Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.[C:22]([CH2:24][S:25][CH2:26][C:27]([O-])=[O:28])#[N:23]>>[C:22]([CH2:24][S:25][CH2:26][C:27]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:13][N:14]=[N:15][N:16]=3)[CH3:10])[CH2:7][S:8][C@H:3]12)=[O:28])#[N:23]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: N#CCSCC(=O)[O-]
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CSCC#N)[C@H]2SC1

Procedure:
The title compound was prepared by the reaction of 7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (3.28 g, 10 mmol) and N-hydroxysuccininimidyl cyanomethylmercaptoacetate (3.4 g, 15 mmol) by the procedure of Example 1.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([NH:22][CH:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)=[N:19][N:18]=4)=[C:13]([NH:36][CH:37]([CH3:39])[CH3:38])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Cl>C(Cl)Cl.CCOCC>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:12]=[C:13]([NH:36][CH:37]([CH3:39])[CH3:38])[C:14]([C:17]4[O:21][C:20]([NH:22][CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)=[N:19][N:18]=4)=[CH:15][N:16]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(NC2CCN(C(=O)OC(C)(C)C)CC2)o1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(NC2CCNCC2)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of tert-butyl 4-((5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)piperidine-1-carboxylate (Example 111) (250 mg, 0.3 mmol) in DCM (10 mL), Ether.HCl (10 mL) was added at −10° C. Stirred the reaction mixture at 0° C. for 30 min. Reaction temperature was slowly brought to room temperature. The reaction mass was concentrated under reduced pressure to dryness. The material obtained was purified by prep. HPLC to afford the title compound, N2-(benzo[d]thiazol-6-yl)-N4-isopropyl-5-(5-(piperidin-4-ylamino)-1,3,4-oxadiazol-2-yl)pyridine-2,4-diamine 1H NMR: 400 MHz, CD3OD: δ 1.37 (d, J=6.40 Hz, 6H), 1.90-2.00 (m, 2H), 2.33-2.37 (m, 2H), 3.20-3.29 (m, 2H), 3.50-3.53 (m, 2H), 3.87-3.93 (m, 2H), 6.28 (s, 1H), 7.63 (dd, J=1.20, 8.40 Hz, 1H), 8.21-8.27 (m, 3H), 9.54 (bs, 1H). LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.277 min; LCMS (ES-API), m/z 451.2 (M−H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 30 min (36 min run time); Flow rate: 1.0 μL/min; Retention time: 8.965 min; Purity: 98.1%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([S:11][C:12](=[O:16])[N:13]([CH3:15])[CH3:14])=[C:4]([CH2:17]O)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:38]([O:40][C:41](=[O:57])[CH2:42][C@@H:43]([N:47]1[C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=2[NH:49][C:48]1=[O:56])[CH2:44][CH2:45][CH3:46])[CH3:39].N#N.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:38]([O:40][C:41](=[O:57])[CH2:42][C@@H:43]([N:47]1[C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=2[N:49]([CH2:17][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]=2[S:11][C:12](=[O:16])[N:13]([CH3:14])[CH3:15])[C:48]1=[O:56])[CH2:44][CH2:45][CH3:46])[CH3:39]
Reactant: CCC[C@@H](CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Reactant: CN(C)C(=O)Sc1c(CO)cc(Br)cc1[N+](=O)[O-]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC[C@@H](CC(=O)OCC)n1c(=O)n(Cc2cc(Br)cc([N+](=O)[O-])c2SC(=O)N(C)C)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
Dimethyl-thiocarbamic acid S-(4-bromo-2-hydroxymethyl-6-nitro-phenyl) ester (250 mg, 0.74 mmol), triphenylphosphine (215 mg, 0.82 mmol) and (S)-3-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-hexanoic acid ethyl ester (303 mg, 0.82 mmol,) are added to a flask with a N2 line. Dry THF (6 mL) is added and the reaction is cooled to 0° C. DIAD (1 ml of THF, 0.82 mmol) is added dropwise over the course of 5 minutes to the reaction and the reaction is warmed slowly to room temperature. The reaction is stirred for 1 hour then evaporated in vacuo and directly purified on silica gel with dichloromethane methanol as the eluent. Reaction is re-purified via-preparative LC/MS to give 166 mg (37%) of the desired compound. LCMS (ESMS): m/z 594.4 (M+H+).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=1>C(O)(=O)C.CCOC(C)=O>[O:11]=[C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:6])[N:12]1[C:13]1[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:17][CH:18]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cccc(CC(=O)O)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)Cc1cccc(N2C(=O)c3ccccc3C2=O)c1

