Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([NH:29][CH3:30])=O)=[CH:20][CH:19]=3)[C:10]2=[S:31])=[CH:5][C:4]=1[C:32]([F:35])([F:34])[F:33])#[N:2].[N:36]1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.N>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27](=[NH:36])[NH:29][CH3:30])=[CH:20][CH:19]=3)[C:10]2=[S:31])=[CH:5][C:4]=1[C:32]([F:34])([F:35])[F:33])#[N:2]
Reactant: c1ccncc1
Reactant: CNC(=O)CCCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Agent: N
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CNC(=N)CCCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a solution of 4-{4-[7-(4-Cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]-phenyl}-N-methyl-butyramide (88) [ND-6] (4.0 mg, 0.008 mmol) and pyridine (1.94 μL, 0.02 mmol) in dichloromethane (3 mL) at −40° C. was slowly added triflic anhydride (Tf2O, 1.75 μL, 0.01 mmol). The mixture was allowed to warm to 0° C. over 3 h. The solution was then cooled to −40° C. and ammonia was introduced by bubbling. The reaction was then warmed to room temperature and stirred overnight. Without aqueous work up, flash chromatography using 10% methanol in ethyl acetate afforded 4-(4-(7-(4-Cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-an-5-yl)phenyl)-N-methylbutanimidamide (87) [ND-3] (2.9 mg, 72%) of as a colorless oil: 1H NMR (CD3CN) δ 8.10 (d, 1H, J=8.2 Hz) 8.04 (s, 1H), 7.92 (d, 1H, J=8.2 Hz) 7.49 (br s, 2H), 7.43 (d, 2H, J=8.3 Hz), 7.30 (d, 2H, J=8.3 Hz) 3.26 (d, 3H, J=5.4 Hz) 2.77 (t, 2H, J=8.0 Hz) 2.56-2.65 (m, 2H), 2.52 (t, 2H, J=7.7 Hz) 2.42-2.52 (m, 2H), 1.95-2.12 (m, 3H), 1.47-1.62 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][N:9]([C:23](=[O:43])[CH2:24][CH2:25][C:26](=[O:42])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:44]1(=[O:50])[O:49][C:47](=[O:48])[CH2:46][CH2:45]1>N1C=CC=CC=1>[CH2:35]([O:34][N:33]([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][NH:27][C:26](=[O:42])[CH2:25][CH2:24][C:23](=[O:43])[N:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:44](=[O:50])[CH2:45][CH2:46][C:47]([OH:49])=[O:48])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)O
Temperature: 81 °C
Yield: 81.4 %

Procedure:
A mixture of (9) (2.2 g, 3.48 mmol), succinic anhydride (0.55 g, 5.5 mmol) and pyridine (70 mL) was heated at 81° C. for 2 hours. Solvent was removed in vacuo and cold 1N HCl (100 mL) was added. Extraction was carried out with CHCl3 (6×75 mL), followed by a water wash (100 mL). Solvent removal and flash column chromatography, eluting with 7% MeOH/CH2Cl2, afforded 1.98 g (81%) of (10) as an oil: 300 MHz NMR δ 1.2-1.7 (m+s, 21 H), 2.53 (t, 2 H, J=7), 2.67 (s, 4 H), 2.78-2.86 (m, 2 H), 3.02-3.11 (m, 2 H), 3.22 (q, 2 H, J=6), 3.56-3.77 (m, 4 H), 4.7 (br s, 1 H), 4.83 (s, 2 H), 4.86 (s, 2 H) , 6.73 (br s, 1 H) , 7.38 (s, 10 H) . Anal. calcd. for C37H54N4O9 : C, 63.59; H, 7.79; N, 8.02. Found: C, 63.4 5; H, 7.81; N, 8.07.
Reaction SMILES: Cl[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14]([CH:18]4[CH2:20][CH2:19]4)=[CH:13][C:12]=3[Cl:21])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:22][C:23]1[N:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:17][C:16]1[CH:15]=[C:14]([CH:18]2[CH2:19][CH2:20]2)[CH:13]=[C:12]([Cl:21])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:29][C:25]3[CH:24]=[C:23]([CH3:22])[N:28]=[CH:27][N:26]=3)=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: Clc1cc(C2CC2)cc(Cl)c1-c1nc2ccnc(Cl)c2s1
Reactant: Cc1cc(N)ncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc3nc(-c4c(Cl)cc(C5CC5)cc4Cl)sc23)ncn1
Temperature: 25 °C
Yield: 3.9 %

