Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([OH:18])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(Cl)=O)C(C)C.[C:27]([O:31][C:32]([C:34]1[N:39]2[C:40](=[O:43])[C@@H:41]([NH2:42])[C@H:38]2[S:37][CH2:36][C:35]=1[CH2:44][O:45][C:46](=[O:48])[CH3:47])=[O:33])([CH3:30])([CH3:29])[CH3:28].P([O-])([O-])(O)=O.[K+].[K+]>C(Cl)Cl.CN1CCOCC1>[C:27]([O:31][C:32]([C:34]1[N:39]2[C:40](=[O:43])[C@@H:41]([NH:42][C:16](=[O:18])[CH2:15][C:13]3[S:14][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:11][CH:12]=3)[C@H:38]2[S:37][CH2:36][C:35]=1[CH2:44][O:45][C:46](=[O:48])[CH3:47])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CC(=O)O)s1
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(C)COC(=O)Cl
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)Cc3ccc(CNC(=O)OC(C)(C)C)s3)[C@H]2SC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
The starting material can be prepared as follows: 8.15 g of 2-(5-tert.-butoxycarbonylaminomethyl-2-thienyl)-acetic acid are dissolved in 500 ml of methylene chloride containing 3.06 ml of N-methylmorpholine, the solution, from which moisture is kept excluded, is cooled to -20° C. and 4.13 ml of chloroformic acid isobutyl ester are added dropwise whilst keeping the temperature at between -15° C. and -20° C. After 30 minutes, a solution of 9.85 g of 3-acetoxymethyl-7β-amino-3-cephem-4-carboxylic acid tert.-butyl ester in 50 ml of methylene chloride is added, after which the solution is stirred for a further 15 hours whilst slowly raising the temperature to 20° C. to 25° C. The mixture is poured out into ice-cold water, neutralised with dipotassium hydrogen phosphate and extracted repeatedly with methylene chloride. The organic extracts are washed with an aqueous saturated sodium chloride solution and dried over magnesium sulphate, after which the solvent is removed under reduced pressure. The residue is recrystallised from diethyl ether and gives 3-acetoxymethyl-7β-[2-(5-tert.-butoxycarbonylaminomethyl-2-thienyl)-acetylamino]-3-cephem-4-carboxylic acid tert.-butyl ester, melting point 76°-78° C., thin layer chromatogram (silica gel): Rf=0.44 (system: chloroform/ethyl acetate/acetic acid, 80:19:1).
Reaction SMILES: [C:1]([C:5]1[NH:6][NH:7][C:8](=[O:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:18][N:19]=[C:20]=[O:21]>O1CCCC1>[C:1]([C:5]1[N:9]=[C:8]([OH:10])[N:7]([C:20](=[O:21])[NH:19][CH3:18])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN=C=O
Reactant: CC(C)(C)c1nc(=O)[nH][nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)n1nc(C(C)(C)C)nc1O
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a mixture of 1.41 g (0.01 mole) of 3-tert-butyl-1H-1,2,4-triazole-5-one and 0.5 g of triethylamine was added 50 ml of tetrahydrofuran, to the mixture was added 2.28 g (0.04 mole) of methylisocyanate while stirring, and the reaction was carried out at 60° C. for 2 hours. By concentration of the reaction mixture under a reduced pressure a white powder was obtained, which was washed with n-hexane to give 1.6 g of white powder of 3-tert-butyl-1-N-methylcarbamoyl-5-hydroxy-1,2,4-triazole. (yield 81%)
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[CH2:25][NH:26][CH3:27])[C:5]1=[O:30])[CH:2]=[CH2:3].[CH3:32][S:33](Cl)(=[O:35])=[O:34].N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[CH2:25][N:26]([CH3:27])[S:33]([CH3:32])(=[O:35])=[O:34])[C:5]1=[O:30])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNC)C1=O
