residue is separated by FCC (25-100% EtOAc/heptane). This product is then treated with 60 mL of 50% TFA/DCM at rt for 1.5 h. After concentration the residue is separated by semi-prep HPLC (C-18; 10-100% I/H2O with 0.1% NH4OH) to provide the title compound. MS (ESI) m/z 525.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (s, 1H), 8.40 (s, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.13 (d, J=3.8 Hz, 1H), 7.95 (d, J=15.2 Hz, 2H), 7.38-7.52 (m, 2H), 7.11 (dd, J=9.0, 2.4 Hz, 1H), 6.78 (d, J=3.8 Hz, 1H), 3.81 (d, J=7.6 Hz, 4H), 3.03 (t, J=5.8 Hz, 2H), 2.68-2.79 (m, 3H), 1.03 (d, J=6.1 Hz, 6H).
Reaction SMILES: [O:1]1[CH:7]=[CH:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[Si]([C:13]#[N:14])(C)(C)C.O.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])[CH3:17]>CO.[I-].[Zn+2].[I-]>[C:13]([C:3]1([N:24]2[CH2:23][CH2:22][N:21]([C:19]([O:18][CH2:16][CH3:17])=[O:20])[CH2:26][CH2:25]2)[CH2:4][CH2:5][CH:6]=[CH:7][O:1][CH2:2]1)#[N:14]
Reactant: O=C1CCC=COC1
Reactant: CCOC(=O)N1CCNCC1
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: O
Solvent: CO
Product: CCOC(=O)N1CCN(C2(C#N)CCC=COC2)CC1
Temperature: 25 °C
Yield: 58.4 %

Procedure:
4,5-Dihydrooxepin-3(2H)-one (220 mg, 1.962 mmole) and zinc iodide (31 mg, 0.097 mmole) were combined neat. To this was added TMSCN (0.28 ml, 2.089 mmole) slowly (cooling with cold water bath). After 1 hr a solution of 1-ethoxycarbonylpiperazine (0.32 ml, 2.195 mmole) in MeOH (10 ml) was added then the mixture was heated to reflux. After 16 hr the mixture was cooled to RT and concentrated. Flash column chromatography (25% EtOAc/hexanes) gave the title compound as a clear oil (320 mg, 58%). 1H-NMR (CDCl3, 500 MHz) 6.32 (d, J=6.34 Hz, 1 H), 4.80 (m, 1 H), 4.31 (d, J=12.94 Hz, 1 H), 4.15 (m, 3 H), 3.55 (bs, 4 H), 2.64 (bs, 4 H), 2.30 (bs, 3 H), 2.16 (m, 1 H), 1.27 (t, J=7.08 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH3:8])[C:3]=1[CH3:9].[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:7]([C:4]1[C:3]([CH3:9])=[C:2]([NH:1][S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[O:6][N:5]=1)[CH3:8]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCc1noc(N)c1C
Product: CCc1noc(NS(=O)(=O)c2ccccc2)c1C
Yield: 68 %

Procedure:
N-(3-Ethyl-4-methyl-5-isoxazolyl)benzenesulfonamide was prepared as described in Example 42 from 5-amino-3-ethyl-4-methylisoxazole and benzenesulfonyl chloride in 68% yield. Purification was achieved by preparative HPLC to give a white solid, m.p. 94°-95° C.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[CH2:17][CH:16]2[O:18][CH:12]([CH2:13][NH:14][CH2:15]2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].CC1C=C(C)C=C(C)C=1S(O[CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])(=O)=O>C1(C)C=CC=CC=1>[C:41]([O:40][C:38](=[O:39])[NH:37][CH2:36][CH2:35][CH2:34][N:14]1[CH2:15][CH:16]2[O:18][CH:12]([CH2:11][N:10]([CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:17]2)[CH2:13]1)([CH3:44])([CH3:43])[CH3:42]
Reactant: c1ccc(CN2CC3CNCC(C2)O3)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)OCCCNC(=O)OC(C)(C)C)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCN1CC2CN(Cc3ccccc3)CC(C1)O2
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 90.1 %

