Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH2:15][C:16]([OH:18])=O)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=2)[N:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH2:15][C:16]([NH:31][C:28]3[CH:27]=[CH:26][C:25]([C:21]4[N:20]=[N:19][CH:24]=[CH:23][CH:22]=4)=[CH:30][N:29]=3)=[O:18])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)Cc1cnc(-c2ccnc(F)c2)c(F)c1
Reactant: Nc1ccc(-c2cccnn2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(Cc1cnc(-c2ccnc(F)c2)c(F)c1)Nc1ccc(-c2cccnn2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(2′,3-difluoro-2,4′-bipyridin-5-yl)acetic acid 205-6 (25 mg, 0.1 mmol), 5-(pyridazin-3-yl)pyridin-2-amine 145-3 (17 mg, 0.1 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 38 mg, 0.1 mmol) were added DMF (0.5 mL) and diispropylethyl amine (DIEA, 0.05 mL, 0.3 mmol) and the mixture was stirred at room temperature overnight. The crude DMF solution was directly purified by reverse phase HPLC to give 2-(2′,3-difluoro-2,4′-bipyridin-5-yl)-N-(5-(pyridazin-3-yl)pyridin-2-yl)acetamide 210 as white solid. MS m/z 405.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.18 (s, 1H), 9.23 (d, 1H), 9.14 (d, 1H), 8.61 (m, 1H), 8.56 (dd, 1H), 8.41 (d, 1H), 8.29 (dd, 1H), 8.23 (d, 1H), 7.95 (dd, 1H), 7.91-7.86 (m, 1H), 7.81 (dd, 1H), 7.65 (s, 1H), 4.02 (s, 2H).
Reaction SMILES: OC1C=CC(CNC(=O)C2C=CC(NC3C4N(C=CN=4)C(C4C=NNC=4)=CN=3)=CC=2)=CC=1.[Br:33][C:34]1[N:39]2[CH:40]=[CH:41][N:42]=[C:38]2[C:37](Br)=[N:36][CH:35]=1.[CH3:44][N:45]1[N:49]=[N:48][C:47]([C:50]2[CH:55]=[CH:54][C:53]([NH2:56])=[CH:52][CH:51]=2)=[N:46]1.CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Br:33][C:34]1[N:39]2[CH:40]=[CH:41][N:42]=[C:38]2[C:37]([NH:56][C:53]2[CH:54]=[CH:55][C:50]([C:47]3[N:48]=[N:49][N:45]([CH3:44])[N:46]=3)=[CH:51][CH:52]=2)=[N:36][CH:35]=1
Reactant: Cn1nnc(-c2ccc(N)cc2)n1
Reactant: Brc1ncc(Br)n2ccnc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Cn1nnc(-c2ccc(Nc3ncc(Br)n4ccnc34)cc2)n1
Yield: 44.1 %

Procedure:
In the same way as described for Compound 90, step 1, using 5,8-dibromoimidazo[1,2-a]pyrazine (334 mg, 1.21 mmol), 4-(2-methyl-2H-tetrazol-5-yl)-phenylamine (211.1 g, 1.21 mmol), NaOtBu (162 mg, 1.69 mmol), Pd2(dba)3 (44.1 mg, 0.0482 mmol), Xantphos (55.8 mg, 0.0964 mmol) and toluene (16 mL). The crude product is purified by silica gel column chromatography eluting with a 8:2:1 mixture petroleum ether:EtOAc:MeOH to afford the title compound as a yellow solid (198 mg, 44%).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6](=[O:13])[CH:7]=[C:8]([C:10]([OH:12])=[O:11])[N:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+].[O-][Cl:17].[Na+].S([O-])([O-])=O.[Na+].[Na+].Cl>O>[Cl:17][C:7]1[C:6](=[O:13])[NH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[N:9][C:8]=1[C:10]([OH:12])=[O:11]
Reactant: [O-]Cl
Reactant: O=C(O)c1cc(=O)[nH]c(C2CC2)n1
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1nc(C2CC2)[nH]c(=O)c1Cl
Temperature: 10 °C
Yield: 95.3 %

