Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[C:14]([OH:21])[CH:13]=1.[C:22](=O)([O:25]C)[O:23][CH3:24].Cl>O1CCCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][C:22]([O:23][CH3:24])=[O:25])=[C:14]([OH:21])[CH:13]=1
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: COC(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CC(=O)c1ccc(F)cc1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
A 1.0 M tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (39.0 mL, 39.0 mmol) was stirred at −78° C. and treated over a 25 min period with a solution of 1-(4-fluoro-2-hydroxyphenyl)ethanone (2.00 g, 13.0 mmol) in 50 mL of tetrahydrofuran. The resulting solution was stirred at −78° C. for 1 h, and then at −15° C. for 2 h. After being cooled again to −78° C., the solution was treated with a solution of dimethyl carbonate (1.20 mL, 14.3 mmol) in tetrahydrofuran (5 mL). The resulting mixture was allowed to warm to rt where it stirred overnight. After this time, the mixture was poured over ice and then concentrated hydrochloric acid (10 mL) was added. The resulting mixture was extracted three times with dichloromethane. The combined organic phases were washed twice with water, dried over sodium sulfate and then concentrated under vacuum to yield a residue. The residue was purified by radial thin-layer chromatography (silica gel, 2-40% ethyl acetate-hexane) to provide methyl 3-(4-fluoro-2-hydroxyphenyl)-3-oxopropanoate as a white solid (1.76 g, 64%). 1H NMR (400 MHz, CDCl3) δ ppm 3.78 (s, 3 H) 3.98 (s, 2 H) 6.62-6.71 (m, 2 H) 7.69 (dd, J=8.9, 6.4 Hz, 1 H) 12.15 (d, J=1.5 Hz, 1 H). Mass spectrum m/z 213.14 (M+H)+.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:26]=[N:27][N:28]([CH3:45])[C:29]=1[N:30]1[CH2:35][C@H:34]([F:36])[CH2:33][C@H:32]([NH:37]C(=O)OC(C)(C)C)[CH2:31]1)=[O:23])=O)(C)(C)C.N>Cl.CO.CO>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[CH:26]=[N:27][N:28]([CH3:45])[C:29]=1[N:30]1[CH2:35][C@H:34]([F:36])[CH2:33][C@H:32]([NH2:37])[CH2:31]1)=[O:23]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1C[C@H](F)C[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: N
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1C[C@@H](N)C[C@@H](F)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.1 %

Procedure:
A mixture of tert-butyl (3S,5R)-1-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-5-fluoropiperidin-3-ylcarbamate (100 mg, 0.15 mmol) in HCl/MeOH (10 mL) was stirred at ambient temperature for 20 hours and concentrated reduced pressure to give a residue. The residue was diluted with MeOH (10 mL), neutralized with 28% ammonia solution, and concentrated to give a crude product. The crude product was purified by preparative HPLC to give 127 (40 mg, 59%). 1H-NMR (500 MHz, CD3OD) δ (ppm): 7.51-7.49 (m, 2H), 7.17-7.12 (m, 2H), 4.95-4.86 (m, 2H), 3.75 (s, 3H), 3.31-3.25 (m, 3H), 2.97-2.90 (m, 1H), 2.31-2.23 (m, 1H), 1.64-1.48 (m, 1H); MS (ESI) m/z: 452 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CC(C)N1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4)nc23)CC1
Yield: 485.7 %