Procedure:
To 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane dihydrochloride (25.08 g, 86.12 mmol; see Preparation O above) was added 2.5 M sodium hydroxide (115 mL). 3-(tert-Butyloxycarbonylamino)propyl 2,4,6-trimethylbenzenesulfonate (32.35 g, 90.50 mmol; see Preparation L above) and toluene (65 mL) were then added and the reaction mixture heated at 65° C. for 12 hours. The phases were separated at 65° C. and the lower (aqueous) layer discarded. The organic phase was re-heated to 65° C. and then extracted with 10% w/w aqueous citric acid (125 mL). The phases were separated and the upper (organic) phase discarded. To the aqueous citric acid phase was added isopropyl acetate (150 mL) and 5 M sodium hydroxide (75 mL). The resulting mixture was stirred at room temperature for 15 minutes. The phases were separated and the lower (aqueous) phase discarded. The resulting organic phase was dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound as a colourless oil (29.13 g, 77.60 mmol, 90%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]([C:14]1[CH:15]=[CH:16][C:17]2[CH2:18][C@H:19]3[N:30]([CH:31]=O)[CH2:29][CH2:28][C@@:25]4([C:26]=2[CH:27]=1)[C@H:20]3[CH2:21][CH2:22][CH2:23][CH2:24]4)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C.O>O1CCCC1>[O:7]([C:14]1[CH:15]=[CH:16][C:17]2[CH2:18][C@H:19]3[N:30]([CH3:31])[CH2:29][CH2:28][C@@:25]4([C:26]=2[CH:27]=1)[C@H:20]3[CH2:21][CH2:22][CH2:23][CH2:24]4)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=CN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Temperature: 25 °C
Yield: 76 %

Procedure:
To a suspension of 1.1 g of lithium aluminum hydride in 120 ml of anhydrous tetrahydrofuran, 10.8 g (0.03 mol) of crude (±)-3-phenoxy-N-formylmorphinan in 50 ml of tetrahydrofuran was added dropwise. After the mixture had been refluxed for 3 hrs, it was cooled to room temperature and ethyl acetate followed by water were added dropwise. The resulting suspension was dried, filtered and the filtrate concentrated in vacuo to give a dark brown oil which was distilled, bp 170°-180° (0.05 mm Hq) to afford 7.6 g (73%) of crude (±)-3-phenoxy-N-methylmorphinan.
Reaction SMILES: [N+:1](=[CH:3][CH2:4][O:5][C:6]([CH2:8][C:9]1(O)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=[O:7])=[N-:2].O(C(C)C)C(C)C.O=P(Cl)(Cl)Cl.[OH-].[Na+]>N1C=CC=CC=1>[N+:1](=[CH:3][CH2:4][O:5][C:6]([CH2:8][C:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=1)=[O:7])=[N-:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CC(=O)OCC=[N+]=[N-])CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)OC(C)C
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC=C(CC(=O)OCC=[N+]=[N-])CC1
Temperature: -10 °C
Reaction time: 12 h

Procedure:
78.0 ml of dry pyridine are added to a solution of 15.12 g of tert-butyl 4-(diazoethoxycarbonylmethyl)-4-hydroxypiperidine-1-carboxylate into 250 ml of iPr2O. The mixture is cooled to −10° C. and 8.86 ml of POCl3 are added slowly with vigorous stirring. The mixture is then left to return to ambient temperature for 12 hours with stirring. The reaction mixture is decomposed with 500 ml of a 0.1M NaOH solution, and is then extracted 3 times with EtOAc. The organic phase is washed with a saturated NaCl solution and dried over MgSO4. The hydrated salt is removed by filtration and the dry filtrate is concentrated under reduced pressure to 1/10 of its initial volume. LC/MS:RT=4.57; [M+1]+=296.31. The product is used as it is for the subsequent step.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Cl:20][C:21]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1COCC1>[Cl:20][C:21]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:22]=1[C:23](/[N:12]=[C:6]1\[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[N:5]\1[CH2:4][CH2:3][O:2][CH3:1])=[O:24]
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Reactant: COCCn1c(C)c(C)sc1=N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1cc(Cl)ccc1Cl
Yield: 26 %

Procedure:
The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.45 mL, 3.2 mmol) and 2,5-dichlorobenzoyl chloride in 15 mL THF were processed using the method described in Example 132 to afford the title compound (0.10 g, 0.28 mmol, 26% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.25 (d, J=1.0 Hz, 3H), 2.28 (d, J=1.0 Hz, 3H), 3.31 (s, 3H), 3.76 (t, J=5.3 Hz, 2H), 4.36 (t, J=5.3 Hz, 2H), 7.28 (d, J=2.4 Hz, 1H), 7.32-7.36 (m, 1H), 7.94 (d, J=2.4 Hz, 1H); MS (DCI/NH3) m/z 359 (M+H)+; Anal. calculated for C15H16Cl2N2O2S: C, 50.15; H, 4.49; N, 7.80. Found: C, 50.22; H, 4.15; N, 7.63.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]([CH3:24])([C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)[C:6]([O:8]C)=[O:7]>CO.O.O1CCCC1>[CH3:4][C:5]([CH3:24])([C:10]1[CH:11]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.7 %

