Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:32](=[O:33])[N:4]2[C:5]([C:16]([O:18]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:17])=[C:6]([S:9][CH2:10][C:11]3[CH:12]=[N:13][NH:14][CH:15]=3)[CH2:7][S:8][C@H:3]12.Cl.C(OCC)(=O)C.CC(C)=O>C(O)=O>[NH2:1][C@@H:2]1[C:32](=[O:33])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([S:9][CH2:10][C:11]3[CH:15]=[N:14][NH:13][CH:12]=3)[CH2:7][S:8][C@H:3]12
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3cn[nH]c3)CS[C@H]12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O=CO
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(SCc3cn[nH]c3)CS[C@H]12
Temperature: 25 °C
Yield: 68.1 %

Procedure:
Diphenylmethyl 7β-amino-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (810 mg) was dissolved in formic acid (3.2 ml) below 5° C. and herein concentrated hydrochloric acid (0.71 ml) was added thereto at the same temperature. After the reaction mixture was stirred at the room temperature for an hour, it was poured into a mixture of ethyl acetate (50 ml) and acetone (25 ml), resulting precipitate was collected by filtration, and dried under reduced pressure. The precipitate was suspended in a mixture of water (6.0 ml) and acetone (2.5 ml). After the suspension was dissolved at pH 7.0 with saturated sodium bicarbonate solution, and adjusted to pH 4.5 with 1N-hydrochloric acid. The mixture was stirred at the room temperature for 30 minutes, and then resulting precipitate was collected, washed with acetone (5.0 ml), and dried under reduced pressure to give 7β-amino-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylic acid (0.36 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][CH:16]2[C:20]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][NH:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:25]([CH2:27][C:28](O)=[O:29])#[N:26].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[C:3]([NH:15][CH:16]2[C:20]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][N:18]([C:28](=[O:29])[CH2:27][C:25]#[N:26])[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1NC1CNCC12CCCC2
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CN(C(=O)CC#N)CC12CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To a solution of 5-methyl-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(2-azaspiro[4.4]nonan-4-yl)pyrimidine-2,4-diamine (130 mg, 0.39 mmol) and 2-cyanoacetic acid (36 mg, 0.42 mmol) in a mixture of DCM (5 mL) and DMF (2 mL) were added Et3N (80 mg, 0.79 mmol) and HATU (0.3 g, 0.79 mmol) and the reaction mixture was stirred at rt for 1 h, then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the product as a yellow solid (0.11 g, 70%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH3:37])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]=[C:12]2[CH3:36])=[CH:7][CH:6]=1.[H-].[Na+].CI.[C:42](OCC)(=O)C>CN(C)C=O.O>[CH3:42][O:1][CH2:2][CH:3]([CH3:37])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]=[C:12]2[CH3:36])=[CH:7][CH:6]=1
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)COC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
To a solution of 4′-({1-[4-(2-hydroxy-1-methylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.70 g) in N,N-dimethylformamide (7 mL) were added 60% sodium hydride (0.07 g) and then methyl iodide (0.18 mL) at 0° C., and the mixture was stirred for 1 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was 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 pale-yellow viscous substance (0.53 g, 74%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:38]=[CH:39][CH:40]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][C:18]=1[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][N:37]=1)[C:32](O)=[O:33])=[O:15])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:75][C:76]([F:86])([F:85])[C:77]1[N:82]=[CH:81][C:80]([CH2:83][NH2:84])=[CH:79][CH:78]=1>CN(C)C=O>[F:85][C:76]([F:75])([F:86])[C:77]1[N:82]=[CH:81][C:80]([CH2:83][NH:84][C:32]([C:31]2[CH:35]=[CH:36][N:37]=[C:29]([C:18]3[CH:19]=[C:20]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[CH:21]=[CH:22][C:17]=3[NH:16][C:14]([C:13]3[CH:12]=[C:11]([CH:40]=[CH:39][CH:38]=3)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:41])=[O:15])[CH:30]=2)=[O:33])=[CH:79][CH:78]=1
Reactant: NCc1ccc(C(F)(F)F)nc1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)O)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3ccc(C(F)(F)F)nc3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
Into a 8-mL sealed tube, was placed a solution of 2-(2-(3-((3-tert-butoxy-3-oxopropylthio)methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinic acid 1.1j (90 mg, 0.16 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL), HATU (90 mg, 0.24 mmol, 1.51 equiv), N,N-diisopropylethylamine (30.6 mg, 0.24 mmol, 1.52 equiv), and (6-(trifluoromethyl)pyridin-3-yl)methanamine (54 mg, 0.31 mmol, 1.96 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was dissolved in ethyl acetate. The resulting mixture was washed with water and brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 114.7 mg (crude) of tert-butyl 3-(3-((2-(4-(((6-(trifluoromethyl)pyridin-3-yl)methyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzylthio)propanoate as red oil.
Reaction SMILES: [NH2:1][C:2]1[C:14](Br)=[C:13]2[C:5]([C:6]3[C:11]([CH2:16][CH3:17])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[CH3:19])=[CH:4][CH:3]=1.[C:20]([Cu])#[N:21].CN1CCCC1=O.CCOC(C)=O>O>[NH2:1][C:2]1[C:14]([C:20]#[N:21])=[C:13]2[C:5]([C:6]3[C:11]([CH2:16][CH3:17])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[CH3:19])=[CH:4][CH:3]=1
Reactant: CCC12CCC(=O)C(C)=C1c1ccc(N)c(Br)c1C2
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCC12CCC(=O)C(C)=C1c1ccc(N)c(C#N)c1C2
Temperature: 25 °C
Yield: 59.7 %