Reactant: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(C)(=O)=O)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylamino)butan-2-yl)piperidin-2-one (72 mg, 0.16 mmol; Example 134 Step A) in DMF (0.40 mL) was added methanesulfonyl chloride (61 μL, 0.79 mmol) and pyridine (76 μL, 0.95 mmol) successively at 0° C. After being stirred at 25° C. for overnight, the reaction was acidified (10% citric acid) and extracted (2×EtOAc). The combined organic layers were washed (sat. aq. NaCl solution), dried (Na2SO4), and concentrated under reduced pressure. Separation by RP-HPLC (50 to 85% MeCN/H2O (0.1% TFA) a gradient elution) provided the title compound as a pale yellow film.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[N:12]([C:13](=[O:17])[CH2:14][CH2:15][SH:16])[C@H:11]([C:18]([OH:20])=[O:19])[CH2:10][S:9]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C.[CH2:32]([N:35]([CH2:48][CH2:49][CH3:50])[S:36]([C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1)(=[O:38])=[O:37])[CH2:33][CH3:34]>O>[CH2:48]([N:35]([CH2:32][CH2:33][CH3:34])[S:36]([C:39]1[CH:47]=[CH:46][C:42]([C:43]([S:16][CH2:15][CH2:14][C:13]([N:12]2[C@H:11]([C:18]([OH:20])=[O:19])[CH2:10][S:9][C@@H:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])=[O:17])=[O:44])=[CH:41][CH:40]=1)(=[O:38])=[O:37])[CH2:49][CH3:50]
Reactant: CCCN(CCC)S(=O)(=O)c1ccc(C(=O)Cl)cc1
Reactant: O=C(O)[C@@H]1CS[C@H](c2ccccc2O)N1C(=O)CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCCN(CCC)S(=O)(=O)c1ccc(C(=O)SCCC(=O)N2[C@@H](c3ccccc3O)SC[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
9.7 g of (2R,4R)--2--(2--hydroxyphenyl) --3--(3--mercaptopropionyl)--4--thiazolidinecarboxylic acid and 12.9 g of potassium carbonate are dissolved in 80 ml of water, and 40 ml of ethyl ether solution of 9.4 g of 4--(dipropylsulfamoyl)benzoyl chloride is added dropwise under ice-cooling. After the addition the reaction mixture is stirred for 1 hour under ice-cooling and for another 1 hour at room temperature. Ether is removed in vacuo and residual solution is adjusted to pH 1 with 6N hydrochloric acid. Produced oily residue is extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue is purified by silica gel column chromatography to give 10.5 g of the titled compound as amorphous powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH:29]([CH3:31])[CH3:30])=[O:24])[C:5]1=[O:32].C(N(C(C)C)CC)(C)C.[C:42](OC(=O)C)(=[O:44])[CH3:43]>CN(C=O)C>[C:42]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH:29]([CH3:30])[CH3:31])=[O:24])[C:5]1=[O:32])(=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)OCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)NCCn1c(=O)c(C(=O)NCCOC(C)C)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-{2-[(1-methylethyl)oxy]ethyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.021 g, 0.046 mmol) and diisopropyl ethylamine (0.04 mL, 0.23 mmol) in DMF (5 mL) under nitrogen was treated with acetic anhydride (0.0046 mL, 0.048 mmol) at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was treated with 1 N NaHSO4. Extracted the mixture twice with EtOAc, combined the organics, dried over MgSO4, filtered and concentrated the filtrate. The residue was then triturated with Et2O, filtered, and dried in vacuo to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-D6) δ ppm 1.1 (d, J=6.0 Hz, 6 H), 1.7 (s, 3 H), 3.3 (q, J=6.1, 2 H), 3.5 (m, 3 H), 3.6 (m, 2 H), 4.1 (s, 2 H), 4.3 (t, J=6.5 Hz, 2 H), 7.1 (m, 2 H), 7.4 (ddd, J=12.1, 5.5, 3.2 Hz, 2 H), 8.0 (d, J=6.0 Hz, 1 H), 8.2 (d, J=1.3 Hz, 1 H), 8.5 (d, J=1.5 Hz, 1 H), 10.4 (t, J=5.1 Hz, 1 H), 17.1 (s, 1 H); ES+ MS: 485 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:22]([OH:24])=[O:23])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:4].B(F)(F)F.[CH3:29]COCC.[ClH:34]>CO.C(O)C>[ClH:34].[CH3:29][O:23][C:22](=[O:24])[C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[NH:5][C:3](=[O:4])[CH2:2][NH2:1].[ClH:34]
Reactant: CCOCC
Reactant: NCC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: FB(F)F
Solvent: CCO
Solvent: CO
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)CN
Temperature: 80 °C

Procedure:
