Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)CCl.[NH:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:6]([C:8]([NH:10][CH2:11][C:12]([OH:14])=O)=[O:9])[CH3:7].[NH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[NH:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:6]([C:8]([NH:10][CH2:11][C:12]([NH:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:14])=[O:9])[CH3:7]
Reactant: NCC(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 22 h

Procedure:
One equivalent of 0.39 g (2 mmol) EDC (Aldrich) is added into a stirred solution of 0.5 g (2 mmol) of Boc Ala-Gly-OH (12), 0.4 g of (2 mmol) of Gly-OBzl (Sigma), 0.27 g of HOBT (Aldrich), and 0.2 ml of NMM in 100 ml of DCM at ice bath temperature. The reaction mixture is stirred for 3 h at 0° C. and 22 h at ambient temperature. The reaction mixture is concentrated using a rotary evaporator, and the residue is dissolved in 100 ml of ethyl acetate. The ethyl acetate solution is extracted with 10% NaHCO3 and water. The organic layer is dried over anhydrous Na2SO4 and isolated by decantation. Then, the ethyl acetate is evaporated to furnish the Boc-Ala-Gly-Gly-OBzl (13) as a yellow oil which is confirmed by MS and NMR. 1H-NMR (CDCl3): 1.28 (3H, d, J=7.2 Hz), 1.31 (9H, s), 3.85-4.15 (5H, m), 5.06 (2H, s), 5.45 (1H, br), 7.25 (5H, br), 7.41 (1H, br). FABMS: 394 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C:16]1[CH:17]=[C:18]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[C:19]([NH:21][NH:22][C:23]([C:25]1[O:26][CH:27]=[C:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:29]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:24])=[O:20])=O)(C)(C)C.ClCCl>C(Cl)(Cl)Cl.[OH-].[Na+]>[NH2:15][C:16]1[CH:17]=[C:18]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[C:19]([NH:21][NH:22][C:23]([C:25]1[O:26][CH:27]=[C:28]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:29]=1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:24])=[O:20]
Reactant: COc1ccc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)cc1NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)cc1N
Reaction time: 8 h
Yield: 98.8 %

Procedure:
Trifluoroacetic acid (8.00 ml) was added dropwise to a mixture of the compound of Example 40 (4.81 g) and dichloromethane (10 ml) at 25° C., and the mixture was stirred overnight. The reaction solution was diluted with chloroform and neutralized with 1 M aqueous sodium hydroxide solution. The thus-precipitated crystals were collected by filtration, thereby giving 3.85 g of the desired compound. HPLC retention time: 3.36 minutes.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:23])(=[O:3])[CH3:2].[CH3:24][CH2:25][O:26][C:27](OCC)(OCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]([C:40](=[O:42])[CH3:41])[S:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])=[CH:10][CH:11]=2)[C:6](=[C:27]([O:26][CH2:25][CH3:24])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5]1=[O:23])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2cc(NS(=O)(=O)c3ccccc3)ccc21
Reactant: CCOC(OCC)(OCC)c1ccccc1
Reactant: CC(=O)OC(C)=O
Product: CCOC(=C1C(=O)N(C(C)=O)c2ccc(N(C(C)=O)S(=O)(=O)c3ccccc3)cc21)c1ccccc1

Procedure:
8.0 g (24.2 mmol) of 1-acetyl-5-phenylsulphonylamino-2-indolinone are dissolved in 150 ml of acetic anhydride and after the addition of 20 ml (88.1 mmol) of triethyl orthobenzoate refluxed for 6 hours. The solvent is distilled off, the residue is triturated with ether, suction filtered and dried.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:18]([O-:20])=[O:19])[C:10](F)=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[NH4+:31].[NH4+]>CN(C=O)C>[NH2:31][C:10]1[C:9]([N+:18]([O-:20])=[O:19])=[C:8]2[C:13](=[C:12]([O:14][CH3:15])[C:11]=1[F:16])[N:4]([CH:1]1[CH2:3][CH2:2]1)[CH:5]=[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:7]2=[O:21]
Reactant: [NH4+]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(OC)c(F)c(N)c([N+](=O)[O-])c2c1=O
Temperature: 90 °C
Reaction time: 18 h
Yield: 51.7 %