Procedure:
A mixture of crude 7-amino-8-bromo-9a-ethyl-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.97 g, 3.02 mmol), CuCN (0.318 g, 3.55 mmol), and 1-methyl-2-pyrrolidinone (NMP, 6 mL) was placed under a N2 atmosphere, stirred, and heated in an oil bath at 160–170° C. for 5.5 hours. After cooling to room temperature, the mixture was added to EtOAc (200 mL) and water (200 mL) and filtered through a pad of solka-floc. The organic portion of the filtrate was washed with water (5×200 mL) and brine (100 mL), dried over MgSO4, filtered, and evaporated under vacuum to a red oil (0.8 g). The crude product was purified by chromatography on EM silica gel 60 (2.75×25 cm column), eluting with 5% EtOAc in CH2Cl2, to afford 7-amino-8-cyano-9a-ethyl-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.48 g) as a solid.
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Li+]>O1CCCC1.CO.O>[CH3:1][N:2]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(CN(C)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1ccc(C(=O)O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
To a solution of methyl 4-((methyl(phenyl)amino)methyl)benzoate (400 mg, 1.57 mmol) in tetrahydrofuran (30 mL) and methanol (10 mL) was added lithium hydroxide (210 mg, 5 mmol) in water (10 mL). The mixture was stirred at room temperature for 2 hours. The suspension was concentrated in vacuo and acidified with concentrated hydrochloric acid (12 N, 5 mL). The mixture was re-dissolved by water (50 mL) and dichloromethane (50 mL). Organic phase was separated and concentrated to give the product 4-((methyl(phenyl)amino)methyl)benzoic acid (200 mg, 53%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.Br.[CH3:9][N:10]1[CH2:14][CH2:13][N:12]([CH3:15])[C:11]1=[NH:16].[C:17]1([N:23]=[C:24]=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)(Cl)Cl>[CH3:9][N:10]1[CH2:14][CH2:13][N:12]([CH3:15])[C:11]1=[N:16][C:24]([NH:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[S:25]
Reactant: CN1CCN(C)C1=N
Reactant: S=C=Nc1ccccc1
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CCN(C)C1=NC(=S)Nc1ccccc1