Nα-Glycyl-Nε-carbobenzoxy-L-lysine (10.1 g.) prepared by the method of Rao et al. (J. Biol. Chem., 198,507 1952) was dissolved in methanol (150 ml.) and treated with boron trifluoride etherate (30 ml.) and the mixture heated at 80°C for 25 hours. The solvent was removed in vacuo and the residual oil dissolved in water (100 ml.) and extracted with ether (2 × 50 ml.) and the extracts discarded. The aqueous solution was adjusted to pH 9.0 with 4N sodium hydroxide, saturated with sodium chloride and extracted with ethyl acetate (3 × 50 ml.). The combined extracts were washed with saturated brine, dried (MgSO4) and the solvent removed in vacuo to give a residual oil which was redissolved in ethanol (10 ml.) and treated with an excess of an ethereal solution of hydrogen chloride. The solid was filtered and recrystallised from isopropanol/diisopropyl ether to give Nα-glycyl-Nε-carbobenzoxy-L-lysine methyl ester hydrochloride, needles (4.5 g.) m.p. 122°C. (Found: C, 53.0; H, 6.8; N, 10.8. C17H25N3O5. HCl requires: C, 52.6; H, 6.7; N, 10.8%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:42][C:43]1[N:48]=[CH:47][N:46]=[C:45]2[N:49]([C:52]3[C:57]([Cl:58])=[CH:56][CH:55]=[CH:54][N:53]=3)[N:50]=[CH:51][C:44]=12)[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][N:35]=1)=[O:32])(C(C)(C)C)(C)C>C1COCC1>[Cl:58][C:57]1[C:52]([N:49]2[C:45]3=[N:46][CH:47]=[N:48][C:43]([O:42][C@@H:30]([CH2:29][CH2:28][CH2:27][OH:26])[C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][N:35]=4)=[O:32])=[C:44]3[CH:51]=[N:50]2)=[N:53][CH:54]=[CH:55][CH:56]=1
Reactant: CC(C)(C)[Si](C)(C)OCCC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(C#N)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)[C@H](CCCO)Oc2ncnc3c2cnn3-c2ncccc2Cl)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tetrabutylammonium fluoride (1M in THF) (1.376 mL, 1.38 mmol) was added to (2S)-5-(tert-butyldimethylsilyloxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-cyanopyridin-2-yl)pentanamide (Intermediate AW2) (797 mg, 1.38 mmol) in THF (5 mL) under nitrogen. The resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl (2 mL), diluted with DCM (25 mL) and poured onto a phase separator. The organic layer was loaded onto a silica column and purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane to afford the product (166 mg, 25.9%, 100% ee). 1H NMR (400 MHz, CDCl3) δ 1.61 (1H, t), 1.81-1.92 (2H, m), 2.22-2.40 (2H, m), 3.76-3.88 (2H, m), 5.95 (1H, t), 7.45-7.50 (1H, m), 7.93-7.98 (1H, m), 7.99-8.04 (1H, m), 8.35-8.41 (1H, m), 8.44 (1H, s), 8.53-8.57 (1H, m), 8.60-8.64 (2H, m), 9.03 (1H, s); m/z (ES−) (M−H)−=463.37; HPLC tR=1.68 min.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)=[N:12][CH:11]=2)=[CH:6][CH:5]=1.CI.O.[C:34](=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([CH3:34])[CH:13](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)[NH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: COc1cc(/C=C/c2ncc(-c3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Reactant: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(/C=C/C2NC=C(c3ccc(F)cc3)N2C)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (containing mineral oil at 60%, 8 mg) was added to a solution of 5-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-1H-imidazole (50 mg) in THF (5 mL), and the reaction solution was stirred at room temperature for one hour. Methyl iodide (23 mg) was added to the reaction solution, and the reaction solution was stirred at room temperature for 12 hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane:ethyl acetate=1:1→ethyl acetate) to obtain 15 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: C(O)(=O)/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7]C)[CH:5]=1.[C:15]([O-])([O-])=O.[K+].[K+].N1C=CN=C1>CN(C)C=O>[CH:3]([C:4]1[CH:5]=[C:6]([OH:7])[C:9]([O:10][CH3:15])=[CH:11][CH:12]=1)=[CH2:2]
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=Cc1ccc(OC)c(O)c1
Yield: 59 %

Procedure:
A mixture of Ferulic acid (0.0083 mol), K2CO3 (10%, 3 ml), imidazole (1 mL) and dimethylformamide (15 ml) were taken in a 250 ml Erlenmeyer flask fitted with a loose funnel at the top. The flask was shaken well and placed inside the microwave oven over an ice bath and irradiated for 30 minutes in parts. After completion of reaction, it was worked up and purified as in example V and provided sweet and pleasant smelling viscous liquid. 59% yield; (Spectral data as in example V)