Procedure:
Beginning with 0.10 gm (0.39 mMol) 5-amino-3-(1-isopropylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.055 mL (0.046 mMol) 4-fluorobenzoyl chloride, 0.085 gm (58%) of the title compound were prepared as an ivory foam essentially by the procedure described in Example 4. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][S:10]SC>CCOCC.C([Li])CCC>[CH3:9][S:10][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[N:3][CH:4]=1
Reactant: CSSC
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CSc1ccc(Br)nc1
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a solution of 2,5-dibromopyridine (23.4 g, 0.099 mol) in ether (500 mL), n-butyl lithium (1.52 M in n-hexane, 68 mL, 0.10 mmol) was added dropwise at −78° C. and the mixture was stirred for 1 hour at the temperature. Dimethyldisulfide (9.8 mL, 0.11 mol) was added slowly at −78° C. and the mixture was stirred for 1 hour at that temperature and further 1 hour at 0° C. The mixture was quenched with aqueous 1 N hydrochloric acid (200 mL) and extracted with ether (100 mL×2), dried over magnesium sulfate (MgSO4), and concentrated in vacuo gave the title compound (18.9 g, 94%).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:12][OH:13]>N1C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:12][OH:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
This material was prepared from 4-cyanobenzaldehyde according to Kawase and Kikugawa (J. Chem. Soc., Perkin Trans I 1979, 643). To a solution of 4-cyanobenzaldehyde (1.31 g, 10 mmol) in 1:1EtOH:pyridine (10 mL) was added hydroxylamine hydrochloride (0.70 g, 10 mmol). The resulting solution was stirred at room temperature for 18 h and was concentrated in vacuo to one-half volume. To this solution was added ice water, causing the product to crystallize from solution. Recrystallization from EtOH--water followed by drying over P2O5 afforded 1.46 g (100%) of the desired oxime; mp: 167.8-169.4° C.
Reaction SMILES: C([O:8][CH2:9][CH:10]([CH:20]1[CH2:23][CH:22]([S:24]([NH:27][C:28]2[C:33]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([I:41])=[CH:37][C:36]=3[F:42])=[C:32]([CH3:43])[C:31](=[O:44])[N:30]3[CH2:45][CH2:46][O:47][C:29]=23)(=[O:26])=[O:25])[CH2:21]1)[CH2:11][O:12]CC1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[OH:8][CH2:9][CH:10]([CH:20]1[CH2:21][CH:22]([S:24]([NH:27][C:28]2[C:33]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([I:41])=[CH:37][C:36]=3[F:42])=[C:32]([CH3:43])[C:31](=[O:44])[N:30]3[CH2:45][CH2:46][O:47][C:29]=23)(=[O:26])=[O:25])[CH2:23]1)[CH2:11][OH:12]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(C(COCc3ccccc3)COCc3ccccc3)C2)c2n(c1=O)CCO2
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC(C(CO)CO)C2)c2n(c1=O)CCO2
Yield: 26.1 %

Procedure:
3-(1,3-Bis(benzyloxy)propan-2-yl)-N-(7-(2-fluoro-4-iodophenylamino)-6-methyl-5-oxo-3,5-dihydro-2H-oxazolo[3,2-a]pyridin-8-yl)cyclobutane-1-sulfonamide (0.3 g, 0.388 mmol) was reacted with 1M BCl3 (1.1 mL, 1.164 mmol) and DCM (10 mL) at 0° C. for 30 minutes to afford the crude product. Purification by column chromatography on silica gel (8% methanol in chloroform) afforded 60 mg of the product (26% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:17][C:18]([F:21])([F:20])[F:19].B1C2CCCC1CCC2.[OH-:31].[Na+].OO>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][OH:31])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:17][C:18]([F:20])([F:19])[F:21]
Reactant: C=Cc1ccc(Oc2ccc(Cl)c(OC(F)(F)F)c2)cc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2ccc(Cl)c(OC(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
To the solution of 1-chloro-2-(trifluoromethoxy)-4-(4-vinylphenoxy)benzene (1.2 g, 3.81 mmol) in dry THF (10 mL), was added 9-BBN (15.25 mL, 7.63 mmol) at 0° C. The mixture was stirred at room temperature overnight. aq. NaOH (6.5 mL, 19.50 mmol), and 30% H2O2 (2.0 mL, 19.58 mmol) were added. The reaction mixture was heated at 55° C. for 4 h. Then THF was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (450 mg, 1.353 mmol, 35.5% yield) as a white oil.
Reaction SMILES: C1(P(=[O:20])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH2:77][N:78]1[CH2:83][CH2:82][S:81][CH2:80][CH2:79]1)[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][C:54]([O:58][CH2:59][CH2:60][O:61][CH3:62])=[CH:53][C:52]=2[N:63]([CH2:73][CH:74]1[CH2:76][CH2:75]1)[S:64]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=1)(=[O:66])=[O:65])=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH:74]1([CH2:73][N:63]([C:52]2[CH:53]=[C:54]([O:58][CH2:59][CH2:60][O:61][CH3:62])[CH:55]=[C:56]3[C:51]=2[NH:50][C:49]([C:47]2[S:43][CH:44]([CH2:77][N:78]4[CH2:83][CH2:82][S:81](=[O:20])[CH2:80][CH2:79]4)[CH2:45][N:46]=2)=[CH:57]3)[S:64]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=2)(=[O:65])=[O:66])[CH2:75][CH2:76]1
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCCOc1cc(N(CC2CC2)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(CN3CCSCC3)SCc3ccccc3)cc2c1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CSc1ccccc1
Product: COCCOc1cc(N(CC2CC2)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCS(=O)CC4)S3)cc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.3 %