Procedure:
30.4 g (0.3 mol) of triethylamine are added to a suspension of 58.2 g (0.3 mol) of 1,3-dimethyl-2-imino-imidazolidine hydrobromide in 470 ml of chloroform, at 5°, with stirring. A solution of 40.6 g (0.3 mol) of phenyl isothiocyanate in 235 ml of chloroform is then added dropwise and the reaction mixture is refluxed for 15 hours. After cooling, it is washed with water, dried over sodium sulfate and evaporated in vacuo. Crude N-(1,3-dimethyl-2-imidazolidinylidene)-N'-phenyl-thiourea is obtained and after recrystallisation from ethanol this melts at 195°-196°.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[N:18]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH:1]1([CH2:4][NH:5][C:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:21]3[CH2:22][CH2:23][CH2:24][N:18]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([C:32]([OH:41])([C:37]([F:38])([F:39])[F:40])[C:33]([F:36])([F:34])[F:35])=[CH:30][CH:31]=4)[CH2:19][CH2:20]3)=[O:14])=[CH:15][CH:16]=2)=[O:17])[CH2:2][CH2:3]1
Reactant: OC(c1ccc(CN2CCCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reaction time: 24 h
Yield: 63.8 %

Procedure:
To a mixture of 4-(3-(cyclopropylmethyl)ureido)benzoic acid (2.134 mmol, 0.5 g), 2-(4-((1,4-diazepan-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (2.134 mmol, 0.761 g) and triethylamine (5.34 mmol, 0.744 mL, 0.540 g) in dichloromethane (30 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.56 mmol, 0.491 g). The reaction was stirred for 24 hours then was chromatographed on silica eluting with dichloromethane to dichloromethane/methanol (6%) then re-chromatographed on silica eluting with ethyl acetate to ethyl acetate/methanol (2%) to give the title compound (780 mg). MS (ESI) m/z 573.0 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[CH2:14][S:15]([NH2:18])(=[O:17])=[O:16])=[O:4].[CH2:19]([N:23]=[C:24]=[O:25])[CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:19]([NH:23][C:24]([NH:18][S:15]([CH2:14][C:6]1[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([O:2][CH3:1])=[O:4])(=[O:17])=[O:16])=[O:25])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN=C=O
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)Cc1c(C(=O)OC)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 7.7 g of the product from Example 4, 3.5 g of n-butyl isocyanate, and 4.8 g anhydrous potassium carbonate in 100 ml of methyl ethyl ketone was stirred at reflux temperature for 4 hours. After cooling to room temperature, the reaction mixture was concentrated to approximately one-third volume and diluted with 150 ml of water. The resulting solid was collected by filtration and washed with one portion of water and one portion of n-butyl chloride. The yield of N-[(n-butyl)aminocarbonyl]-2-(methoxycarbonyl)-6-nitrophenylmethanesulfonamide, m.p. 144°-150°, was 9.1 g as a tan solid; IR(nujol): 1725, 1665 cm-1, NMR (CDCL3 /DMSO-d6): δ 0.6-1.7 (7H, m), 2.9-3.4 (2H, m), 4.0 (3H, s, CO2CH3), 5.7 (2H, s, --CH2 --), 7.4-8.3 (3H, m), 10.5 (1H, br s, NH).
Reaction SMILES: [OH:1][CH2:2][CH:3]([S:6][C:7]([CH3:27])([CH3:26])[C:8]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)([OH:15])[CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)[CH2:4][OH:5].FC(F)(F)[C:30]1[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[CH:38]=[CH:39]/[CH:40]=O)=[CH:32][CH:31]=1>>[CH3:26][C:7]([S:6][C@@H:3]1[CH2:4][O:5][C@@H:40](/[CH:39]=[CH:38]/[CH:37]=[CH:36]/[C:33]2[CH:32]=[CH:31][CH:30]=[CH:35][C:34]=2[C:22]([F:25])([F:24])[F:23])[O:1][CH2:2]1)([CH3:27])[C:8]([C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=1)([OH:15])[CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: O=C/C=C/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(SC(CO)CO)C(O)(Cn1cncn1)c1ccc(C(F)(F)F)cc1
Product: CC(C)(S[C@H]1CO[C@H](/C=C/C=C/c2ccccc2C(F)(F)F)OC1)C(O)(Cn1cncn1)c1ccc(C(F)(F)F)cc1