Procedure:
A solution of phthalic anhydride (1.2 g, 8.3 mmol) and (3-aminophenyl)acetic acid (1.0 g, 6.9 mmol) in acetic acid (25 mL) was heated to reflux for 16 hours. The reaction was cooled, and diluted with 25 mL of EtOAc. A lot of solids crashed out from the solution. The solids were collected by filtration, and identified as the desired [3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]acetic acid. LC-MS (IE, m/z): 282 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:19][CH3:20])=[CH:5][C:6]2[O:12][CH2:11][CH2:10][CH:9]([C:13]([O:15]C)=[O:14])[C:8](=O)[C:7]=2[CH:18]=1.[BH4-].[Na+].Cl>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[C:4]([O:19][CH3:20])=[CH:5][C:6]2[O:12][CH2:11][CH2:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][C:7]=2[CH:18]=1
Reactant: COC(=O)C1CCOc2cc(OC)c(OC)cc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(cc1OC)OCCC(C(=O)O)=C2

Procedure:
In a mixture of methylene chloride (60 ml) and methanol (80 ml) is dissolved methyl 7,8-dimethoxy-5-oxo-2,3,4,5-terahydro-1-benzoxepin-4-carboxylate obtained in Reference Example 11 (1.9 g). To the solution is added, while stirring, sodium borohydride (0.6 g) in limited amounts taking one hour. The reaction mixture is treated with dilute hydrochloric acid, followed by extraction with methylene chloride. The organic layer is washed with a small volume of a saturated aqueous saline solution, dried, and concentrated under reduced pressure. The residue is dissolved in methanol (5 ml), and to the solution is added a 2N aqueous solution of sodium hydroxide (20 ml). The mixture is stirred at room temperature for two hours. After addition of water (50 ml), the reaction mixture is washed with ether. The aqueous layer is acidified with dilute hydrochloric acid, and extracted with methylene chloride. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is dissolved in dioxane (10 ml), to the solution is added concentrated hydrochloric acid (3 ml), and then the mixture is stirred for one hour at 90° C. After cooling, the reaction mixture is extracted with ethyl acetate. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate to afford 7,8-dimethoxy-2,3-dihydro-1-benzoxepin-4carboxylic acid as colorless needles (1.2 g), m. p. 209°-210° C.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([CH:9]=[N:10]O)[C:6]([C:12]2[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[N:5]1)([CH3:3])[CH3:2].S(Cl)(Cl)=O>ClCCCl>[CH:1]([N:4]1[CH:8]=[C:7]([C:9]#[N:10])[C:6]([C:12]2[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cc(C=NO)c(-c2ccc([N+](=O)[O-])o2)n1
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: CC(C)n1cc(C#N)c(-c2ccc([N+](=O)[O-])o2)n1
Yield: 99 %

