Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])[CH:6]=1)[CH3:3].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:29]=[N:30][C:31]([CH3:35])=[C:32]([CH3:34])[CH:33]=2)=[CH:22][N:21]=1)([O-])=O>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:20]2[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([CH3:35])=[C:32]([CH3:34])[CH:33]=3)=[CH:22][N:21]=2)[CH:6]=1)[CH3:1]
Reactant: Cc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cnc1C
Reactant: CN(C)Cc1ccnc(CSCCN)c1
Solvent: c1ccncc1
Product: Cc1cc(Cc2cnc(NCCSCc3cc(CN(C)C)ccn3)[nH]c2=O)cnc1C
Yield: 40.7 %

Procedure:
A mixture of 2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamine (1 g) and 2-nitroamino-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone (1.11 g) in pyridine (3 ml) was heated under reflux for 5 hours and evaporated to dryness in vacuo. The residue was purified by chromatography on silica gel eluted with 20% methanol/chloroform followed by recrystallisation from acetonitrile/water 1:1 to give 2-[2-(4-dimethylaminomethyl-2-pyridylmethylthio)ethylamino]-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone (0.72 g) m.p. 72°-78°.
Reaction SMILES: ClC(=C(Cl)Cl)C([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(#N)C>CO>[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)C(Cl)=C(Cl)Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: Nc1ccc(C(=O)O)cc1

Procedure:
N-Trichloroacryloyl-p-aminobenzoic acid (440 μg) was dissolved in 1 mL of methanol, and 100 μL of this solution was added to 300 μL of potassium phosphate buffer (0.1 M, pH 8). In the same way a solution of p-aminobenzoic acid was prepared. Both solutions were analyzed by HPLC (C18-silica column, 0.01 M potassium phosphate buffer pH 4.5 initially, then 0 to 38% acetonitrile over 29 minutes. This gave a retention time of 6.8 min for p-aminobenzoic acid and 26 min for the product. The solutions were kept at room temperature. Analysis by HPLC demonstrated that the N-trichloroacryloyl-p-aminobenzoic acid was stable at least for four days. By this last day the solution of the p-aminobenzoic acid had discolored and additional peaks were seen.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[NH:34][C:33](=[O:35])[O:32][N:31]=3)=[CH:26][CH:25]=2)O1>>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:34][C:33](=[O:35])[O:32][N:31]=4)=[CH:26][CH:25]=3)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Reactant: CC1(C)OB(c2ccc(-c3noc(=O)[nH]3)cc2)OC1(C)C
Product: CCCCNc1ccc2ncc(-c3ccc(-c4noc(=O)[nH]4)cc3)n2n1
Yield: 25.3 %

Procedure:
Following the Suzuki coupling conditions described in example 5.6.45 from (3-bromo-imidazo[1,2-b]pyridazin-6-yl)-butyl-amine (213.1 mg, 0.8 mmol), and 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,4-oxadiazol-5(4H)-one (308.2 mg, 1.1 mmol) to provide 70.9 mg of 3-[4-(6-butylamino-imidazo[1,2-b]pyridazin-3-yl)-phenyl]-4H-[1,2,4]oxadiazol-5-one as white crystalline powder, mp. 253-254° C. (dec.). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96 (t, J=7.33 Hz, 3H) 1.44 (sxt, J=7.38 Hz, 2H) 1.65 (quin, J=7.26 Hz, 2H) 3.26-3.35 (m, 2H) 6.75 (d, J=9.85 Hz, 1H) 7.15 (t, J=5.31 Hz, 1H) 7.77 (d, J=9.60 Hz, 1H) 7.88 (m, J=8.84 Hz, 2H) 8.05 (s, 1H) 8.44 (m, J=8.59 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ ppm 13.73, 19.89, 30.15, 40.81, 112.82, 120.91, 125.38, 125.50, 126.11, 131.05, 133.01, 137.80, 153.62, 157.06, 159.94. LRMS (ESI) m/z 351.2 [(M+H)]+, calc'd for C18H18N6O2: 350.38.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)O.[NH2:38][C:39]1[N:43]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)[N:42]=[CH:41][C:40]=1[C:51]([NH:53][CH2:54][C:55]([CH2:61][NH:62][CH2:63][CH3:64])([OH:60])[C:56]([F:59])([F:58])[F:57])=[O:52]>CN(C)C=O>[NH2:38][C:39]1[N:43]([C:44]2[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=2)[N:42]=[CH:41][C:40]=1[C:51]([NH:53][CH2:54][C:55]([CH2:61][N:62]([CH2:63][CH3:64])[C:7]([C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[S:2]([CH3:1])(=[O:3])=[O:4])=[O:9])([OH:60])[C:56]([F:59])([F:58])[F:57])=[O:52]
Reactant: CS(=O)(=O)c1ccccc1C(=O)O
Reactant: CCNCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Agent: CN(C)C(O)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F)C(=O)c1ccccc1S(C)(=O)=O
Reaction time: 0.17 h
Yield: 91.2 %