Procedure:
Reaction was carried out in the same manner as in Example 4 using (RS)-3-[(1,3-dihydroxy-2-propyl)thio]-3-methyl-2-[4-(trifluoromethyl)phenyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol as described in Reference example 55 and (2E,4E)-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienal as described in Reference example 25 to obtain the title compound, a major product as a colorless foam.
Reaction SMILES: [N:1]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5]N1C(=O)CCC1=O)=O.[NH2:23][C@@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1>>[N:1]1([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([NH:23][C@@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Yield: 70 %

Procedure:
Condensation of BocProOSu (6.00 g.) and HDTrpOH (4.08 g.) by the salt coupling method gave BocPro-DTrpOH in 70% yield. Condensation of BocPro-DTrpOH (2.93 g.) and HGlyOBz p-toluenesulfonate salt (2.47 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-DTrp-GlyOBz in 68% yield. Debenzylation of BocPro-DTrp-GlyOBz by hydrogenation with palladium catalyst gave BocPro-DTrp-GlyOH in 95% yield.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([CH2:22][CH2:23][N:24]2[CH2:40][CH2:39][C:27]3([N:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:30][NH:29][C:28]3=[O:38])[CH2:26][CH2:25]2)=O)=[CH:15][CH:14]=1.O>C1C=CC=CC=1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][CH2:20][CH2:22][CH2:23][N:24]2[CH2:40][CH2:39][C:27]3([N:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:30][NH:29][C:28]3=[O:38])[CH2:26][CH2:25]2)=[CH:17][CH:18]=1
Reactant: O=C(CCN1CCC2(CC1)C(=O)NCN2c1ccccc1)Nc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: O=C1NCN(c2ccccc2)C12CCN(CCCNc1ccc(F)cc1)CC2

Procedure:
To a mixture of 4 g of lithium aluminum hydride and 40 ml of tetrahydrofuran was added portionwise 2 g of 8-{2-[N-(p-fluorophenyl)carbamoyl]ethyl}-1-phenyl-4-oxo-1, 3, 8-triazaspiro[4, 5]decane under cooling. Then, the mixture was heated under reflux for 4 hours. To the reaction mixture were gradually added water and benzene under cooling, and the precipitate was filtered off. The organic layer was separated, dried over sodium sulfate evaporated under reduced pressure. The residue was triturated with ether, cooled and filtered to give 8-{3-(p-fluoroanilino)propyl}-1-phenyl-4-oxo-1, 3, 8-triazaspiro[4, 5]decane, m.p. 158°-162° C; recrystallized from benzene, m.p. 177°-178° C.
Reaction SMILES: C(OC(=O)[N:7]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1)[C:8]1[C:9]2[N:10]([N:25]=[CH:26][N:27]=2)[C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[C:20](=[O:24])[NH:19][CH2:18][CH2:17]3)=[CH:12][N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:34]1([C:31]2[CH:30]=[CH:29][C:28]([NH:7][C:8]3[C:9]4[N:10]([N:25]=[CH:26][N:27]=4)[C:11]([C:14]4[CH:15]=[C:16]5[C:21](=[CH:22][CH:23]=4)[C:20](=[O:24])[NH:19][CH2:18][CH2:17]5)=[CH:12][N:13]=3)=[CH:33][CH:32]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(-c2ccc3c(c2)CCNC3=O)n2ncnc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCc2cc(-c3cnc(Nc4ccc(N5CCOCC5)cc4)c4ncnn34)ccc21

Procedure:
A solution of (4-morpholin-4-yl-phenyl)-[5-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (30 mg, 0.055 mmol) in a 1:1 mixture of TFA:DCM (1 drop of H2O), is stirred at room temperature for 2 hours. The solvent is removed in vacuo and the residue partitioned between ethyl acetate and sat. NaHCO3 (aq). The water layer is extracted with ethyl acetate (2×). The organic layers are combined and evaporated to afford a residue purified by silica gel column chromatography eluting with ethyl acetate. The title compound is isolated (18 mg, 75%) and converted into the mesylate salt (16.6 mg, 97%) using 0.1M methanesulfonic acid (0.317 mL) in MeOH. 1H-NMR (400 MHz, d6-DMSO) δ(ppm) 2.36 (3H, s MsOH), 3.04 (2H, t), 3.21 (4H, m), 3.47 (2H, t), 3.83 (4H, m), 7.11 (2H, d), 7.95-8.02 (6H, m), 8.05 (1H, s), 8.74 (1H, s), 10.09 (1H, br s). LCMS: Rt 2.81 min (97.9%), m/z (APCI) 442 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH3:15])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1.CI>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][C:14]([CH3:20])([C:16]([O:18][CH3:19])=[O:17])[CH3:15])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C)Cc1ccc(C(=O)OC(C)(C)C)s1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(C)Cc1ccc(C(=O)OC(C)(C)C)s1
Reaction time: 2 h
Yield: 89.4 %