Procedure:
A mixture of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (5.00 g, 13.5 mmol) and ammonium carbonate (11.7 g, 122 mmol) in DMF (50 mL) was stirred at 90° C. for 18 h. After the reaction mixture was poured into ice-water, the crude product was extracted with CH2Cl2, washed with brine, dried over MgSO4 and the solvent was removed in vacuo. The crude product washed with EtOH and dried to yield ethyl 6-amino-1-cyclopropyl-7-fluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (2.55 g, 52%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[Br:11]Br>CC(O)=O.CCOC(C)=O>[Br:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[Cl:1]
Reactant: BrBr
Reactant: Clc1n[nH]c2ccccc12
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Clc1n[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a room temperature solution of 3-chloro-1H-indazole (10.0 g, 65.5 mmol) in AcOH (250 ml) was added Br2 (3.54 ml, 68.8 mmol) dropwise. The reaction mixture was stirred at room temperature for 18 hours, then diluted with EtOAc (500 ml), washed with aqueous NaOH solution (10%), saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered, concentrated, and the residue was recrystallized from toluene. The solid was washed with hexanes and dried in vacuo affording 5-Bromo-3-chloro-1H-indazole CCXIV as a white solid (54% yield).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=O)=[CH:6][CH:5]=1)=O.S([CH2:23][N+:24]#[C-])(C1C=CC(C)=CC=1)(=O)=O.[K].[OH2:27]>COCCOCCOC.C(O)(C)(C)C>[N+:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:2]([CH3:1])[C:23]#[N:24])=[CH:9][CH:8]=1)([O-:12])=[O:27]
Reactant: O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [K]
Solvent: CC(C)(C)O
Solvent: COCCOCCOC
Product: CC(C#N)c1ccc([N+](=O)[O-])cc1
Temperature: -15 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A −15° C. solution of 4-nitroacetophenone (16.5 g, 100 mmol) and tosylmethyl isocyanide (2.9.3 g, 150 mmol) in methoxyethyl ether (400 mL) was slowly treated with a room temperature solution of the potassium t-butbxide. (28 g, 250 mmol) in t-butanol (200 mL). The reaction mixture was stirred at −15° C. for 1 h and then allowed to warm to room temperature over night. Water (100 mL) was added to the mixture and the organic layer was extracted with ether (3×200 mL). The combined organic fraction was washed with water (3×200 mL), brine (100 mL), dried over sodium sulfate, and concentrated in vacuo to give the crude material which was further purified by flash chromatography (SiO2, 30% EtOAc: Hexane) to give 13.6 g (77%) of the title compound. The NMR spectrum was consistent with the proposed title structure. Field Desorption Mass Spectrum: M+=176.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([OH:22])=[CH:7][C:8]([C:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1.[ClH:33].[CH3:34][CH:35]([CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[C:36](O)=[O:37].C1(N=C=NC2CCCCC2)CCCCC1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.Cl>C(Cl)Cl.C1CCCCC1.C(Cl)Cl.C(OCC)C.C(OCC)C.C(Cl)Cl>[ClH:33].[CH3:32][C:2]1([CH3:1])[C:24]2[CH2:25][CH2:26][N:27]([CH2:29][C:30]#[CH:31])[CH2:28][C:23]=2[C:5]2[C:6]([O:22][C:36](=[O:37])[CH:35]([CH3:34])[CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)=[CH:7][C:8]([C:10]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)([CH3:14])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3]1
Reactant: CC(CCN1CCCCC1)C(=O)O
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)C(C)CCN3CCCCC3)cc(C(C)(CCC)c3ccc(F)cc3)cc1OC2(C)C
Reaction time: 16 h