Procedure:
2-(Methylsulphonyl)benzoic acid (0.204 g, 1.017 mmol) was dissolved in dry dimethylformamide before diisopropylethylamine (0.531 ml, 3.05 mmol) was added. O-7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.464 g, 1.22 mmol) was added and the reaction stirred for 10 minutes. The reaction mixture was cooled in ice and then 5-amino-N-{2-[(ethylamino)methyl]-3,3,3-trifluoro-2-hydroxypropyl}-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (0.46 g, 1.118 mmol, 1.1 equiv) was added (washed in with dimethylformamide) (total volume of dimethylformamide used 2.5 ml). The reaction was then stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure and the residue was partitioned between dichloromethane and water. The product was extracted into dichloromethane and concentrated under reduced pressure. The crude product was purified on silica (50 g) with a 0-100% ethyl acetate:dichloromethane over 40 minutes as gradient to give the title compound (0.53 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[C:11]([Cl:16])[C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20].CC(C)([O-])C.[Na+]>>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])[CH:12]=[C:11]([Cl:16])[C:10]=1[F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCC
Reactant: CC(C)(C)OC(=O)NCc1cc(Br)cc(Cl)c1F
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CCN(CC)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1

Procedure:
was prepared according to Scheme C1 (step A) from (5-bromo-3-chloro-2-fluoro-benzyl)-carbamic acid tert-butyl ester (300 mg, 0.89 mmol), diethylamine (0.14 mL, 1.3 mmol), sodium tert-butoxide (170 mg, 1.8 mmol) and di-μ-bromobis(tri-tert-butylphosphino)dipalladium (I) [CAS 185812-86-6] (34 mg, 0.04 mmol). MS (LC-MS): 331.2 [M]+; tR (HPLC conditions c): 4.08 min.
Reaction SMILES: [CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[N:6]=[C:5]1S(C)(=O)=O)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[CH2:34]([NH2:36])[CH3:35].O1CCCC1>C(OCC)C.CN(C)C=O>[CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[N:6]=[C:5]1[NH:36][CH2:34][CH3:35])[CH:2]=[CH2:3]
Reactant: CCN
Reactant: C=CCn1c(S(C)(=O)=O)nc2c(c1=O)C1(CCCCC1)Cc1ccccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CCn1c(NCC)nc2c(c1=O)C1(CCCCC1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
3-Allyl-2-(methylsulfonyl)-3H-spiro[benzo[h]quinazoline-5,1′-cyclohexan]-4(6H)-one (6, 306 mg, 0.796 mmol) and potassium carbonate (165 mg, 1.19 mmol) were added to 1 mL of dry dimethylformamide stirring under nitrogen atmosphere. A 2.0M solution of ethylamine in tetrahydrofuran (1 mL, 2 mmol) was then added, and the reaction was tightly capped and allowed to stir at room temperature for 5 hours. Another 1 mL portion of ethylamine solution was added at 5 hours, and the reaction allowed to stir for another 12 hours. At this point, the reaction mixture was diluted with diethyl ether and washed twice with water and once with brine. The organic layer was dried over MgSO4, vacuum filtered, and concentrated in vacuo. The residue was then loaded onto a silica flash column (50 g column, 10% to 33% ethyl acetate:hexanes), which isolated title compound in 85% yield (237 mg, 0.678 mmol) as a white crystalline solid. 1H NMR (500 MHz, CDCl3) δ ppm: 8.15, 7.33, 7.22, 5.94, 5.35, 5.31, 3.60, 3.04, 2.61, 1.72, 1.58, 1.39, 1.30.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1[O:13][CH2:12][CH2:11][CH2:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][C:8]1[O:13][CH2:12][CH2:11][CH2:10][CH:9]=1)(=[O:4])=[O:3]
Reactant: OCC1=CCCCO1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1=CCCCO1
Reaction time: 1 h
Yield: 112043.6 %