Procedure:
A mixture of 4-chloro-2-(2,6-dichloro-4-cyclopropylphenyl)thiazolo[5,4-c]pyridine (0.148 g, 0.416 mmol), 6-methylpyrimidin-4-ylamine (0.044 g, 0.458 mmol), XantPhos (0.024 g, 0.0416 mmol), Cs2CO3 (0.271 g, 0.832 mmol) and Pd2(dba)3 (0.019 g, 0.021 mmol) in dioxane (1 mL) was degassed with a stream of argon and was then irradiated at 150° C. for 0.5 hour in a microwave reactor. After cooling to room temperature, the crude reaction mixture was filtered through Celite® washing with DCM and the filtrate was concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-2% MeOH in DCM followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a 30 minute gradient 50-90%, 0.1% HCO2H in MeOH/H2O) to afford the title compound (7 mg, 4% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.63 (s, 1H), 8.63 (d, J=1.2 Hz, 1H), 8.45 (d, J=5.6 Hz, 1H), 7.82 (d, J=5.6 Hz, 1H), 7.62 (s, 1H), 7.45 (s, 2H), 2.40 (s, 3H), 2.14-2.05 (m, 1H), 1.13-1.07 (m, 2H), 0.94-0.89 (m, 2H). LCMS (Method C): RT=4.17 min, m/z: 428 [M+H+].
Reaction SMILES: [S:1]1[N:5]=[CH:4][C:3]([CH2:6][S:7][CH2:8][CH2:9][SH:10])=[N:2]1.[C:11]([NH:13][C:14](=[N:17][CH3:18])SC)#[N:12]>>[S:1]1[N:5]=[CH:4][C:3]([CH2:6][S:7][CH2:8][CH2:9][S:10][C:14](=[N:17][CH3:18])[NH:13][C:11]#[N:12])=[N:2]1
Reactant: SCCSCc1cnsn1
Reactant: CN=C(NC#N)SC
Product: CN=C(NC#N)SCCSCc1cnsn1

Procedure:
Conversion of 3-bromomethyl-1,2,5-thiadiazone into 2-((1,2,5-thiadiazol-3-yl)methylthio)ethane thiol by the precedure of Example 1 and treatment of this product with N-cyano-N',S-dimethylisothiourea according to the procedure of Example 2 leads to the production of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:18]2)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:46]1([CH3:69])[CH:51]=[CH:50][C:49]([S:52]([O:55][CH2:56][CH2:57]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:54])=[O:53])=[CH:48][CH:47]=1>CN(C)C=O>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH:8]([NH:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:28][CH2:27]2)[CH2:18]1)=[O:16])[C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:57][CH2:56][O:55][S:52]([C:49]2[CH:50]=[CH:51][C:46]([CH3:69])=[CH:47][CH:48]=2)(=[O:54])=[O:53])=[CH:3][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1ccc(OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.9 %