Procedure:
Lithium hydroxide monohydrate (2.13 g, 50.6 mmol) was added to a suspension of methyl α,α-dimethyl-3,5-bis(trifluoromethyl)benzeneacetate (Description 9, 5.3 g, 16.88 mmol) in methanol (60 mL), water (20 mL) and tetrahydrofuran (20 mL) and the mixture was degassed and stirred at room temperature for 3 days. The solvent was evaporated under reduced pressure and the residue was suspended in hydrochloric acid (1M). The mixture was extracted with ethyl acetate and the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (5.05 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.84 (2H, s), 7.80 (1H, s), and 1.68 (6H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:20]([O:22][CH3:23])=[O:21])=[CH:13]3)[CH:10]([CH2:24][O:25]N2C(C)(C)CCCC2(C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O>C1COCC1.CC(O)=O.[Zn]>[C:1]([O:5][C:6]([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:20]([O:22][CH3:23])=[O:21])=[CH:13]3)[CH:10]([CH2:24][OH:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2c3c(ccc2[nH]1)N(C(=O)OC(C)(C)C)CC3CON1C(C)(C)CCCC1(C)C
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1cc2c3c(ccc2[nH]1)N(C(=O)OC(C)(C)C)CC3CO
Yield: 79 %

Procedure:
Zinc powder (7.39 g, 113 mmol) was added to a solution of 54 (6.86 g, 14.1 mmol) in THF (150 mL), HOAc (150 mL), and H2O (50 mL). The mixture was stirred at reflux for 40 min, cooled, and filtered through Celite eluting with EtOAc. The filtrate was evaporated and the residue diluted with H2O and extracted with EtOAc (×2). The extracts were washed with H2O, aq NaHCO3, and dried (Na2SO4) and evaporated. Recrystallization from MeOH gave methyl 3-(t-butyloxycarbonyl)-1-hydroxymethyl-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylate (55) as a white solid (3.86 g, 79%), mp 189.5-191° C. (dec.). The mother liquor was purified by chromatography (40% EtOAc-petroleum ether) to give more alcohol (0.74 g, 15%). 1H NMR [(CD3)2SO] δ 11.88 (s, 1 H, NH), 7.87 (v br s, 1 H, H-4), 7.29 (d, J=8.9 Hz, 1 H, H-5), 7.11 (d, J=1.4 Hz, 1 H , H-8), 4.95 (t, J=5.2 Hz, 1 H, OH), 4.03 (t, J=10.5 Hz, 1 H), 3.92-3.86 (m, 1 H), 3.87 (s, 3 H, CO2Me), 3.82-3.75 (m, 1 H), 3.67 (br s, 1 H), 3.55-3.48 (m, 1 H), 1.51 (s, 9 H, t-Bu); 13C NMR δ 161.6, 151.8, 136.2, 134.6, 127.8, 123.7, 122.6, 113.3, 113.3, 111.3, 105.5, 79.3, 63.1, 51.7, 51.2, 42.2, 28.1. Anal. Calculated for C18H22N2O5 : C, 62.4; H, 6.4; N, 8.1. Found: C, 62.3; H, 6.6; N, 8.3%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: [H][H]
Reactant: CCOc1cc(C(=CC#N)c2ccccc2)ccc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOc1cc(C(CC#N)c2ccccc2)ccc1OC
Yield: 16.7 %

Procedure:
To a solution of 3-(3-ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile (0.9 g, 3.2 mmol) in a mixture of ethanol and ethyl acetate (20 mL/ 30 mL) was added 0.5 g of 10% palladium on carbon catalyst in portions. The mixture was hydrogenated in a Parr-Shaker apparatus at 55-60 psi of hydrogen for 12 days. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford the crude product. The crude product was purified by flash column chromatography (silica gel, 4% hexane/methylene chloride) to afford 0.15 g (15%) of the product as an oil: 1H NMR (CDCl3) δ 7.40-7.16 (m, 5H); 6.88-6.78 (m, 3H), 4.32 (t,J=7.5 Hz, 1H), 4.03 (q,J=7 Hz, 2H), 3.85 (s, 3H), 3.00 (d,J=7.5 Hz, 2H), 1.42 (t, J=7 Hz, 3H); 13C NMR (CDCl3) δ 148.7, 148.5, 141.5, 133.7, 128.8, 127.4, 127.3, 119.5, 118.5, 112.7, 111.6, 64.4, 55.9, 46.7, 24.5, 14.7; Anal. Calcd for C18H17NO2. Theoretical: C, 76.84; H, 6.81; N, 4.98. Found: C, 76.53; H, 6.92; N, 4.95.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]1)[C:5](=[O:16])[N:6]2[CH2:11][C:12](=[N:14][OH:15])[NH2:13].C(NC(C)C)(C)C.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]1)[C:5](=[O:16])[N:6]2[CH2:11][C:12](=[N:14][O:15][C:38]([CH:35]1[CH2:37][CH2:36]1)=[O:39])[NH2:13]
Reactant: NC(CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Cl)cccc21)=NO
Reactant: O=C(Cl)C1CC1
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: NC(CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Cl)cccc21)=NOC(=O)C1CC1
Yield: 54.8 %