Procedure:
51.5 g (0.45 mol) of methanesulfonyl chloride are added dropwise to 45 g (0.39 mmol) of 6-hydroxymethyl-2,3-dihydropyran (Example 7a) and 50 g (0.5 mol) of triethylamine in 400 ml of methylene chloride at 0°-5° C. Stirring is carried out for 1 hour at 0° C. and the reaction mixture is poured onto water. The aqueous phase is separated off and the organic phase is extracted once again with water and is then dried over MgSO4 and evaporated down. 84 g of title compound are obtained as a red oil, which is used directly in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][C:33]1[N:37]=[CH:36][NH:35][N:34]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][C:33]3[N:37]=[CH:36][NH:35][N:34]=3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: Nc1nc[nH]n1
Product: Cc1cc(F)ccc1-c1nc(Nc2nc[nH]n2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 18.9 %

Procedure:
Following the general procedure outlined in Example 217, the product of Example 48 (150 mg, 0.33 mmol) and 3-amino-1,2,4-triazole (141 mg, 1.68 mmol) were reacted to give the crude material. Preparative hplc afforded the title compound 28 mg (15%). LC-MS: 450.2 (MH+, m/z), 1.79 (Rt, min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH2:10][CH:11]([OH:16])[CH2:12][CH2:13][CH:14]=[CH2:15].[Br:17]N1C(=O)CCC1=O>C(Cl)Cl>[Br:17][CH2:15][CH:14]1[CH2:13][CH2:12][CH:11]([CH2:10][C:4]2[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[O:16]1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCCC(O)Cc1cc(F)ccc1OC
Solvent: ClCCl
Product: COc1ccc(F)cc1CC1CCC(CBr)O1
Temperature: 25 °C

Procedure:
To a solution of 1-(2′-methoxy-5′-fluorophenyl)hex-5-en-2-ol (1.35 g, 6.0 mmol) in dry CH2Cl2 (30 mL) at 0° C. was added N-bromosuccinimide (NBS, 1.30 g, 7.2 mmol) portionwise and the reaction was warmed to room temperature for 12 h. Solvent was then removed in vacuo and the residue was purified by flash column chromatography (5% EtOAc in Hexane, Rf=0.12) to give in the trans isomer (663 mg, 36%) as an oil.
Reaction SMILES: O.[CH2:2]([O:9][C:10]([N:12]1[C@H:16]([CH3:17])[C@H:15]([CH2:18][OH:19])[C@H:14]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:13]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC>CS(C)=O>[CH2:2]([O:9][C:10]([N:12]1[C@H:16]([CH3:17])[C@H:15]([CH:18]=[O:19])[C@H:14]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:13]1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H]1[C@H](CO)[C@H](NC(=O)OC(C)(C)C)[C@H](c2ccccc2)N1C(=O)OCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@@H]1[C@H](C=O)[C@H](NC(=O)OC(C)(C)C)[C@H](c2ccccc2)N1C(=O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 141.5 %

