Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:13]([Si:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].N1C=CN=C1.O>C(Cl)Cl>[CH2:22]([Si:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[O:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCC[Si](Cl)(CCCC)CCCC
Reactant: CCOC(=O)c1ncccc1O
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CCCC[Si](CCCC)(CCCC)Oc1cccnc1C(=O)OCC
Reaction time: 8 h
Yield: 49.7 %

Procedure:
A mixture of ethyl 3-hydroxypicolinate (15 g, 900 mmol), tributylsilyl chloride (16.23 g, 110 mmol), imidazole (8.0 g, 120 mmol) in methylene chloride was stirred overnight under a nitrogen atmosphere. Water was added and the methylene chloride layer was separated and concentrated in vacuo. Purification on a silica gel column using ethyl acetate-hexane (1:4) as the eluant gave ethyl 3-(tributylsilyloxy)picolinate as a solid (20 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:39]([O:43][C:44]([N:46]1[CH2:50][CH:49]([C:51]#[N:52])[CH2:48][CH:47]1[C:53]1[NH:54][C:55]([C:58]2[CH:67]=[CH:66][C:65]3[C:60](=[CH:61][CH:62]=[C:63](Br)[CH:64]=3)[CH:59]=2)=[CH:56][N:57]=1)=[O:45])([CH3:42])([CH3:41])[CH3:40].C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:39]([O:43][C:44]([N:46]1[CH2:50][CH:49]([C:51]#[N:52])[CH2:48][CH:47]1[C:53]1[NH:54][C:55]([C:58]2[CH:67]=[CH:66][C:65]3[C:60](=[CH:61][CH:62]=[C:63]([C:26]4[CH:25]=[CH:24][C:23]([C:20]5[NH:19][C:18]([CH:17]6[CH2:16][C:13]7([CH2:14][CH2:15]7)[CH2:12][N:11]6[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:38])[CH:6]([CH3:8])[CH3:7])=[N:22][CH:21]=5)=[CH:28][CH:27]=4)[CH:64]=3)[CH:59]=2)=[CH:56][N:57]=1)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)CC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CC(C#N)CN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Temperature: 25 °C
Yield: 51 %

Procedure:
[2-Methyl-1-(6-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-propyl]-carbamic acid methyl ester (997 mg, 1.91 mmol), 2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester, Pd(PPh3)4 (184 mg, 0.159 mmol), and K2CO3 (2 M in H2O, 1.9 mL, 3.8 mmol) were combined in 1,2-dimethoxyethane (16 mL). The reaction mixture was degassed with bubbling N2 for 10 minutes then heated to reflux for 3.5 h. After heating, the reaction mixture was cooled to RT, diluted with EtOAc and washed with H2O and brine. The organic phase was dried over MgSO4, then filtered and concentrated. The resulting residue was purified with silica column chromatography 0% to 100% (10% MeOH/DCM)/EtOAc to afford the title compound (641 mg, 51%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:14]([CH2:17]Br)[CH2:15][S:16][C@H:11]12)=[O:8].CN(C)P(N(C)C)(N(C)C)=O.[OH:48][CH2:49][CH2:50][CH2:51][C:52]([O-:54])=[O:53].[Na+]>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C:14]([CH2:17][O:54][C:52](=[O:53])[CH2:51][CH2:50][CH2:49][OH:48])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C([O-])CCCO
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)CS[C@H]12
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(COC(=O)CCCO)=CS[C@H]12
Reaction time: 1.5 h

Procedure:
To a solution of 2.24 g. (3.8 mmol) of benzhydryl 7-(2-thienylacetamido)-3-bromomethyl-3-cephem-4-carboxylate in 20 ml. of hexamethylphosphoramide (HMPA) at 0° C. under nitrogen was added a suspension of 0.530 g. (4.2 mmol) of sodium 4-hydroxybutanoate in 25 ml. of HMPA. After stirring 1.5 hours, ethyl acetate was added, and the resulting solution was washed with water (5X) and brine and dried over anhydrous MgSO4. Evaporation in vacuo to dryness provided 2.12 g. of product which was combined with that of an identical reaction ran on a 1 mmol scale. The combined products were chromatographed on a silica gel column using a cyclohexane:ethyl acetate (1:2) eluant to provide 293 mg. of a mixture of the title product and the corresponding 3-cephem compound. For the title product: nmr (CDCl3) δ1.7-2.6 ##STR26## 3.55 (m, 2, CH2OH), 3.83 (s, 2, side chain CH2), 4.63 (bs, 1, --CH2OH), 5.0 (s, 1, C4 --H), 5.23 (d, 1, J = 4 Hz, C6 --H), 5.58 (dd, 1, J = 4 and 8 Hz, C7 --H), 6.42 (bs, 1, C2 --H), 6.95 (s, 1, ester CH), and 7.36 (m, 13, thienyl + ArH).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[NH2:13][NH2:14]>CO>[Br:1][C:2]1[C:3]([Cl:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([NH:13][NH2:14])=[O:8]
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Reactant: NN
Solvent: CO
Product: NNC(=O)c1cnc(Cl)c(Br)c1
Temperature: 70 °C
Yield: 20 %