Procedure:
To a mixture of triphenylphosphine oxide (557 mg) and dichloromethane (1 mL) was added trifluoromethanesulfonic anhydride (0.17 mL) at 0° C., and the mixture was stirred at 0° C. for 15 min, followed by an addition of dichloromethane (3 mL). A mixture of N-[2-(benzylthio)-3-thiomorpholinopropyl]-7-[(cyclopropylmethyl)(pyridin-2-ylsulfonyl)amino]-5-(2-methoxyethoxy)-1H-indole-2-carboxamide (355 mg), thioanisole (0.12 mL) and dichloromethane (3 mL) was added thereto at 0° C., and the mixture was stirring at 0° C. for 10 min. Aqueous sodium bicarbonate solution was added to the reaction mixture, and the organic layer was separated. The organic layer was extracted with concentrated hydrochloric acid, and after basified with the aqueous layer with potassium carbonate, the whole mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give the amorphous solid from a fraction eluted with ethyl acetate. To the mixture of the obtained amorphous solid, tetrahydrofurane (5 mL), ethanol (5 mL) and water (5 mL) was added OXONE (registered trade mark, 369 mg) at room temperature, and the mixture was stirred at room temperature for 1 hr. To the resulting mixture was added 10% aqueous sodium sulfite solution, and the mixture was extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give amorphous solid, which was crystallized from diisopropyl ether to give the title compound (146 mg, yield 47%) as colorless crystals.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C[O:6][C:7]1[CH:23]=[CH:22][C:10]2[CH2:11][CH:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:13](=[O:16])[NH:14][CH2:15][C:9]=2[CH:8]=1.C(S)C>C(Cl)Cl>[OH:6][C:7]1[CH:23]=[CH:22][C:10]2[CH2:11][CH:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:13](=[O:16])[NH:14][CH2:15][C:9]=2[CH:8]=1
Reactant: COC(=O)CC1Cc2ccc(OC)cc2CNC1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: COC(=O)CC1Cc2ccc(O)cc2CNC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
Anhydrous aluminum chloride (7.6 g, 57 mmol) was added portionwise to a stirred solution of methyl (±)-8-methoxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (3.0 g, 11 mmol) and ethanethiol (4.2 mL, 57 mmol) in methylene chloride (100 mL) at 0° C. under argon. The resulting mixture was allowed to warm to room temperature and stir overnight, then was concentrated. The residue was triturated with ice-water, and the resulting solid was collected by filtration and dried to give the title compound (2.64 g, 91%) as an off-white solid: MS (ES) m/e 250.2 (M+H)+.
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[C:7]([N:12]([CH3:14])[CH3:13])=[N:8][CH:9]=[CH:10][CH:11]=1)#[N:2].[C:22]1([C:28]2([NH2:32])[CH2:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN1CCOCC1>O1CCOCC1>[CH3:14][N:12]([CH3:13])[C:7]1[C:6]([NH:5][C:4]([NH:32][C:28]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][CH2:30][CH2:31]2)=[N:3][C:1]#[N:2])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: NC1(c2ccccc2)CCC1
Reactant: CN(C)c1ncccc1NC(=NC#N)Oc1ccccc1
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: CN(C)c1ncccc1NC(=NC#N)NC1(c2ccccc2)CCC1
Yield: 44.2 %

Procedure:
A stirred mixture of the product from Step 1 (3.23 g, 0.0115 mol), 1-phenylcyclobutylamine (1.73 g, 0.0126 mol) (A. Kalir and Z. Pelah, Israel J. Chem. 5:223 (1967)), N-methylmorpholine (2.74 ml, 0.0249 mol) and dioxane (40 ml) was refluxed, under nitrogen for 18 hours and concentrated in vacuo. The residue was mixed with EtOAc and concentrated to give a solid which was recrystallized from EtOAc-hexane to give 1.7 g, mp 204°-205° C. of the titled product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cr](Cl)([O-])(=O)=O.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl.CCOCC>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.7 %