Procedure:
To a stirred and water-cooled solution of (2S*,3S*,4R*,5R*)-1-benzyloxycarbonyl-3-[N-(t-butoxycarbonyl)amino]-4-hydroxymethyl-5-methyl-2-phenylpyrrolidine (2.60 g, 5.90 mmol) and Et3N (5.70 ml, d0.726, 40.9 mmol) in DMSO (dried over molecular sieves 4, 36 ml) was added sulfer trioxide pyridine complex (SO3Py, Wako, 5.42 g, 34.1 mmol) portionwise. Just after the addition the water bath was removed, and the stirring was continued at room temperature for 1.5 hours. The reaction mixture was poured into a mixture of ice and water (80 ml). The mixture was extracted with CH2Cl2 (30 ml×5). The combined CH2Cl2 extracts were washed with 10% citric acid aq. solution (30 ml×4) until the aqueous washing reached the acidity of citric acid (pH ca.3), H2O (30 ml×1), sat. NaHCO3 aq. solution (40 ml×1), and sat. NaCl aq. solution (×1), dried (MgSO4), and concentrated in vacuo to give crude title compound (3.66 g, quant.) as a pale yellow viscous oil; while the yield was overestimated owing to contamination with the solvent employed, this crude product solidified on standing in a refrigerator: IRmax (film): 3400(m, shoulder), 3350(m), 2720(w), 1710(vs), 1690(vs, shoulder), 1605(w), 1585(w), 1520(s), 1500(s), 1165(s), 770(m), 730(s), 700(s) cm-1 ; 1H-NMR δ: 9.65(d, J=3.7 Hz, 1H), 7.40-7.10(m, 9H), 7.05(br.s, 1H), 5.27(d, J=8.5 Hz, 1H), 5.06(br.s, 2H), 4.78-4.57(m, 1H), 4.24(dq, J=9.5, 6.1 Hz, 1H), 4.05(br.d, J=9.2 Hz, 1H), 2.77-2.50(m, 1H), 1.61(d, J=6.1 Hz, 1H), 1.37(s, 9H) ppm. This was employed in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]([O:35][CH3:36])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][CH2:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1.CCO>[CH3:36][O:35][CH:5]([CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:18][CH2:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:9][CH:8]=1)[C:4]([OH:37])=[O:3]
Reactant: CCOC(=O)C(Cc1ccc(OCCCc2nc(-c3ccc(OC)cc3)oc2C)c2ccccc12)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(CCCOc3ccc(CC(OC)C(=O)O)c4ccccc34)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
0.143 g of the above prepared [rac]-2-methoxy-3-(4-{3-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-propoxy}-naphthalen-1-yl)-propionic acid ethyl ester (0.28 mmol) was dissolved in 1.5 ml of THF/EtOH=1/1 and treated with 0.47 ml of 3N NaOH (5 eq.). The reaction mixture was stirred at ambient temperature for 2 h and was then poured onto crashed ice/HCl dil. and extracted twice with AcOEt. The organic layer was washed with water, dried over sodium sulfate, and evaporated to dryness. Crystallization from AcOEt/hexane afforded finally 0.120 g of the title product as white crystals of mp. 67-70°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[CH:21][N:20]=[C:19]3Cl)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:27][C:28]1[CH:29]=[C:30]([NH2:41])[CH:31]=[CH:32][C:33]=1[O:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.ClC(Cl)C>C(O)(C)(C)C>[CH3:27][C:28]1[CH:29]=[C:30]([NH:41][C:19]2[C:18]3[C:23](=[CH:24][CH:25]=[C:16]([C:15]#[C:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:17]=3)[N:22]=[CH:21][N:20]=2)[CH:31]=[CH:32][C:33]=1[O:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2ccc3ncnc(Cl)c3c2)CC1
Reactant: Cc1cc(N)ccc1Oc1cccnc1
Solvent: CC(Cl)Cl
Solvent: CC(C)(C)O
Product: Cc1cc(Nc2ncnc3ccc(C#CC4CCNCC4)cc23)ccc1Oc1cccnc1
Yield: 105 %