Procedure:
Stir an admixture of 3.4 g of finely pulverized 1-isopropyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehydeoxime in 15 ml of 1,2-dichloroethane with 1.8 g of thionyl chloride for 80 minutes at 55° C. Evaporate the resulting solution to dryness in vacuo and then evaporate to dryness twice more after mixing with 1,2-dichloroethane to obtain a 99% yield of 1-isopropyl-3-(5-nitro-2-furyl)pyrazole-4-carbonitrile [m.p. 181° to 182° C (from ethanol)].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=O)[CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.C(OC([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[CH2:39][NH2:40])=O)(C)(C)C.C(Cl)CCl>CN(C=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([NH:40][CH2:39][CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38][NH:33]3)=[O:22])[CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: O=C(O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCC1CCCCN1)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 9 (1 mmol) was coupled with 2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (3 mmol) using EDC (2 mmol) in DMF (10 mL). The DMF was removed by rotary evaporation and the residue purified by flash chromatography on silica gel (ethyl acetate as eluent.) The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 432. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.5-8.65 (m, 2H) 8.38 (m, 1H) 8.22 (m, 1H) 7.95 (m, 1H) 7.55 (m, 1H) 7.28 (m, 1H) 7.20 (d, 1H) 7.05 (d, 2H) 6.68 (d, 2H) 3.5 (m, 2H) 3.3 (m, 2H) 2.95 (m, 1H) 2.6-2.85 (m, 3H) 2.48 (m, 1H) 1.0-1.7 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH:6][CH:5]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:48]([CH3:50])([CH3:49])[CH:47]2[OH:51])=[O:20]
Reactant: COC(=O)c1ccc(N=Cc2cccc(OC)c2)cc1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cccc(OC)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a stirred mixture solution of 4-[(3-methoxy-benzylidene)-amino]-benzoic acid methyl ester (2.7 g, 10.0 mmol) and ytterbium(III) triflate hydrate (620.3 mg, 1.0 mmol) in dry tetrahydrofuran (10 mL) at 25° C. was added isobutyraldehyde (0.93 mL, 10.2 mmol) and water (0.2 mL, 10.2 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-hydroxy-2-(3-methoxy-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (3.4 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C20H23NO4 (M+H)+: 342.41, observed: 324.2 & 342.2.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH:17]([NH:19][C:20]2[N:25]=[C:24]([N:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=[CH:27]3)[CH:23]=[CH:22][N:21]=2)[CH3:18])[CH2:12]1)=O)C1C=CC=CC=1.Br>C(Cl)Cl.C(O)(=O)C>[NH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH:17]([NH:19][C:20]2[N:25]=[C:24]([N:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=[CH:27]3)[CH:23]=[CH:22][N:21]=2)[CH3:18])[CH2:12]1
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCN(C(=O)OCc2ccccc2)C1
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.5 %

Procedure:
The 2-[1-(1-benzyloxycarbonylpiperidin-3-yl)-ethylamino]-4-[benzimidazol-1-yl]pyrimidine (900 mg, 1.97 mmol) was dissolved in CH2Cl2 (25 mL), and the mixture was cooled down to 0° C. To this was added 30% HBr in acetic acid (5 mL) slowly and continued stirring at 0° C. for 15 min The bath was removed, and the reaction mixture was stirred at room temperature for 45 min and then was diluted with H2O (25 mL). The reaction mixture was extracted with CH2Cl2 (2×20 mL; discarded), then the aqueous layer was made neutral with 5N NaOH and extracted with EtOAc (3×25 mL; discarded). The aqueous layer was made strongly basic (>pH 12) with SN NaOH, and was extracted with EtOAc (4×30 mL). The combined extracts were washed with brine and dried over Na2SO4. After removal of solvent under reduced pressure, 543 mg of the title compound was obtained which was used without purification. Partial 1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H); 8.36 (br s, 1H); 8.16 (d, J=8 Hz, 1H); 7.85 (d, J=8.5 Hz, 1H); 7.38 (m, 2H); 6.75 (d, J=5.4 Hz, 1H); 5.14 (s, 2H); 4.1 (m, 1H); 3.18 (d, J=12 Hz, 1H); 3.02 (d, J=12 Hz, 1H); 1.23 (d, J=6.6 Hz, 3H).
Reaction SMILES: [BH4-].[Na+].OC(C(F)(F)F)=O.[C:10]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:11]([C:16]([N:18]2[CH2:23][C:22](=[O:24])[CH2:21][CH2:20][CH:19]2[CH2:25][NH:26][C:27]([C:29]2[CH:30]=[CH:31][CH:32]=[C:33]3[C:38]=2[N:37]=[CH:36][CH:35]=[CH:34]3)=[O:28])=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=1>CO>[C:10]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:11]([C:16]([N:18]2[CH2:23][CH:22]([OH:24])[CH2:21][CH2:20][CH:19]2[CH2:25][NH:26][C:27]([C:29]2[CH:30]=[CH:31][CH:32]=[C:33]3[C:38]=2[N:37]=[CH:36][CH:35]=[CH:34]3)=[O:28])=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(CNC(=O)c2cccc3cccnc23)N(C(=O)c2ccccc2-c2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(NCC1CCC(O)CN1C(=O)c1ccccc1-c1ccccc1)c1cccc2cccnc12
Temperature: 25 °C