Procedure:
2.0 g. (5.05 mm.) of 5,5-dimethyl-10-hydroxy-8-(4-fluorophenyl-1-methylbutyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine are combined with 1.12 g. (5.05 mm.) of α-methyl-γ-piperidino butyric acid hydrochloride and 1.08 g. (5.25 mm.) of dicyclohexylcarbodiimide in 110 ml. of methylene chloride and the mixture is stirred at room temperature for 16 hours. After cooling for 4 hours, the by-product of dicyclohexylurea is removed by suction filtration. The mother liquor is evaporated to give a colorless foamy residue which is dissolved in a methylene chloride/cyclohexane mixture and stored for 16 hours in the cold. A small amount of solid is separated by gravity filtration, and the solvents are removed using a rotary evaporator. The residue is dried to give a colorless solid which is dissolved in a mixture of methylene chloride/diethyl ether and converted to the dihydrochloride by the addition of a solution of hydrogen chloride in diethyl ether. The solvents are decanted, and the gummy residue crystallized upon trituration with diethyl ether. The solid is filtered and recrystallized from 20 ml. of methylene chloride/20 ml. diethyl ether to give the desired product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)#[N:8].[C:17]([C:21]1[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:24]=[CH:23][C:22]=1[OH:31])([CH3:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[C:17]([C:21]1[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:24]=[C:23]([CH:13]([C:12]2[CH:15]=[CH:16][C:9]([C:7]#[N:8])=[CH:10][CH:11]=2)[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:22]=1[OH:31])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: C1CCNCC1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C(c2ccc(C#N)cc2)N2CCCCC2)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
8.29 g (97.33 mmol) of piperidine are added, at room temperature, to a solution of 5.83 g (44.43 mmol) of 4-cyanobenzaldehyde in 50 ml of toluene. The slightly yellow-colored solution is boiled under reflux for 4 hours; approximately 1 ml of water is separated off using a water separator, and a solution of 8.73 g (42.32 mmol) of 2,4-di-tert-butylphenol in 15 ml of toluene is then added dropwise. The reaction mixture is boiled at reflux for further 6 hours and then cooled to room temperature; the solvent is distilled off using a vacuum rotary evaporator. Crystallisation of the residue from methanol yields 12.95 g (75%) of compound (206) (Table 2), m.p. 165-166° C. Molecular weight C27H36N2O (404.60). Analysis, calculated: C 80.15; H 8.97; N 6.92%. Analysis, found: C 80.01; H 9.00; N 6.78%. 1HNMR (300 MHz, CDCl3, ppm): 1.12 (s, 9H); 1.36 (s, 9H); 1.57 (m, 4H); 2.28 (bm, 6H); 4.34 (s, 1H); 6.63 (d, 1H); 7.09 (d, 1H); 7.51 (m, 4H).
Reaction SMILES: C1(SC)C=CC=CC=1.COC1C=CC(C[NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3([C:29]#[N:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[N:21][CH:22]=2)=CC=1.[OH-].[Na+]>>[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2([C:29]#[N:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:21][CH:22]=1
Reactant: COc1ccc(CNc2ccc(C3(C#N)CCCCC3)nc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CSc1ccccc1
Product: N#CC1(c2ccc(N)cn2)CCCCC1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
Trifluoroacetc acid (4 ml) and thioanisole (1.2 ml) were added to 1-{5-[(4-methoxybenzyl)amino]pyridin-2-yl}cyclohexanecarbonitrile (632 mg) and stirred at 40° C. for 1.5 hours. An aqueous solution of sodium hydroxide was added and the mixture was adjusted to pH 10. The solution was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified with silica gel chromatography (n-hexane/ethyl acetate) to give the titled compound (360 mg) as a solid.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[C:9]=2[C:10]#[N:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCOC(C)=O>C1COCC1.CC(O)=O.[Fe]>[NH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:8]([O:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:9]=1[C:10]#[N:11]
Reactant: N#Cc1c(OC2CCCCC2)cccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1c(N)cccc1OC1CCCCC1
Temperature: 25 °C
Yield: 104 %