Procedure:
4-(4-Chloro-quinazolin-6-ylethynyl)-piperidine-1-carboxylic acid tert-butyl ester (80 mg, 0.21 mmol) and 3-Methyl-4-(pyridin-3-yloxy)-phenylamine (43 mg, 0.21 mmol) were mixed together in tert-butanol (1 mL) and dichloroethane (1 mL) and heated in a sealed vial at 90° C. for 20 minutes. The reaction was cooled down and HCl (gas) was bubbled through for 5 minutes. EtOAC was then added whereupon yellow precipitation occurred. The precipitate was collected and dried to afford the desired product [3-Methyl-4-(pyridin-3-yloxy)-phenyl]-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine as a yellow solid (96 mg, 95%). 1H NMR (CDCl3) δ 2.01 ((m, 2H), 2.22 (m, 2H), 2.35(s, 3H), 3.20 (m, 2H), 3.45(m, 2H), 7.28 (d, 1H, J=8.7 Hz), 7.75(dd, 3H, J1=8.7, J2=8.7 Hz), 8.06 (dd, J=8.7), 8.10 (dd, J1=J2=8.7 Hz), 8.17 (m, 1 H), 8.60 (d, 1H, J=5.4 Hz), 8.80 (s, 1H), 8.89 (s, 1H). MS: M+1, 436.6.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O:15][C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([C:25]#[C:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:19]=1)([CH3:14])([CH3:13])[CH3:12].N1C=CC=CC=1>C(Cl)Cl>[C:11]([O:15][C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[C:20]([C:25]#[C:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:19]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(C#Cc2ccccc2)n1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(NS(=O)(=O)c2ccccc2)c(C#Cc2ccccc2)n1
Reaction time: 1 h

Procedure:
Benzenesulfonyl chloride (20 μl, 0.4 mmol) diluted with 400 μl DCM is added to a mixture of tert-butyl-N-[5-amino-6-(2-phenylethynyl)pyridin-2-yl]carbamate B5a (40 mg, 0.13 mmol), pyridine (32 μl, 0.4 mmol) and 400 μl DCM at RT and stirred for 1 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 37 mg (64%). HPLC-MS: M+H=450; tR=2.16 min (*Method—2).
Reaction SMILES: [CH3:1][C:2]1[CH2:9][S:8]C2[N:4](C(=O)C2NC(=O)CC2C=CC=CC=2)[C:3]=1[C:21]([O:23][CH3:24])=[O:22].C1C(=O)N(Cl)C(=O)C1>ClCCl.C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[C:3]([C:21]([O:23][CH3:24])=[O:22])=[N:4][S:8][CH:9]=1
Reactant: COC(=O)C1=C(C)CSC2C(NC(=O)Cc3ccccc3)C(=O)N12
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nscc1C
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
Methyl 3-methyl-8-oxo-7-[(phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (I127) (971 mg, 2.80 mmol) was dissolved in dry dichloromethane (DCM) (37 mL), treated with NCS (749 mg, 5.61 mmol) before adding 2 drops of TFA (0.05 mL, 0.649 mmol) and stirring at RT for 80 mins. LCMS as run and the desired product seen. Reaction left to stand for 16 hours before work up by diluting with DCM (20 ml), washing with saturated sodium bicarbonate solution (50 ml), then water (40 ml), dried over Na2SO4 before filtering and evaporating to afford an oil. Purified on a 100 g SNAP cartridge eluting with chloroform over 10 CV. 2 spots were isolated, desired product identified and solvent evaporated to afford an orange yellow gum of desired material in 57 mg.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.3 %