Procedure:
100 mg (0.18 mmol) Tert-butyl 4-[3-((3R)-3-{[1-(4-hydroxyphenyl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl)-3-oxopropyl]piperidine-1-carboxylate (example 2b) were dissolved in 7 ml N,N-dimethylformamide. 179 mg (0.55 mmol) cesium carbonate and 102 mg (0.28 mmol) ethylene glycol bis-p-toluenesulfonate were added. The mixture was stirred at room temperature for 48 hours and concentrated. The remainder was taken up with saturated ammonium chloride solution and ethyl acetate. The aqueous phase was extracted with 3×20 ml ethyl acetate. The extracts were dried over sodium sulfate and concentrated to yield 195 mg. Chromatography over 5 g silica gel (dichloromethane/ethanol 100/0-95/5) gave 95 mg (63%) tert-butyl 4-{3-[(3R)-3-({3-methoxy-1-[4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)phenyl]-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: C1(N2C(C(F)(F)F)=C(C3ON=C4C5C(CCC=34)=CC(C=C)=CC=5)C=N2)C=CC=CC=1.[CH:31]([C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)/[C:39](=[N:43]/[OH:44])/[CH2:38][CH2:37][CH2:36]2)=[CH2:32].[CH:45]1([C:51]2[CH:60]=[CH:59][C:54]([C:55](OC)=O)=[CH:53][C:52]=2[C:61]([F:64])([F:63])[F:62])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>>[CH:45]1([C:51]2[CH:60]=[CH:59][C:54]([C:55]3[O:44][N:43]=[C:39]4[C:40]5[C:35]([CH2:36][CH2:37][C:38]=34)=[CH:34][C:33]([CH:31]=[CH2:32])=[CH:42][CH:41]=5)=[CH:53][C:52]=2[C:61]([F:62])([F:63])[F:64])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]1
Reactant: C=Cc1ccc2c(c1)CCC/C2=N\O
Reactant: COC(=O)c1ccc(C2CCCCC2)c(C(F)(F)F)c1
Agent: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(C2CCCCC2)c(C(F)(F)F)c1

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 89A employing 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 1) and methyl 4-cyclohexyl-3-(trifluoromethyl)benzoate (Preparation 118C) as starting materials. The compound had an HPLC retention time=4.83 min. (condition C); LC/MS M+1=424.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]3[N:21]4[CH2:22][CH2:23][O:24][CH2:25][C:20]4=[N:19][C:14]=3[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]3[N:21]4[CH2:22][CH2:23][O:24][CH2:25][C:20]4=[N:19][C:14]=3[C:15]([NH2:38])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: c1ccc(COc2ccc3c(c2)ncc2nc4n(c23)CCOC4)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: Nc1nc2cc(OCc3ccccc3)ccc2c2c1nc1n2CCOC1
Temperature: 25 °C