Procedure:
Alternative Methode a): To a solution of 2-(cyclohexyloxy)-6-nitrobenzonitrile (Example 36c, 50.0 g, 0.20 mol) in THF/AcOH (1:1 by volume, 500 mL) was added iron powder (34.0 g, 0.61 mol) in one portion at room temperature under nitrogen. The reaction mixture was refluxed for 40 min under nitrogen and cooled down to room temperature and EtOAc (2 L) was added. The precipitate that formed was filtered off and washed with EtOAc. The organic layer was separated and washed successively with water (2×300 mL), aqueous NaOH (1.0 N, 2×300 mL), saturated Na2CO3 solution (300 mL), brine (300 mL), dried over Na2SO4 filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with 25% EtOAc in hexanes to give 2-amino-6-(cyclohexyloxy)benzonitrile as a pale yellow oil (45.0 g, 94%), which solidified after storage overnight at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12](=S)[NH:13][S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[N:4]=1.CC(C)=[O:26]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:13][S:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])=[O:26])[N:4]=1
Reactant: COc1nc(NC(=S)NS(=O)(=O)c2cccnc2)nc(OC)n1
Reactant: CC(C)=O
Product: COc1nc(NC(=O)NS(=O)(=O)c2cccnc2)nc(OC)n1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture containing 2.7 g of N-[(4,6-dimethoxy-1,3,5-triazin-2-yl)aminothioxomethyl]-3-pyridinesulfonamide, 2.98 g of mercuric oxide and 75 ml of acetone was stirred at ambient temperature for 60 hours and then filtered. Evaporation of the filtrate in vacuo yielded the desired product as a residual white solid of m.p. 182°-185° dec.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[C:3]#[C:4][CH3:5].CN(C)C(N(C)C)C.C([Li])(C)(C)C.CCCCC.[Si:26]([O:33][C@H:34]([CH2:43][O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])/[CH:35]=[N:36]/[S@:37]([C:39]([CH3:42])([CH3:41])[CH3:40])=[O:38])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>C(OCC)C.C1COCC1>[Si:45]([O:44][CH2:43][C@@H:34]([O:33][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[C@@H:35]([NH:36][S@:37]([C:39]([CH3:40])([CH3:41])[CH3:42])=[O:38])[CH2:5][C:4]#[C:3][Si:2]([CH3:7])([CH3:6])[CH3:1])([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]
Reactant: CC(C)(C)[S@](=O)/N=C/[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: CC#C[Si](C)(C)C
Agent: CC(N(C)C)N(C)C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@H](CC#C[Si](C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Trimethyl(prop-1-ynyl)silane (4 mL, 28 mmol) and N,N,N′,N′-tetramethylethanediamine (5 mL, 36 mmol) were dissolved in dry diethyl ether (50 mL) and cooled to −78° C. Tert-butyllithium, 1.7 M solution in pentane (17 mL, 28 mmol) was added dropwise and the heterogenous solution was allowed to warm to 0° C. for 15 min to give a clear yellow solution, which was recooled to −78 C. Azeotropically (S,E)-N—((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide (3.0 g, 7 mmol) in dry THF (20 μL) was added dropwise and the solution was stirred for 1 h until the starting material was consumed. The reaction mixture as quenched with NH4Cl and extracted with EtOAc. The combined organics were washed with water, brine, dried over Na2SO4, filtered, and concentrated to afford a yellow oil as (S)—N-((2S,3S)-1,2-bis(tert-butyldimethylsilyloxy)-6-(trimethylsilyl)hex-5-yn-3-yl)-2-methylpropane-2-sulfinamide.
Reaction SMILES: C(OC(N[C@H](C1C=CC=C(NC(OCCC2C=CC(Br)=CC=2C)=O)C=1)CC(OCC)=O)=O)C1C=CC=CC=1.[N:39]([C:42]1[CH:43]=[C:44]([CH:54]=[CH:55][CH:56]=1)[CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[C:40]=[O:41].[Br:57][C:58]1[CH:63]=[CH:62][C:61]([CH2:64][CH2:65][OH:66])=[C:60]([Cl:67])[CH:59]=1>>[C:49]([O:48][C:47]([NH:46][CH2:45][C:44]1[CH:43]=[C:42]([NH:39][C:40]([O:66][CH2:65][CH2:64][C:61]2[CH:62]=[CH:63][C:58]([Br:57])=[CH:59][C:60]=2[Cl:67])=[O:41])[CH:56]=[CH:55][CH:54]=1)=[O:53])([CH3:51])([CH3:52])[CH3:50]
Reactant: OCCc1ccc(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)NCc1cccc(N=C=O)c1
Agent: CCOC(=O)C[C@H](NC(=O)OCc1ccccc1)c1cccc(NC(=O)OCCc2ccc(Br)cc2C)c1
Product: CC(C)(C)OC(=O)NCc1cccc(NC(=O)OCCc2ccc(Br)cc2Cl)c1
Yield: 50 %