Procedure:
To a suspension of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (1.0 g, 3.3 mmol) in THF (6 mL) was added a solution of lithium hydroxide monohydrate (248 mg, 9.8 mmol) in water (6 mL) added and the resulting mixture stirred at room temperature for 5 h. The mixture was acidified to pH 4 with HCl (1 N, 4.5 mL) and the resulting mixture extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, heptane:ethyl acetate=1:0 to 0:1) afforded the title compound (654 mg, 76%) which was obtained as a white solid. MS: m/e=291.2 [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]([NH2:7])=[NH:6].[C:8]1(=O)[CH2:12][CH2:11][CH2:10][C:9]1=O.[NH4+].[OH-]>O.C(O)C.Cl>[NH2:6][C:5]1[NH:7][C:9]2=[CH:10][CH:11]=[CH:12][C:8]2=[N:3][CH:4]=1
Reactant: N=C(N)CN
Reactant: O=C1CCCC1=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cnc2cccc-2[nH]1

Procedure:
A solution of aminoacetamidine dihydrochloride (Mengelberg, M. Chem. Ber. 89, 1185 (1956)) (2.4 g, 0.01 mol, 1 equiv.) in H2O (~10 mL) was added dropwise to a cold (0° C.) stirring solution of 1,2-cyclopentanedione (1.0 g, 0.01 mol) in ethanol (8-10 mL). After allowing the reaction mixture to come to room temperature, concentrated NH4OH (aq.) was added slowly until the pH was 8-9. Small amounts of concentrated NH4OH were added as needed in order to maintain a pH of 8-9. When the 1,2-cycopentanedione was no longer visible on TLC (30% EtOAc/hexanes) the reaction mixture was diluted with 5% HCl, washed (3×) with CH2Cl2 and the organic portions discarded. The aqueous portion was made basic with 6N NaOH (aq.), extracted (4×) with CH2Cl2 and the combined extracts dried over sodium sulfate. Concentration of the solution under reduced pressure gave 2-amino-cyclopent[b]pyrazine as a greenish-yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5](Cl)=[N:6][CH:7]=1.C[O-].[Na+].[C:23](=O)(O)[O-:24].[Na+].Cl>>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]([O:24][CH3:23])=[N:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccc(O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COc1ncc(Br)cc1NS(=O)(=O)c1ccc(O)cc1
Yield: 82 %

Procedure:
N-(5-Bromo-2-chloropyridin-3-yl)-4-hydroxybenzenesulfonamide (587 mg, 1.61 mmol) and sodium methoxide (25% in methanol, 10 ml, 43.73 mmol) were stirred at 120° C. for 20 min under microwave conditions. The reaction mixture was poured into sodium bicarbonate saturated solution, neutralized with concentrated chlorohydric acid and extracted with ethyl acetate (×3). The organic phase was dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure to obtain 475 mg (82% yield, 100% purity) of the title compound, which was used in the next synthetic step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][O:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1>CN(C=O)C>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:31]5[C:26]([O:25][CH3:24])=[N:27][CH:28]=[CH:29][CH:30]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: COc1ncccc1B(O)O
Solvent: CN(C)C=O
Product: COc1ncccc1-c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)sc1CCO2
Yield: 60 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 2-methoxypyridin-3-ylboronic acid were reacted. The crude material was dissolved in DMF and purified by reverse phase HPLC to provide 129 (200 mg, 60%). 1H NMR (400 MHz, DMSO) δ 8.66 (d, J=2.2, 1H), 8.19 (dd, J=4.9, 1.7, 1H), 8.10 (s, 1H), 7.79 (dd, J=7.3, 1.8, 1H), 7.50 (dd, J=8.4, 2.3, 1H), 7.21-7.09 (m, 2H), 5.75 (dt, J=13.3, 6.7, 1H), 4.42 (t, J=4.9, 2H), 3.91 (s, 3H), 3.47 (t, J=4.9, 2H), 1.52 (d, J=6.6, 6H). MS (ESI(+)): m/z 420.1 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2].[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>>[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:9]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: BrCc1ccccc1Br
Reactant: N#Cc1ccc(Nn2cncn2)cc1
Product: N#Cc1ccc(N(Cc2ccccc2Br)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 2-bromobenzyl bromide