Procedure:
A 1-liter round bottom flask was charged with 3-(benzyloxy)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (5.0 g, 15.1 millimoles (mmol)) and dichloromethane (200 mL). To this solution was slowly added in small portions 3-chloroperoxybenzoic acid (mCPBA) (5.2 g of 50% pure material, 15.1 mmol, 1.0 eq). The reaction was maintained at room temperature for 3 hours. Concentrated ammonium hydroxide (100 mL) was added followed by p-toluenesulfonyl chloride (3.2 g, 16.6 mmol, 1.1 eq) in small portions. The reaction was maintained at room temperature overnight. The reaction was quenched with water (200 mL) and stirred for an additional hour. The aqueous layer was separated and extracted with dichloromethane (3×50 mL). The combined organic fractions were concentrated to provide 3-(benzyloxy)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine as an off-white solid. A small amount of product was recrystallized from acetonitrile and carried on to the next step.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH:5]=[C:4]([C:13]#[N:14])[N:3]=1.CCN(CC)CC.[NH2:22][C@H:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1>CN1C(=O)CCC1>[Cl:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([NH:22][C@H:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1)=[N:3][C:4]([C:13]#[N:14])=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: N#Cc1cc2cccc(Cl)c2c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3cccc(Cl)c23)C1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To a suspension of 1,8-dichloroisoquinoline-3-carbonitrile (0.3 g, 1.35 mmol) and Et3N (0.27 g, 2.7 mmol) in NMP (5 mL) was added (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (0.3 g, 1.62 mmol) at RT. The resulting mixture was stirred at 160° C. for 30 minutes in a microwave reactor. The reaction was subsequently quenched with water and the mixture was extracted with EtOAc (3×30 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography eluting with ethyl acetate and petroleum ether (EtOAc/PE=1:10-1:2 gradient) on silica gel to give the title compound (0.45 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-7.90 (d, J=8.0 Hz, 1H), 7.85-7.83 (m, 2H), 7.79-7.77 (d, J=8.0 Hz, 1H), 7.63 (s, 1H), 4.66-4.58 (m, 1H), 3.75-3.72 (t, J=8.0 Hz, 3H), 3.52-3.35 (m, 3H), 2.31-2.30 (br s, 1H), 2.11-2.07 (br s, 1H), 1.47-1.45 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([N:31]([CH2:38][CH2:39]O)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:30])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:39][CH2:38][N:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:29](=[O:30])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccc(Cl)cc4)CCCC3)n2CCN1c1ccccc1
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
To a stirred solution of 5-(benzyloxy)-2-((1-(4-chlorophenyl)cyclopentyl)methyl)-6-hydroxy-N-(2-hydroxyethyl)-N-phenylpyrimidine-4-carboxamide (48) (100.1 mg, 179 μmol, Eq: 1.00) in dichloromethane (5 ml) at room temperature was added triphenylphosphine (70.6 mg, 269 μmol, Eq: 1.5) and stirred for 10 min. Then diisopropyl azodicarboxylate (54.4 mg, 52.3 μl, 269 μmol, Eq: 1.5) was added and the reaction mixture was stirred for 18 hrs, concentrated, and chromatographed (silica gel, gradient 0 to 5% methanol-dichloromethane) to obtain 9-(benzyloxy)-6-((1-(4-chlorophenyl)cyclopentyl)methyl)-2-phenyl-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (49) (white foam, 88.5 mg, 164 μmol, 91.4% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[NH2:16][C:17]1[NH:21][N:20]=[CH:19][C:18]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:13]([NH:16][C:17]2[NH:21][N:20]=[CH:19][C:18]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[O:15])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[N:7]=1
Reactant: Nc1[nH]ncc1-c1ccccn1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1[nH]ncc1-c1ccccn1
Temperature: 25 °C

Procedure:
A mixture comprising 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate 2) (0.179 g, 0.624 mmol), 5-amino-4-(pyridin-2-yl)-1H-pyrazole (0.1 g, 0.624 mmol), HATU (0.237 g, 0.624 mmol) and N-methylmorpholine (0.123 ml, 1.249 mmol) in DMF (5 ml) was stirred at 80° C. for 2.5 hours. After cooling to RT, the mixture was diluted with water (40 ml) and the resulting yellow precipitate was filtered under vacuum and washed with water (20 ml). MeOH (150 ml) was added to the solid and the suspension ultrasonicated to give a fine suspension. The suspension was filtered under vacuum and the solid was rinsed with MeOH (20 ml) and dried under vacuum at 45° C. for 1.5 hours to afford the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]([OH:8])([CH2:6][CH3:7])[C:4]#[CH:5])[CH3:2].CCN(CC)CC.[C:16](OC(=O)C)(=[O:18])[CH3:17].CO>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:16]([O:8][C:3]([CH2:6][CH3:7])([CH2:1][CH3:2])[C:4]#[CH:5])(=[O:18])[CH3:17]
Reactant: C#CC(O)(CC)CC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CO
Solvent: CCN(CC)CC
Product: C#CC(CC)(CC)OC(C)=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 75 %