Procedure:
NaBH4 (3.49 mmol, 0.13 g) was added to a solution of N-((1-(biphenylcarbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide TFA salt (0.46 mmol, 0.26 g) in MeOH (10 mL) at 0° C. in three portions. The resulting mixture was stirred at rt and the reaction was tracked by analytical HPLC. The reaction was quenched with water and extracted with EtOAc. The organic layer was separated, dried with MgSO4, and concentrated in vacuo to give crude residue which was purified by preparative HPLC to give desired N-((1-(biphenylcarbonyl)-5-hydroxypiperidin-2-yl)methyl)quinoline-8-carboxamide with unidentified stereochemistry (Y: 75%). MS (ESI) 466 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:22])=[C:4]([CH:9]=[C:10](B2OC(C)(C)C(C)(C)O2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].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.O>[N:31]1([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][C:10]3[C:11]([CH3:12])=[C:2]([F:1])[C:3]([OH:22])=[C:4]([CH:9]=3)[C:5]([O:7][CH3:8])=[O:6])=[CH:26][CH:27]=2)[CH:35]=[CH:34][CH:33]=[N:32]1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(F)c1O
Reactant: ClCc1ccc(-n2cccn2)cc1
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: COCCOC
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)c(F)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (2.52 g) was added to a mixture of methyl 3-fluoro-2-hydroxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (13.5 g), 1-(4-(chloromethyl)phenyl)-1H-pyrazole (8.39 g), sodium carbonate (9.23 g), DME (195 mL) and water (65.0 mL) under argon atmosphere, and the mixture was stirred overnight at 80° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with a mixed solvent of diisopropyl ether-ethyl acetate to give a crude product. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol). The obtained crude products are combined, and washed with diisopropyl ether-ethyl acetate to give the title compound (12.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[H-].[Na+].[Cl:13][CH:14]1[N:19](Cl)[CH:18]=[CH:17][CH:16]=[N:15]1>CN(C=O)C>[Cl:13][C:14]1[N:19]=[C:18]([NH:1][C:2]2[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=2)[CH:17]=[CH:16][N:15]=1
Reactant: ClC1N=CC=CN1Cl
Reactant: CC(C)(C)c1cc(N)no1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Nc2ccnc(Cl)n2)no1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 3-amino-5-t-butylisoxazole (922 mg 6.58 mmol) in 15 mL of DMF at 0° C. was added 268 mg (6.71 mmol) of NaH (60% dispersion in mineral oil) in 4 portions over 1 min. The resulting mixture was stirred at 0° C. for 30 min when 1.0 g (6.71 mmol) of 2,3-dichloropyrimidine was added in 1 portion. The resulting mixture was warmed to RT (ice melt in dewar) and was stirred at RT for 22 h. The reaction mixture was quenched with saturated aqueous NH4Cl and diluted with H2O and EtOAc. The organic layer was washed 1× with brine. The combined aqueous layer and brine wash were extracted 1× with EtOAc. The combined organics were dried over Na2SO4, concentrated and purified by flash chromatography (elution with 2/1 hexanes/EtOAc) to give (2-chloro-pyrimidin-4-yl)-(5-tert-butyl-isoxazol-3-yl)-amine as a yellowish white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.Br[C:16]1[CH:17]=[CH:18][C:19]([F:24])=[C:20]([CH:23]=1)[C:21]#[N:22]>>[F:24][C:19]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[CH:4][C:5]3[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=3[CH:14]=2)=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: CC1Nc2ccc(Br)cc2C(C)(C)O1
Reactant: N#Cc1cc(Br)ccc1F
Product: CC1Nc2ccc(-c3ccc(F)c(C#N)c3)cc2C(C)(C)O1