Procedure:
Methyl 5-bromo-6-chloronicotinate (100 mg, 0.399 mmol) was added to hydrazine (19.19 mg, 0.599 mmol) in methanol (8 mL) and heated overnight at 70° C. The reaction was monitored by TLC. Upon completion of the reaction, the solvent was removed by vacuum, and the compound was purified by column chromatography affording the title compound (20 mg). 1H NMR (400 MHz, CD3OD): δ 8.33 (d, 1H, J=2.4 Hz), 8.01 (d, 1H, J=2.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:19])=O.CN(C)C=O>O1CCCC1>[Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:19])=[O:5]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-3-(1-cyano-1-methylethyl)benzoic acid (3.0 g, 13.4 mmol) was dissolved in tetrahydrofuran (67 mL), and oxalyl chloride (1.35 mL, 15.8 mmol) and N,N-dimethylformamide (20 μL) were added. The reaction mixture was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure to give 2-chloro-3-(1-cyano-1-methylethyl)benzoyl chloride. To a solution of 3-amino-4-fluorophenol (1.62 g, 12.8 mmol) in tetrahydrofuran (20 ml) was added a suspension of sodium hydrogen carbonate (3.22 g, 38.3 mmol) in water (40 mL), and the mixture was vigorously stirred at room temperature. To this mixture was added dropwise at 0° C. a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoyl chloride produced above in tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added ethyl acetate (100 mL), and the aqueous layer was separated. The organic layer was washed with saturated brine (150 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was purified by basic silica gel column chromatography (eluate: ethyl acetate). The obtained solution was concentrated under reduced pressure, and the obtained residue was crystallized from ethyl acetate/n-hexane to give the title compound (4.13 g, 97%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH2:10][N:11]2C(=O)C3C(=CC=CC=3)C2=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.NN.Cl>CCO>[NH2:11][CH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Br:1])[CH:9]=1
Reactant: N#Cc1ccc(CN2C(=O)c3ccccc3C2=O)cc1Br
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(CN)cc1Br
Yield: 75.8 %

Procedure:
To a suspension of 2-bromo-4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzonitrile (8.0 g, 23.5 mmol) in EtOH (150 mL) was added hydrazine hydrate (85%, 2.76 g). The mixture was refluxed for 3 h. At room temperature 2 N HCl (60 mL) was added (pH=3), and the mixture was filtered and rinsed with water (50 mL×4). The filtrate was concentrated to about 150 mL and filtered again. After addition of NaHCO3 to pH=9, the filtrate was extracted with CH2Cl2 (100 mL×3). The combined extract was washed with brine, dried over anhydrous sodium sulfate. After removing the solvent, 1N HCl in MeOH (50 mL) was added and the solvent was concentrated to afford crude material as a white solid. Recrystallization from MeOH-Et2O yielded 4.3 g of the product, 4-(aminomethyl)-2-bromobenzonitrile (yield: 75.8%). 1H NMR (400 MHz, D2O): δ 4.21 (S, 2 H), 7.43 (dd, J=8.0 Hz, J=1.2 Hz, 1 H), 7.71 (d, J=8.0 Hz, 2 H); 13C NMR (100 MHz, D2O): δ 42.3, 115.5, 118.0, 125.6, 128.4, 133.4, 135.5, 139.9; HPLC: retention time: 4.709 min; purity: 99.7%.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:8]([CH:10]=1)[NH2:9].[CH3:22][S:23](Cl)(=[O:25])=[O:24].N1C=CC=CC=1.Cl.C(=O)([O-])O.[Na+]>ClCCl>[CH3:22][S:23]([NH:9][C:8]1[CH:10]=[C:4]([CH:5]=[CH:6][C:7]=1[O:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH:3]=[O:2])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: COC(OC)c1ccc(OCCN2CCOCC2)c(N)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(C=O)ccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 93.7 %