Procedure:
Using a procedure analogous to that used to prepare 34D, 61C (1.94 g, 8.73 mmol) was reacted with 61B to give 61D (1.84 g, 50%) as an oil. MS (ESI) m/z 385.1 (M+H)+.
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: C[Si](C)(C)C#CC=N[Si](C)(C)C
Reactant: CC(=O)OC(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 and pharmaceutically acceptable acid addition salt thereof which comprises treating (trimethylsilyl)acetylene sequentially with n-butyllithium and 4-formylmorpholine followed by acid hydrolysis to give 3-(trimethylsilyl)-2-propynal; treating 3-(trimethylsilyl)-2-propynal with lithium bis(trimethylsilyl)amide to give in situ N,3-bis(trimethylsilyl)-2-propyn-1-imine; condensation of N,3-bis(trimethylsilyl)-2-propyn-1-imine with lithium t-butyl acetate 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 to give (±)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate, mono p-toluenesulfonic acid salt, treatment of resulting salt with ethanol in the presence of p-toluenesulfonic acid to give (±)ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate; desilylation of (±)ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate 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: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:31]=[CH:30][C:18]([C:19]([N:21]([CH3:29])[CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=O)=[CH:17][CH:16]=1.[C:32](#[N:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[NH4+].[Cl-]>C1COCC1>[CH3:29][N:21]1[C:22]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:39]=[C:19]1[C:18]1[CH:30]=[CH:31][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: COc1ccc(C(=O)N(C)Cc2ccncc2)cc1
Reactant: N#Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(-c2nc(-c3ccccc3)c(-c3ccncc3)n2C)cc1
Temperature: -40 °C
Reaction time: 10 h
Yield: 16.5 %

Procedure:
To a solution of diisopropylamine (0.16 mL, 1.1 mmol) in THF at -78° C. was added n-butyllithium (0.38 mL of 2.5 M solution, 0.95 mmol). To the resulting mixture was added a solution of 4-methoxy-N-methyl-N-(4-picolyl)benzamide (0.16 g, 0.62 mmol) in THF. The resulting dark red solution was warmed to -40° C. and stirred for 15 min, at which time benzonitrile (0.13 mL, 1.2 mmol) was added. The mixture to warmed to rt and stirred for 10 h. Aqueous NH4Cl (0.5 mL,) was added, and the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a solvent gradient of 2-4% MeOH/CHCl3. The material which was isolated was triturated with Et2O and recrystallized from EtOAc to provide the title compound as an off-white solid (35 mg, 17%): nap 193°-194° C.
Reaction SMILES: [CH:1]1([C:4](OC)=O)C[CH2:2]1.[CH3:8][C:9]1[C:10]([N+:17]([O-:19])=[O:18])=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O.[NH2:20][C:21]1[CH:25]=[CH:24][NH:23][N:22]=1>>[C:10]([C:9]1[CH:12]([C:11]2[CH:14]=[CH:15][CH:16]=[C:9]([CH3:8])[C:10]=2[N+:17]([O-:19])=[O:18])[C:25]2[C:21](=[N:22][NH:23][CH:24]=2)[NH:20][C:8]=1[CH:4]1[CH2:1][CH2:2]1)#[N:17]
Reactant: Nc1cc[nH]n1
Reactant: Cc1cccc(C=O)c1[N+](=O)[O-]
Reactant: COC(=O)C1CC1
Product: Cc1cccc(C2C(C#N)=C(C3CC3)Nc3n[nH]cc32)c1[N+](=O)[O-]

Procedure:
The title compound was prepared from methyl cyclopropanecarboxylate, 3-methyl-2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]3[CH2:22][CH2:21][N:20]([CH3:23])[C:19](=[O:24])[C:9]3=[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[C:5](=[O:25])[N:4]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[C:43](Cl)(=[O:45])[CH3:44]>C(Cl)(Cl)Cl>[CH2:12]([O:11][C:10]1[C:6]2[C:5](=[O:25])[N:4]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[N:3]=[C:2]([NH:1][C:43](=[O:45])[CH3:44])[C:7]=2[N:8]2[CH2:22][CH2:21][N:20]([CH3:23])[C:19](=[O:24])[C:9]=12)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)cc4)nc(N)c32)C1=O
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-amino-2-(4-fluorobenzyl)-10-benzyloxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (21 mg, 47 μmol) and diisopropylethylamine (10 μL, 56 μmol) in anhydrous chloroform (2 mL), acetyl chloride (8 μL, 104 μmol) was added. The mixture was stirred at room temperature for 30 minutes and concentrated under vacuum. The intermediate bisacetylated product was dissolved in methanol, stirred at room temperature overnight, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel. Collection and concentration of appropriate fractions provided the title monoacetylated product.