Procedure:
To a solution of 3.2 mL (20.8 mmol) of 4-phenyl-1-butanol (Aldrich Chemical Co.) in 20 mL of CH2Cl2 at 0° C. was added 3.2 g of powdered 3 Å molecular sieves and then 5.37 g (24.9 mmol) of pyridinum chlorochromate (PCC). The resulting suspension was stirred at 0° C. for 1 h at which time an additional 2.16 g (10.0 mmol) of PCC was added and the reaction mixture was warmed to room temperature. After stirring at ambient temperature for 0.5 h, the reaction mixture was diluted with ether and filtered through celite to give 2.5 g of the crude product. Flash chromatography (elution with 5% ethyl acetate in hexane) yielded 700 mg of the aldehyde 119. 1H NMR was consistent with the structure.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]([N:11]2[CH2:15][CH2:14][C@H:13]([O:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[Br:24])[CH2:12]2)=[N:9][N:10]=1)=O)C.[NH3:25]>C1COCC1>[Br:24][C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1[O:16][C@H:13]1[CH2:14][CH2:15][N:11]([C:8]2[O:7][C:6]([C:4]([NH2:25])=[O:3])=[N:10][N:9]=2)[CH2:12]1
Reactant: CCOC(=O)c1nnc(N2CC[C@H](Oc3cc(F)ccc3Br)C2)o1
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)c1nnc(N2CC[C@H](Oc3cc(F)ccc3Br)C2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl-5-[(3S)-3-(2-bromo-5-fluorophenoxy)pyrrolidin-1-yl]-1,3,4-oxadiazole-2-carboxylate (480 mg, 1.2 mmol) in THF (4 mL) was saturated with ammonia gas for 2 min. The mixture was stirred at room temperature for 0.5 h. The solvent was evaporated and the crude product was dissolved in Et2O, filtered and washed with Et2O to afford the title product as a solid.
Reaction SMILES: C[Si](C)(C)[N:3]=[CH:4][C:5]#[C:6][Si:7]([CH3:10])([CH3:9])[CH3:8].[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[Li]>>[NH2:3][CH:4]([C:5]#[C:6][Si:7]([CH3:10])([CH3:9])[CH3:8])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)C#CC=N[Si](C)(C)C
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(N)C#C[Si](C)(C)C

Procedure:
The present invention relates to a novel process for the preparation of ethyl 3S-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoate having the following structural formula ##STR1## and the pharmaceutically acceptable acid addition salt thereof which comprises treating (trimethylsilyl) acetylene sequentially with n-butyllithium and 4-formylmorpholine in the presence of an aprotic solvent followed by acid hydrolysis to give 3-(trimethylsilyl)-2-propynal; treating 3-(trimethylsilyl)-2-propynal with lithium bis(trimethylsilyl)amide in the presence of an aprotic solvent to give N,3-bis(trimethylsilyl)-2-propyn-1-imine in situ; condensation of N,3-bis(trimethylsilyl)-2-propyn-1-imine with lithium t-butyl acetate followed by hydrolytic cleavage to give (±)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate; treating (±)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate with p-toluenesulfonic acid in the presence of aprotic solvents to give (±)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate, mono p-toluenesulfonic acid salt; treatment of the resulting salt with ethanol in the presence of p-toluenesulfonic acid, followed by neutralization to give (±)ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate; desilylation of (±)ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate in the presence of a catalytic amount of base and an alkanol solvent to give in situ (±)ethyl 3-amino-4-pentynoate; resolution of (±)ethyl 3-amino-4-pentynoate using (R)-(-)-mandelic acid and treatment of the resolved product with gaseous hydrochloric acid to give ethyl 3S-amino-4-pentynoate, monohydrochloride; coupling the ethyl 3S-amino-4-pentynoate, monohydrochloride to 4-[[4-(aminoiminomethyl)phenyl]amino]-4-oxobutanoic acid, monohydrochloride in the presence of isobutyl chloroformate and N-methylmorpholine to give ethyl 3S-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoate, monohydrochloride.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13](S(C2C=CC=CC=2)(=O)=O)[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH3:34][S:35]SC.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO.O>[CH2:1]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]=1[S:35][CH3:34])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reactant: CSSC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CSc1[nH]c2ccccc2c1C(=O)NCc1ccccc1
Temperature: -20 °C
Yield: 85.9 %