Procedure:
A solution of 5-dimethoxymethyl-2-(2-morpholinoethoxy)aniline obtained in Step 3 (0.27 g, 0.91 mmol) in dichloromethane (2.00 mL) was added with methanesulfonyl chloride (0.11 mL, 1.42 mmol) and pyridine (0.50 mL, 6.18 mmol), followed by stirring at room temperature for 10 hours. The reaction mixture was added with hydrochloric acid (3 mol/L, 3.00 mL), was stirred at room temperature for 20 minutes, was neutralized with a saturated aqueous sodium hydrogencarbonate solution (50 ml) and was extracted with ethyl acetate (50 mL×3). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. the crude product was purified by silica gel column chromatography (chloroform, then methanol/chloroform=1/6) to obtain 3-methanesulfonylamino-4-(2-morpholinoethoxy)benzaldehyde (0.28 g, 95%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:9][C:10]([N:12]1[CH2:17][CH:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:14]2[N:28]=[CH:29][C:30]([C:31]#[N:32])=[C:13]12)=[O:11].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][C:10]([N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=3)[N:14]3[N:28]=[CH:29][C:30]([C:31]#[N:32])=[C:13]23)=[O:11])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: N#Cc1cnn2c1N(C(=O)CCl)CC=C2c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN1CCN(CC(=O)N2CC=C(c3cccc(C(F)(F)F)c3)n3ncc(C#N)c32)CC1
Reaction time: 8 h
Yield: 34.9 %

Procedure:
A mixture of 1.3 g of N-methylpiperazine, 4.4 g of 4-(chloroacetyl)-4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile and 1.5 g of sodium carbonate in 75 ml of toluene was refluxed for 4 hours, then allowed to stand at room temperature overnight. The mixture was treated with 30 ml of 1N sodium hydroxide and the phases were separated. The aqueous phase was extracted twice with chloroform. The organic phases were combined, washed with water, dried, filtered and concentrated. The residue was heated to solution in 50 ml of ethyl acetate, filtered and cooled. The crystalline solid was collected, washed with ethyl acetate and hexane and dried, giving 1.8 g of the desired product, mp 178°-180° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]#[N:29])[CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]#[N:29])[CH2:24][CH2:23]3)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: N#CC1CCNCC1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)[C@H](C(=O)N1CCC(C#N)CC1)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Yield: 25.8 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (10 mg, 0.032 mmol). THF (0.5 mL), piperidine-4-carbonitrile (3.58 mg, 0.032 mmol) and HATU (14.83 mg, 0.039 mmol) were added and the solution was stirred at 25° C. for 1 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (3.3 mg, 25.4%). 1H NMR (400 MHz, CD3OD) δ 0.84-0.93 (m, 3 H) 0.96-1.08 (m, 3 H) 1.42-1.60 (m, 1 H) 1.72-1.82 (m, 2 H) 1.82-2.00 (m, 1 H) 2.49-2.66 (m, 1 H) 2.92-3.07 (m, 1 H) 3.49-3.73 (m, 2 H) 3.78-4.00 (m, 1 H) 4.00-4.11 (m, 1 H) 4.90 (d, J=7.58 Hz, 1 H) 4.92-5.01 (m, 1 H) 5.53 (dd, J=10.86, 3.54 Hz, 1 H) 7.82-7.92 (m, 1 H) 8.15-8.30 (m, 1 H). [M+H] calc'd for C20H22ClN5O2, 400; found, 400.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC(O)=O.[CH3:37][C:38]([CH3:40])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:38]([CH3:40])[CH3:37])[CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CCNCC4)cc(Nc4cccc(Cl)c4)nc23)N1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)N1CCC(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=C4NC(=O)NC4=O)cnn23)CC1
Temperature: 60 °C