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:15][C:16]=3[Br:17])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:24][CH:25]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:26]([O:28]C)=[O:27].[OH-].[Na+]>C1COCC1.CO.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[S:15][C:16]=3[Br:17])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:24][CH:25]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:26]([OH:28])=[O:27]
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3nc(-c4ccccc4)sc3Br)ccc2c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C(Cc1ccccc1)Oc1ccc2cc(-c3nc(-c4ccccc4)sc3Br)ccc2c1Br
Yield: 51.9 %

Procedure:
A mixture of methyl 2-{[1-bromo-6-(5-bromo-2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}-3-phenylpropanoate (134 mg, 0.215 mmol), prepared in the previous step, and 1 N NaOH (323 μL, 0.323 mmol) in 10 mL of THF plus 10 mL of methanol plus 5 mL of water was refluxed under nitrogen 2 h. The reaction was filtered, acidified with 1 N HCl and then concentrated under reduced pressure to remove the THF and methanol. The solid present was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (68 mg, 52%) as a yellow solid, mp 221-223° C. Elemental Analysis for C28H19Br2NO3S Calc'd: C, 55.19; H, 3.14; N, 2.30. Found: C, 56.17; H, 3.45; N, 2.05.
Reaction SMILES: C1(S([N:10]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]2[C:19]([O:21][CH3:22])=[O:20])(=O)=O)C=CC=CC=1.[F:23][C:24]([F:47])([C:29]1[CH:33]=[CH:32][N:31]([S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:30]=1[C:43]([O:45][CH3:46])=[O:44])[C:25]([F:28])([F:27])[F:26].O(C)[Na]>O1CCCC1>[F:18][C:15]([F:16])([F:17])[C:12]1[CH:13]=[CH:14][NH:10][C:11]=1[C:19]([O:21][CH3:22])=[O:20].[F:47][C:24]([F:23])([C:29]1[CH:33]=[CH:32][N:31]([S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:30]=1[C:43]([O:45][CH3:46])=[O:44])[C:25]([F:28])([F:27])[F:26]
Reactant: COC(=O)c1c(C(F)(F)F)ccn1S(=O)(=O)c1ccccc1
Agent: COC(=O)c1c(C(F)(F)C(F)(F)F)ccn1S(=O)(=O)c1ccccc1
Agent: CO[Na]
Solvent: C1CCOC1
Product: COC(=O)c1[nH]ccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 100-mL round-bottom flask, was placed methyl 1-(benzenesulfonyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate and methyl 3-(perfluoroethyl)-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate (1.8 g, 5.40 mmol, 1.00 equiv) and tetrahydrofuran (15.0 mL). To the resulting mixture was then added NaOCH3 (1.17 g, 21.67 mmol, 4.01 equiv), in portions at 0° C. The resulting solution was stirred for 30 min at 0° C. in a water/ice bath. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of 2N hydrogen chloride until the solution became clear. The resulting solution was extracted with ethyl acetate (3×20 mL) and the organic layers combined. The resulting mixture was washed with sodium chloride (1×20 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield methyl 3-(trifluoromethyl)-1H-pyrrole-2-carboxylate and methyl 3-(perfluoroethyl)-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate as a yellow solid. The yellow soli, was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:5]=[C:4](Cl)[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:5]=[C:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])[N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: N#Cc1ccc(-c2cc(Cl)nc(N)n2)cc1F
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: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A mixture of 4-(2-amino-6-chloro-4-pyrimidinyl)-2-fluorobenzonitrile (298 mg, 1.2 mmol), [2-(methyloxy)phenyl]boronic acid (273 mg, 1.8 mmol) and Na2CO3 (318 mg in 2 mL of water) in 1,4-dioxane (8 mL), was degassed with N2. Pd(PPh3)4 (69 mg, 0.06 mmol) was added, and the reaction mixture was stirred overnight at 95° C. The reaction was poured onto water and EtOAc. The organic layer was separated, and the aqueous layer was further extracted with EtOAc (2×). The combined organic layers were dried (MgSO4), filtered and concentrated to afford the crude title compound (306 mg). LC-MS (ES) m/z=321 [M+H]+.