Procedure:
Prepared according to the coupling procedure for Example 13 from 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine and 5-bromo-2-fluorobenzonitrile. A white solid: mp 184-186° C.; 1H-NMR (DMSO-d6) δ 8.17 (dd, 1H, J=5.86, 3.42 Hz), 8.00-7.98 (m, 1H), 7.52 (t, 1H, J=9.28 Hz), 7.45 (d, 1H, J=1.95 Hz), 7.34 (dd, 1H, J=8.30, 1.95 Hz), 6.63 (d, 1H, J=8.3 Hz), 6.45 (d, 1H), 4.8 (q, 1H, J=5.37 Hz), 1.53 (s, 3H), 1.49 (s, 3H), 1.29 (d, 3H, J=5.37 Hz); MS (ES) m/z 297 ([M+H]+).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:15][Si:16]([CH3:25])([CH3:24])[C:17]1[O:18][CH:19]=[CH:20][C:21]=1[CH:22]=[O:23]>O1CCCC1>[OH:23][CH:22]([C:21]1[CH:20]=[CH:19][O:18][C:17]=1[Si:16]([CH3:25])([CH3:24])[CH3:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCCCCCC[Mg]Br
Reactant: C[Si](C)(C)c1occc1C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(O)c1ccoc1[Si](C)(C)C

Procedure:
A solution of dodecylmagnesium bromide (a 1M solution in tetrahydrofuran; 14.3 ml; 14.3 mmol) was added to a solution of 2-trimethylsilyl-3-furaldehyde (1.20 g, 7.1 mmol) in tetrahydrofuran (30 ml) at 0°. After all the aldehyde has reacted, as shown by tlc, the mixture was quenched with dilute hydrochloric acid and was extracted with ethyl ether. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by a silica column using 5% ethyl ether/hexane to give the title furan.
Reaction SMILES: Cl.[NH2:2][NH:3][C:4](=[NH:7])[NH:5][NH2:6].C(N[C:12](=[O:19])[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=O)(=O)C>O>[NH2:7][C:4]1[N:5]([NH2:6])[C:12](=[O:19])[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[N:2][N:3]=1
Reactant: CC(=O)NC(=O)C(=O)C(C)(C)C
Reactant: N=C(NN)NN
Agent: Cl
Solvent: O
Product: CC(C)(C)c1nnc(N)n(N)c1=O

Procedure:
3.8 g (0.03 mole) of diaminoguanidine hydrochloride are dissolved in 35 ml of water. To this solution are added 5.1 g (0.03 mole) of N-acetyl-3,3,3-trimethylpyruvamide and the reaction mixture is heated for 15 minutes to 90° C. The reaction mixture is filtered and the filtrate is neutralised by addition of crystalline sodium bicarbonate. At pH 7, 3.6 g (66.7% of theory) of 3,4-diamino-6-(1,1-dimethylethyl)-4H-1,2,4-triazin-5-one precipitate in the form of a yellowish crystalline solid with a melting point of 223°-224° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:12][O:13][C:14](=[O:39])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:23](=[O:32])[C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:16]=1>>[CH3:12][O:13][C:14](=[O:39])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)/[C:24](=[C:25](\[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]([CH3:11])(=[O:10])=[O:9])/[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)/[C:23]2=[O:32])[CH:16]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Reactant: CS(=O)(=O)c1ccccc1I
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccccc3S(C)(=O)=O)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-iodo-2-methanesulfonyl-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 1.89 (s, 1.5H), 2.50 (s, 1.5H), 3.90 (s, 3H), 4.98 (dd, 2H), 5.98 (dd, 1H), 6.65-6.68 (m, 2H), 7.07 (m, 1H), 7.35-7.58 (m, 8H), 7.61 (t, 1H), 7.78 (t, 1H), 7.99 (d, 1H), 8.02 (d, 1H), 8.20 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[N:23]=1.O>CN(C)C=O>[Cl:34][C:30]1[CH:29]=[C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][O:17][C:4]3[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[N:13]4)=[C:2]([CH3:1])[CH:3]=3)[N:23]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: ClCc1cccc(-c2cccc(Cl)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2cccc(-c3cccc(Cl)c3)n2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of 97 mg (0.42 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 17 mg (0.42 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 100 mg (0.42 mmol) 2-Chloromethyl-6-(3-chloro-phenyl)-pyridine were added and stirred continued at r. t. over night. After addition of 8 ml water, the mixture was extracted with ethyl acetate tree times. The combined organic phases were dried (sodium sulphate) and evaporated. Chromatography on silica (eluent: ethyl acetate/n-heptane 2:1) gave 0.151 g (83%) the title compound as white powder.