Procedure:
To 5-((5-(3-chlorophenylamino)-7-(piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (20 mg, 0.04 mmol) in THF and AcOH (4.8 mg, 0.08 mmol) was added acetone (2.0 mL, 0.2 mmol) and sodium triacetoxy borohydride (85.0 mg, 0.4 mmol). The mixture was heated at 60° C. for one hour. Saturated sodium bicarbonate solution was added to the reaction mixture. The mixture was extracted with ethyl acetate and dried over sodium sulfate. Then the mixture was, diluted with MeOH, and purified by prep HPLC to yield 5-((5-(3-chlorophenylamino)-7-(1-isopropylpiperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=495)
Reaction SMILES: CC[N:3]=C=NCCCN(C)C.[Cl:12][C:13]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:14]=1[CH2:15][O:16][C:17]1[CH:32]=[CH:31][C:20]2[C:21]([O:27][CH2:28][O:29][CH3:30])=[C:22]([C:24](O)=[O:25])[S:23][C:19]=2[CH:18]=1.CN(C=O)C>O>[Cl:12][C:13]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:14]=1[CH2:15][O:16][C:17]1[CH:32]=[CH:31][C:20]2[C:21]([O:27][CH2:28][O:29][CH3:30])=[C:22]([C:24]([NH2:3])=[O:25])[S:23][C:19]=2[CH:18]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COCOc1c(C(=O)O)sc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1c(C(N)=O)sc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 73 %

Procedure:
A mixture of HOBt ammonia complex (387 mg), EDCI (487 mg), 6-((2,4-dichlorobenzyl)oxy)-3-(methoxymethoxy)-1-benzothiophene-2-carboxylic acid (700 mg) and DMF (5 mL) was stirred at room temperature for 15 h. Water was added to the mixture and the mixture was extracted with THF-AcOEt. The organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was washed with IPE and hexane to give the title compound (510 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:22])[C:5]([C:8]2[CH2:13][CH2:12][CH:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:10][CH:9]=2)=[N:6][CH:7]=1.BrC1C=C(C)C(C2CCC(N3CCOCC3)CC=2)=[N:28]C=1>>[Si:15]([O:14][CH:11]1[CH2:12][CH2:13][C:8]([C:5]2[N:6]=[CH:7][C:2]([NH2:28])=[CH:3][C:4]=2[CH3:22])=[CH:9][CH2:10]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: Cc1cc(Br)cnc1C1=CCC(N2CCOCC2)CC1
Reactant: Cc1cc(Br)cnc1C1=CCC(O[Si](C)(C)C(C)(C)C)CC1
Product: Cc1cc(N)cnc1C1=CCC(O[Si](C)(C)C(C)(C)C)CC1

Procedure:
5-Bromo-2-(4-{[tert-butyl(dimethyl) silyl]oxy}cyclohex-1-en-1-yl)-3-methylpyridine (8.4 g) was used inn place of 4-[4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]morpholine in Reference Example 108, and reacted and treated in a similar manner to give the titled compound (5.76 g) as a brown solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](Cl)(=[O:18])[CH3:17].O>N1C=CC=CC=1>[C:16]([O:15][CH:10]([CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]([F:13])([F:14])[F:12])(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: OC(CCCc1ccccc1)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC(CCCc1ccccc1)C(F)(F)F
Reaction time: 2 h
Yield: 98.1 %

Procedure:
18.5 g (85 mmol) of the above product (15-1) was dissolved in 100 ml of pyridine, then added with 7.1 g (90 mmol) of acetyl chloride at 0°-5° C. and stirred at the same temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The resulting organic layer was washed with 10% hydrochloric acid, water, a 5% sodium bicarbonate solution and brine successively in that order, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 21.7 g of 2-acetoxy-5-phenyl-1,1,1-trifluoropentane (16-1) as a pale yellow liquid. Yield: 98%.
Reaction SMILES: [H][H].[OH:3][C:4]1[CH:23]=[C:22]([O:24][CH2:25][O:26][CH3:27])[CH:21]=[C:20]([O:28][CH2:29][O:30][CH3:31])[C:5]=1[C:6](=[O:19])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:11][CH:10]=1>C(OCC)(=O)C.[Pd]>[OH:3][C:4]1[CH:23]=[C:22]([O:24][CH2:25][O:26][CH3:27])[CH:21]=[C:20]([O:28][CH2:29][O:30][CH3:31])[C:5]=1[C:6](=[O:19])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: COCOc1ccc(C=CC(=O)c2c(O)cc(OCOC)cc2OCOC)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCOc1ccc(CCC(=O)c2c(O)cc(OCOC)cc2OCOC)cc1
Yield: 91.8 %