Reaction SMILES: C(O[CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:6]1)(=O)C.C[Si]([N:23]=[N+:24]=[N-:25])(C)C.Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.O>ClCCCl>[N:23]([CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:6]1)=[N+:24]=[N-:25]
Reactant: CC(=O)OC1C=C(c2ccccc2C)CCCC1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClCCCl
Solvent: O
Product: Cc1ccccc1C1=CC(N=[N+]=[N-])CCCC1

Procedure:
To a solution of the compound obtained in Step C (3.52 g/14.65 mmol) in 50 ml of 1,2-dichloroethane there are added dropwise trimethylsilyl azide (TMSN3), and then 0.326 g (1.46 mmol) of magnesium perchlorate (Mg(ClO4)2), and the whole is stirred at room temperature overnight. Hydrolysis is then carried out using H2O, followed by extraction with AcOEt; the organic phases are then combined, washed with a saturated NaCl solution, dried over MgSO4 and concentrated to dryness. The yellow oil so obtained is chromatographed over a column of silica gel (cyclohexane, 2% AcOEt) to yield the title product in the form of a translucent oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([NH:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCNc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCNc1ccc(N2CCNCC2)cc1

Procedure:
A solution of 1-(4-ethylaminophenyl)-4-phenylmethylpiperazine in ethanol is catalytically hydrogenated at about 70° C. and 50 p.s.i., in the presence of 10% palladium on carbon. After hydrogen uptake ceases, the catalyst is removed by filtration and the filtrate concentrated to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([O:8]C)=O.[OH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[OH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:6](=[O:8])[CH2:5][C:4](=[O:10])[CH2:3][O:2][CH3:1])[CH2:14][CH2:13]1
Reactant: COCC(=O)CC(=O)OC
Reactant: OC1CCNCC1
Product: COCC(=O)CC(=O)N1CCC(O)CC1
Yield: 32.4 %

Procedure:
0.34 mol (48.7 g) of methyl 4-methoxy-acetoacetate and 0.36 mol (36.0 g) of 4-hydroxypiperidine were stirred for 5 h at 120° C. at a Dean-Stark apparatus. 45 g of the crude product was purified over 1 kg of silica gel with ethyl acetate/ethanol 9/1. 23.7 g of the title compound were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].I[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: COc1ccc(I)cc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Product: COc1ccc(-c2ccc(Br)cc2[N+](=O)[O-])cc1

Procedure:
2,5-Dibromo-1-nitrobenzene and 4-iodoanisole were reacted under Ullmann conditions to give 4-bromo-4'-methoxy-2-nitrobiphenyl, m.p. 130°-131°C. This was reduced to give 2-amino-4-bromo-4'-methoxybiphenyl, m.p. 128°-130°C., which was subjected to the Schiemann reaction using hydrofluoroboric acid to give the product, b.p. 134°-138°C./0.15mm.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:24]=[CH:23][C:11]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][CH3:22])=[O:20])[CH:14]=3)=[CH:10][CH:9]=2)[N:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][C:27]=1[C:36]([F:39])([F:38])[F:37]>N1C=CC=CC=1>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:1][C:2]2[N:3]=[N:4][CH:5]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([O:12][C:13]4[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][CH3:22])=[O:20])[CH:14]=4)=[CH:23][CH:24]=3)[N:7]=2)(=[O:33])=[O:34])=[CH:28][C:27]=1[C:36]([F:39])([F:37])[F:38]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNC(=O)c1cc(Oc2ccc(-c3cnnc(N)n3)cc2)ccn1
Solvent: c1ccncc1
Product: CNC(=O)c1cc(Oc2ccc(-c3cnnc(NS(=O)(=O)c4ccc(Cl)c(C(F)(F)F)c4)n3)cc2)ccn1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
108.6 mg (0.337 mmol, 1.0 equivalent) of 4-[4-(3-amino-[1,2,4]triazin-5-yl)-phenoxy]-N-methylpyridine-2-carboxamide can be dissolved in 2 mL of anhydrous pyridine with heating to about 100° C. 0.405 mmol (1.2 equivalent) of 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride can be added. The reaction mixture can be allowed to stir at ambient temperature for 1-2 hours. The product can be isolated by a number of methods known to one skilled in the art, such as precipitation or by extraction with a number of solvents, such as ethyl acetate, methylene chloride or diethyl ether or by silica gel column chromatography, or by reverse-phase preparative HPLC.