Procedure:
5-(2-Methoxycarbonylpropyl)thiophene-2-carboxylic acid tert-butyl ester (13.14 g, 46.3 mmol) was dissolved in tetrahydrofuran (250 mL), 1.09 M lithium bis(trimethylsilyl)azanide/tetrahydrofuran solution (65 mL, 70.9 mmol) was added dropwise at −78° C., and the mixture was stirred for 2 hours. To the reaction mixture was added methyl iodide (11.7 g, 82.4 mmol) at −78° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was added to ethyl acetate and 0.5N-hydrochloric acid solution, the organic layer was extracted, and the aqueous layer was extracted two times with ethyl acetate. The organic layers were collected, washed with sodium thiosulfate solution and brine, and dried over anhydrous magnesium sulfate. The solvent of the filtrate after filtration was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (12.36 g, 41.4 mmol, 89%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5]([C:7]1[S:11][CH:10]=[C:9]([C:12]#[N:13])[CH:8]=1)=[O:6].O.Cl>CN(C=O)C>[NH:1]1[C:12]([C:9]2[CH:8]=[C:7]([CH:5]=[O:6])[S:11][CH:10]=2)=[N:13][N:3]=[N:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1csc(C=O)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(-c2nnn[nH]2)cs1
Temperature: 25 °C
Yield: 20 %

Procedure:
Sodium azide (2.9 g, 44.6 mmol) and TEA hydrochloride (4.13 g, 30 mmol) were added to a solution of 5-formyl-thiophene-3-carbonitrile (2 g, 15 mmol, prepared according to Intern. application WO 02/26718) in DMF (50 ml). The solution was refluxed for 12 h. After cooling to RT, water was added and the solution was carefully acidified with HCl. The solution was extracted 3 times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to yield the desired product as a brown solid (540 mg) which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH:6]=O)[CH3:2].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][N:11]=1.C(#N)C.C(O)C>C(=O)(O)[O-].[Na+]>[CH2:1]([O:3][C:4]([C:5]1[N:11]2[CH:12]=[C:13]([I:16])[CH:14]=[CH:15][C:10]2=[N:9][CH:6]=1)=[O:8])[CH3:2]
Reactant: CCOC(=O)CC=O
Reactant: Nc1ccc(I)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(I)cn12
Yield: 78 %

Procedure:
Reflux a solution of 3-oxo-propionic acid ethyl ester (J. Med. Chem. 2001, 44(12), 1193-2003; 3.4 g, 23.7 mmol) and 2-amino-5-iodopyridine in 1:1 acetonitrile/ethanol (100 mL) overnight. Dilute with saturated aqueous sodium bicarbonate, extract into dichloromethane (4×100 mL), combine organics, and concentrate. Flash chromatography using appropriate ethyl acetate/hexane mixtures gives 3.7 g (78%) of the subtitled compound as an off-white solid. ES+ m/e 316.7 (M+1).
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].[CH2:5]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]>>[CH2:1]([O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:18][CH:19]=1)[CH:2]=[CH2:3]
Reactant: C=CCCl
Reactant: CC(C)CCCCCCCCCc1ccc(O)cc1
Product: C=CCOc1ccc(CCCCCCCCCC(C)C)cc1
Temperature: 63 °C

Procedure:
Next, 363 grams (4.75M) of allyl chloride were added, and mixed with the fluid initial reaction product. The mixture was then heated to 63° C., and exothermed slowly to 73° C. A sample was taken at this point, then acidified and stripped under reduced pressure. TLC revealed the presence on the sample of a small amount of unreacted p-isododecylphenol.