Procedure:
Then, a suspension of 4.10 g of 5% palladium/carbon in 50 ml of ethyl acetate was saturated with hydrogen, and 60 ml of an ethyl acetate solution of 6.61 g of 2'-hydroxy-4,4',6'-tris(methoxymethoxy)chalcone was added to the suspension and hydrogenation was carried out. After the reaction, the reaction liquid was filtered and concentrated under a reduced pressure to obtain 6.10 g (yield=91.8%) of 1-[2-hydroxy-4,6-bis(methoxymethoxy)phenyl]-3-(4-methoxymethoxyphenyl)-1-propanone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH2:23][CH2:24][C:25](=O)[CH3:26])[CH:20]=[CH:21][CH:22]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:25]([CH3:26])[CH2:24][CH2:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:28])[F:29])[CH:18]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(=O)CCc1cccc(C(F)(F)F)c1
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(3-trifluoromethyl-phenyl)-butan-2-one.
Reaction SMILES: C([Li])CCC.[CH2:6]([N:8]1[C:12]([CH3:13])=[N:11][N:10]=[N:9]1)[CH3:7].Cl[CH2:15][C:16]([CH3:18])=[CH2:17].O>C1COCC1>[CH2:6]([N:8]1[C:12]([CH2:13][CH2:17][C:16]([CH3:18])=[CH2:15])=[N:11][N:10]=[N:9]1)[CH3:7]
Reactant: CCn1nnnc1C
Reactant: C=C(C)CCl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)CCc1nnnn1CC
Temperature: -70 °C
Yield: 80.2 %

Procedure:
n-Butyl lithium (1.53 M) hexane solution (6.5 ml, 9.98 mmol) was added dropwise to a solution of 1-ethyl-5-methyl-1H-tetrazole (0.80 g, 7.13 mmol) in THF (15 ml) while stirring at −70° C., and the mixture was further stirred for 1.5 hours. A solution of 3-chloro-2-methyl-1-propene (0.77 ml, 7.84 mmol) in THF (5 ml) was added to the mixture, and the resulting mixture was stirred for 2 hours. Water was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate, and the extract was dried over magnesium sulfate, and then concentrated under reduced pressure to afford 1-ethyl-5-(3-methyl-3-butenyl)-1H-tetrazole (0.95 g, yield 80%) as a brown oil.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([OH:12])=[O:11].S(Cl)(Cl)=O.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([N+:26]([O-:28])=[O:27])=[C:22]([CH:25]=1)[CH2:23]O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:1]1[CH:6]=[C:5]([C:7]([O:9][CH2:23][C:22]2[CH:25]=[C:18]([CH3:17])[CH:19]=[CH:20][C:21]=2[N+:26]([O-:28])=[O:27])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([O:12][CH2:23][C:22]1[CH:25]=[C:18]([CH3:17])[CH:19]=[CH:20][C:21]=1[N+:26]([O-:28])=[O:27])=[O:11]
Reactant: O=C(O)c1ccc(C(=O)O)nc1
Reactant: Cc1ccc([N+](=O)[O-])c(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])c(COC(=O)c2ccc(C(=O)OCc3cc(C)ccc3[N+](=O)[O-])nc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Analogously to Example 1, 5 g of pyridine-2,5-dicarboxylic acid are converted into the acid chloride with 40 ml of thionyl chloride in 30 ml of methylene chloride and this is reacted with 10 g of 5-methyl-2-nitro-benzyl alcohol in 50 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature, sodium bicarbonate solution is then added, the mixture is extracted with methylene chloride and the organic phase is dried, After the solvent has been stripped off, the residue is stirred with ethyl acetate, filtered off with suction and recrystallized twice from methylene chloride.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:6]=[CH:5][N:4]=1)#[N:2].Cl>C(OCC)C.C(Cl)(Cl)Cl>[NH:2]=[C:1]1[C:3]2[C:12]3[C:7]([CH:6]=[CH:5][N:4]=2)=[CH:8][CH:9]=[CH:10][C:11]=3[N:13]2[C:17]1=[CH:16][CH:15]=[CH:14]2
Reactant: N#Cc1nccc2cccc(-n3cccc3)c12
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: N=c1c2nccc3cccc(c32)n2cccc12
Yield: 80.1 %

Procedure:
A solution of 1-cyano-8-(pyrrol-1-yl)isoquinoline (279 g.) in diethyl ether (7 liters) and pure chloroform (7 liters) saturated with anhydrous hydrogen chloride is kept at a temperature of between 0° and 5° C. for 72 hours. After extraction with ice-water (15 liters) followed by alkalinisation of the blood red acid solution thus obtained, 7-imino-7H-indolizino[5,6,7-ij]isoquinoline (223.4 g.) is obtained in the form of green-yellow needles melting at 201° C. with decomposition.