Procedure:
In a 250-mL r.b., a solution of 3-ethyl-1-pentyn-3-ol (11.5 g, 102 mmol) in pyridine (10.2 mL) was treated sequentially with Et3N (15.0 mL, 0.107 mol, 1.4 equiv), acetic anhydride (13.5 mL, 143 mmol, 1.4 equiv), and DMAP (1.25 g, 10.2 mmol, 10.0 mol %). The reaction mixture was stirred at rt for 5 d, then treated with MeOH (5 mL) and stirred for 1 h. The mixture was partitioned between ether (100 mL) and water (100 mL), and the aqueous layer was extracted with ether (100 mL). The organic layers were washed sequentially with 2 N NaHSO4 and brine (50 mL), dried (MgSO4), filtered, and concentrated. Distillation under reduced pressure afforded 11.8 g (58.8%) 3-ethylpent-1-yn-3-yl acetate, a colorless oil, bp 38-39° C. @ 15 mm Hg. Data for 3-ethylpent-1-yn-3-yl acetate: 1H NMR (400 MHz, CDCl3) 2.54 (s, 1H), 2.03 (s, 3H), 1.96-2.08 (m, 2H), 1.84-1.95 (m, 2H), 0.97 (t, J=7.4, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][C:15]([N+:17]([O-])=O)=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].CO>[Pd]>[CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCCOc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)N1CCCOc2cc(N)ccc21
Reaction time: 0.5 h
Yield: 100 %

Procedure:
3-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester (338 mg, 1.27 mmol) was placed in methanol (10.0 mL, 0.247 mol) and 10% Palladium on Carbon (50% Wet) (67.5 mg) was added. The reaction was hydrogenated at 25 psi. for 30 minutes and then filtered through a pad of celite to remove the catalyst. The product was then concentrated under reduced pressure to obtain 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester as a light brown solid (300 mg, 100%). m.p.=140-143° C.; LCMS (m/e) 237 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.18-6.91 (m, 1H), 6.41-6.30 (m, 2H), 4.30-3.93 (m, 4H), 3.83-3.50 (m, 4H), 2.13-1.93 (m, 2H), 1.40-1.10 (m, 3H).
Reaction SMILES: [C:1]([C:5]([C:7]1[N:12]2[C:13](=[S:17])[C@H:14]([O:15][CH3:16])[C@H:11]2[S:10](=[O:19])(=[O:18])[CH:9]([C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)[C:8]=1[CH3:26])=[O:6])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH:34]([O:47][C:48](=[O:57])[C:49]1[CH:54]=[CH:53][C:52]([CH2:55]Br)=[CH:51][CH:50]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CS(C)=O.ClCCl>[CH:34]([O:47][C:48]([C:49]1[CH:50]=[CH:51][C:52]([CH2:55][C:9]2([C:20]3[N:24]([CH3:25])[N:23]=[N:22][N:21]=3)[C:8]([CH3:26])=[C:7]([C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[O:6])[N:12]3[C:13](=[S:17])[C@H:14]([O:15][CH3:16])[C@H:11]3[S:10]2(=[O:19])=[O:18])=[CH:53][CH:54]=1)=[O:57])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CO[C@H]1C(=S)N2C(C(=O)C(C)(C)C)=C(C)C(c3nnnn3C)S(=O)(=O)[C@H]12
Reactant: O=C(OC(c1ccccc1)c1ccccc1)c1ccc(CBr)cc1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CO[C@H]1C(=S)N2C(C(=O)C(C)(C)C)=C(C)C(Cc3ccc(C(=O)OC(c4ccccc4)c4ccccc4)cc3)(c3nnnn3C)S(=O)(=O)[C@H]12
Reaction time: 1 h
Yield: 28.5 %