Procedure:
A solution of the above N-benzyl-1-(phenylsulfonyl)indole-3-carboxamide [XXIV: R8 =CH2Ph] (4.2 g, 11 mmol) in dry THF (200 mL) was treated at -78° C. with a solution of 2.5M n-BuLi in hexanes (9.1 mL, 23 mmol), and the stirred mixture was allowed to warm to -20° C. for 15 minutes, before being recooled to -78° C., when it was treated with methyldisulfide (2.5 mL, 28 mmol). The mixture was allowed to warm to 20° C., then quenched with water (25 mL). Volatiles were removed under reduced pressure, and the residue was extracted with EtOAc. Workup of the organic layer gave a crude product. This was dissolved in MeOH (300 mL), mixed with a solution of K2CO3 (6.9 g, 50 mmol) in water (125 mL), and heated under gentle reflux under N2 for 2 hours to ensure complete hydrolysis of the phenylsulfonyl group (J. Org. Chem. 1985;50:5451-5457). MeOH was removed under reduced pressure, and the residue was diluted with water and extracted with CH2Cl2. Chromatography of the resulting oil on Al2O3 (eluting with CH2Cl2) gave N-benzyl-2-(methylthio)indole-3-carboxamide [XXV: R8 =CH2Ph] (2.8 g, 88% yield) as an oil.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]([CH2:8][CH2:9]2)[CH2:6]1)=[O:4].[OH-].[NH4+]>CO>[NH4+:5].[OH-:4].[CH:7]12[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:10]([CH2:9][CH2:8]1)[CH2:11][NH:5][CH2:6]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)C(F)(F)F)C2
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C2CCC1CNC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 3-(trifluoroacetyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6.54 mmol) in methanol (85 mL) was treated with ammonium hydroxide (8.5 mL) and stirred overnight at room temperature. The mixture was concentrated under reduced pressure and purified by chromatography on silica gel (5% MeOH, 0.5% NH4OH in CH2Cl2; then 10% MeOH, 1% NH4OH in CH2Cl2) to provide the title compound. MS (DCI/NH3) m/z: 213 (M+H)+; 1H NMR (CDCl3) δ 1.47 (s, 9H), 1.81 (m, 2H), 1.94 (m, 2H), 2.65 (dd, 2H), 3.00 (br, 2H), 4.11 (br, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[O:24]=[C:25]([CH2:31][CH3:32])[CH2:26][CH2:27][C:28](Cl)=[O:29].S(Cl)(Cl)=O.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:28](=[O:29])[CH2:27][CH2:26][C:25](=[O:24])[CH2:31][CH3:32])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCC(=O)CCC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(NCc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCC(=O)CCC(=O)N(Cc1ccccc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a solution of 22.8 g (0.1 mol) of 4-nitro-N-(phenylmethyl)benzenamine and 7.9 g (0.1 mol) of pyridine in 150 mL of methylene chloride cooled to 0° C. add slowly a solution of 16.3 g (0.11 mol) of 4-oxohexanoyl chloride (prepared from the acid and thionyl chloride or oxalyl chloride). When the addition is complete stir the solution and allow to warm slowly to room temperature. Follow the progress of the reaction by thin-layer chromatography on silica gel. At the completion of the reaction wash the solution with two 25 mL portions of 5% hydrochloric acid solution, two 25 mL portions of 5% sodium carbonate solution and 50 mL of saturated sodium chloride solution. Dry the organic phase over anhydrous sodium sulfate. Remove the drying agent by filtration and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH:13]=[CH:12][C:11]=2[CH:15]=1.[CH3:16][Sn:17](Cl)([CH3:19])[CH3:18]>C1COCC1>[CH3:16][Sn:17]([CH3:19])([CH3:18])[C:13]1[O:14][C:10]2[CH:9]=[CH:8][C:7]([CH3:6])=[CH:15][C:11]=2[CH:12]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1ccc2occc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc2oc([Sn](C)(C)C)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.4 %

Procedure:
n-Butyl lithium (1.57M in hexane, 75 ml) was added dropwise to a stirred solution of 5-methylbenzofuran (14 g) in dry THF (150 ml) at -70° under nitrogen over 45 min. The solution was then allowed to warm to -55° before a solution of trimethyltin chloride (23 g) in THF (70 ml) was added dropwise. The solution temperature rose to -32°. The cooling bath was removed and the solution was stirred at room temperature for 2 h. The solution was diluted with ethyl acetate (250 ml) and washed with water (200 ml). The organic layer was dried and concentrated in vacuo to afford a yellow liquid (32 g). Kugelrohr distillation of this liquid gave the title compound (23.3 g) as a colourless liquid, b.p. 115° at 7 mbar.