Procedure:
A stirred solution of 2-(4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)-N′-hydroxyacetimidamide (0.40 g, 1.0 mmol), diisopropylamine (0.16 g, 1.6 mmol) and cyclopropane carbonyl chloride (0.16 g, 1.6 mmol) in dichloromethane (20 mL) was stirred for 16 h at ambient temperature. The colorless solid that precipitated from the solution was filtered, washed with water (5 mL) and diethyl ether (5 mL) to afford 2-(4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)-N′-[(cyclopropylcarbonyl)oxy]ethanimidamide as a colorless solid (0.25 g, 53%): 1H NMR (300 MHz, DMSO-d6) δ7.31 (dd, J=8.0, 8.0 Hz, 1H), 7.02 (d, J=8.0 Hz, 2H), 6.64 (br s, 2H), 6.54 (s, 1H), 6.47 (s, 1H), 5.88 (s, 2H), 4.77 (ABq, 2H), 4.43 (ABq, 2H), 1.75-1.67 (m, 1H), 0.86-0.73 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.9, 171.9, 156.5, 153.6, 148.9, 144.8, 141.9, 130.8, 130.0, 128.6, 117.4, 108.8, 104.4, 101.8, 104.5, 101.8, 104.4, 101.8, 93.0, 77.5, 58.4, 11.7, 8.45, 8.42; MS (ES+) m/z 456.1 (M+1), 478.1 (M+23).
Reaction SMILES: [CH3:1][N:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]([CH3:7])[C:4]([OH:6])=O.C1(N=C=NC2CCCCC2)CCCCC1.[C:30]1([C:36]#[C:37][C:38]2[N:43]=[C:42]([NH2:44])[CH:41]=[C:40]([C:45]3[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=3)[CH:39]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN1C(=O)CCC1>[C:11]([O:10][C:8](=[O:9])[N:2]([CH3:1])[CH:3]([C:4](=[O:6])[NH:44][C:42]1[CH:41]=[C:40]([C:45]2[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=2)[CH:39]=[C:38]([C:37]#[C:36][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:43]=1)[CH3:7])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: Nc1cc(-c2ccncc2)cc(C#Cc2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)Nc1cc(-c2ccncc2)cc(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid (1.44 g, 7.1 mmol) and N,N′-dicyclohexylcarbodiimide (0.73 g, 3.55 mmol) in DCM (4 ml) is stirred for 30 minutes at RT. This mixture is added in 4 portions over 48 h via syringe filter to a mixture of 6-(2-phenylethynyl)-4-(pyridin-4-yl)pyridin-2-amine G1 (0.24 g, 0.89 mmol), DIPEA (166 μl, 0.98 mmol) and NMP (2 ml) at 50° C. After stirring for another 16 h at 50° C. the mixture is filtered and the product purified by RP HPLC. Yield: 56 mg (14%). HPLC-MS: M+H=457; tR=.2.08 min (METHOD—2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=2)=[C:6]([CH:8]=1)[NH2:7].[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([CH2:16][CH2:17][CH3:18])[CH:15]=2)=[C:6]([NH:7][S:28]([C:20]2[O:19][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH:21]=2)(=[O:29])=[O:30])[CH:8]=1
Reactant: CCCn1cnc(CSc2ccc(Cl)cc2N)c1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: CCCn1cnc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Yield: 48.1 %

Procedure:
Following General Procedure B, the title compound (463 mg, 48%) was prepared from 5-chloro-2-(((1-propyl-1H-imidazol-4-yl)methyl)thio)aniline (587 mg, 2.082 mmol) and benzofuran-2-sulfonyl chloride (451 mg, 2.082 mmol) in pyridine (10 ml).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:8])[C:4](=[O:7])C=1Cl.[CH3:9][OH:10].[CH2:11]1COCC1>>[Cl:1][C:2]1[C:3](=[O:8])[C:4](=[O:7])[C:9]=1[O:10][CH3:11]
Reactant: O=c1c(Cl)c(Cl)c1=O
Reactant: C1CCOC1
Reactant: CO
Product: COc1c(Cl)c(=O)c1=O
Temperature: 25 °C

Procedure:
To a solution of the product from Example 94A (5.92 g, 39.2 mmol) in 100 mL of THF was added MeOH (1.26 g, 39.2 mmol). The mixture was heated at reflux for 2 hours then allowed to cool to ambient temperature. The solvent was removed under reduced pressure and the crude product was dissolved in 100 mL of EtOAc/hexanes (1:1). The mixture was filtered through a ½″ silica gel frit and the frit was washed with an additional 50 mL of EtOAc/hexanes (1:1). The solvent was removed in vacuo to provide a pale yellow oil which solidified on standing. The product (4.56 g, 80% crude yield) was used without further purification.