Procedure:
A solution of 4-tert-butylcarbonyl-7α-methoxy-3-methyl-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-3-cephem 1,1-dioxide (500 mg) in dimethyl sulphoxide (4 ml) was treated at room temperature with triethylamine (0.185 ml) and benzhydryl-4-bromomethylbenzoate (1.4 g). The solution was stirred for 1 hr, diluted with dichloromethane, washed with brine and eventually dried over Na2SO4. Removal of the solvent left a crude residue which afforded the title compound as a yellowish solid (250 mg) after flash chromatography.
Reaction SMILES: C([SiH2][O:6][C:7](C1C=CC=CC=1)(C1C=CC=CC=1)[C@@H:8]([NH:24][C:25]([NH:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[CH:29]=1)=[O:26])[CH2:9][CH2:10][N:11]1[CH2:14][CH:13]([C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:12]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:37][O:36][C:30]1[CH:29]=[C:28]([NH:27][C:25]([NH:24][C@H:8]([CH2:7][OH:6])[CH2:9][CH2:10][N:11]2[CH2:12][CH:13]([C:15](=[O:23])[C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH2:14]2)=[O:26])[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=1
Reactant: COc1cc(NC(=O)N[C@@H](CCN2CC(C(=O)c3ccc(F)cc3)C2)C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)cc(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(NC(=O)N[C@H](CO)CCN2CC(C(=O)c3ccc(F)cc3)C2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-{(S)-1-(tert-butyl-diphenyl-silanyloxymethyl)-3-[3-(4-fluoro-benzoyl)-azetidin-1-yl]-propyl}-3-(3,5-dimethoxy-phenyl)-urea (0.862 g, 0.126 mmol) in THF (3 ml) is treated with a 1 M solution of tetrabutyl ammonium fluoride (TBAF, 0.126 ml), and the reaction mixture stirred at ambient temperature for 2 hours. The reaction mixture is partitioned between ethylacetate and saturated NaHCO3 solution. The ethylacetate phase is washed with water and brine, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with a 5:95 methanol/dichloromethane) to afford 1-(3,5-dimethoxy-phenyl)-3-{(S)-3-[3-(4-fluoro-benzoyl)-azetidin-1-yl]-1-hydroxymethyl-propyl}-urea.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=1[CH3:15])[CH2:4][CH3:5])[CH3:2].[OH:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([NH:23]O)=[NH:22])=[C:19]([O:27][CH3:28])[CH:18]=1>>[CH2:4]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:14][N:23]=[C:21]([C:20]3[CH:25]=[CH:26][C:17]([OH:16])=[CH:18][C:19]=3[O:27][CH3:28])[N:22]=2)=[CH:9][C:8]=1[CH3:15])[CH2:1][CH3:2])[CH3:5]
Reactant: COc1cc(O)ccc1C(=N)NO
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(O)cc3OC)no2)cc1C
Yield: 16 %

Procedure:
The title compound (7 mg) is prepared starting from 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (30 mg, 130 μmol) and 4,N-dihydroxy-2-methoxy-benzamidine (21 mg, 117 μmol) according to Method A; LC-MS: tR=0.50 min; [M+1]+=374.12.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:14])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[CH:11]([C:29](=[O:30])[NH:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC1=NN(c2ccc(Cl)cc2)C(=O)C1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC1=NN(c2ccc(Cl)cc2)C(=O)C1C(=O)Nc1ccccc1
Reaction time: 2 h

Procedure:
The stirred suspension of 4.2 g of 1-(p-chlorophenyl)-3-methyl-2-pyrazolin-5-one in 100 ml of benzene is gently warmed with 2.4 g of triethylamine until all solid is dissolved. The deep red solution is combined with 2.4 g of phenylisocyanate, and after 2 hours' standing at ambient temperature, a lower layer is present. The mixture is evaporated, the residue taken up in 0.3 N hydrochloric acid and the mixture extracted with ethyl acetate. The extract is washed with water, dried, evaporated, the residue is triturated with diethyl ether and recrystallized from methanol to yield the 1-(p-chlorophenyl)-3-methyl-4-phenylcarbamoyl-2-pyrazolin-5-one of Formula II with R'=R"=H and R=Cl, melting at 212°-215° (dec.).