Procedure:
A 500 mL multi-neck flask with overhead stirrer, thermocouple and addition funnel was charged with 2-cyclopropyl-1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid (36 g, 0.20 mol), water (70 mL) and 50 wt. % aqueous NaOH (14.4 g, 0.18 mol). The mixture was stirred at 10° C., and 10.3% aqueous NaOCl (160 g, 0.22 mol) was added over 1.5 h with cooling to maintain the reaction mixture at 10° C. The mixture was cooled to 5° C., and sodium sulfite was added until KI-starch paper gave negative test results. Hydrochloric acid (37 wt. % in water, 44.3 g, 0.443 mol) was added at 5° C. over about 30 minutes to lower the pH to 0.8. The mixture was filtered, and the collected solid was washed with cold 1 N HCl (20 mL), and dried to constant weight in a vacuum-oven at 50° C. to give 40.9 g (95% yield) of the title compound as a solid melting at 189-190° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)=[N:6][N:7]2[C@H:12]3[CH2:13][O:14][CH2:15][C@H:11]3[N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=12)(=[O:3])[NH2:2].Cl>O1CCOCC1>[ClH:30].[Cl:30][C:25]1[CH:24]=[C:23]([C:5]2[C:4]([C:1]([NH2:2])=[O:3])=[C:8]3[CH2:9][NH:10][C@@H:11]4[CH2:15][O:14][CH2:13][C@@H:12]4[N:7]3[N:6]=2)[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(-c3ccc(F)c(Cl)c3)nn2[C@H]2COC[C@H]21
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1c(-c2ccc(F)c(Cl)c2)nn2c1CN[C@@H]1COC[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 198.9 %

Procedure:
To a stirred solution of Intermediate 352G (0.2 g, 0.458 mmol) in dioxane (1 mL) was added a solution of HCl in dioxane (2 mL, 8.0 mmol, 4 M). After stirring at RT for 2 h, the reaction mixture was concentrated and the crude product was triturated with hexanes to afford Intermediate 352H (0.17 g, 71%) as an off-white solid. MS(ES): −m/z=337 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.90 (ddd, J=1.8, 7.5, 14.3 Hz, 1H), 7.80-7.68 (m, 2H), 7.54-7.47 (m, 1H), 7.38 (dd, J=8.3, 9.8 Hz, 1H), 5.10 (br. s., 1H), 4.63 (br. s., 1H), 4.56 (s, 2H), 4.20-3.98 (m, 4H), 3.57 (s, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:12][N:13]3[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.CCCCCC>[C:1]1([C:7]([C:9]2[CH:10]=[C:14]3[C:15]([C:11]([CH:26]=[CH:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[N:12][N:13]3[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:16][CH:17]=2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2c(C(O)c3ccccc3)cccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCCCCC
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(C(=O)c3ccccc3)cc21
Temperature: 23 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of phenyl-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-yl}-methanol (68 mg, 0.15 mmol) in dichloromethane (3 mL) at 23° C. under an atmosphere of argon was added periodinane (Dess-Martin reagent) (190 mg, 0.45 mmol). The resulting mixture was stirred at 23° C. for 1 hour. The solution was then diluted with hexane (3 mL) then filtered through Celite and concentrated under reduced pressure to a solid. The crude mixture was purified by silica gel chromatography (eluting with hexane:EtOAc 9:1) to give phenyl-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanone (54 mg, 79% yield). Rf sm=0.41, Rf p=0.63 (7:3 hexane:EtOAc); FTIR (thin film) 3059, 2952, 2894, 1659, 1474, 1448, 1307, 1249, 1078, 836, 649 cm−1. MS (ESI) [M+H]/z Calc'd 455, found 455.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]=[C:33]=[O:34])[CH:27]=1>>[N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH:23][C:33]([NH:32][C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)=[O:34])=[CH:21][CH:20]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C=Nc1cccnc1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Product: O=C(Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1)Nc1cccnc1

Procedure:
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.08 g 0.23 mmoles) and 3-pyridyl isocyanate (30 mg, 0.25 mmoles) the title compound was isolated as a white solid. The product was purified by Silica gel column chromatography by eluting it with 10% MeOH: ethyl acetate. Yield; 60 mg (56%); (M+H)=463.5.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[CH:11][C:10]=1[CH2:16][C:17]([NH2:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NCC1CCCN1CC1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[N:12]=[CH:11][C:10]=1[CH2:16][C:17]([NH2:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccncc1
Reactant: NC(=O)Cc1cnc(Cl)cc1NCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: NCC1CCCN1Cc1ccccc1
Solvent: Cc1ccccc1
Product: NC(=O)Cc1cnc(Nc2ccncc2)cc1NCc1ccccc1
Temperature: 100 °C
Reaction time: 28 h
Yield: 15.9 %

Procedure:
25 mg of 4-benzylamino-6-chloropyridine-3-carboxyamide (the compound of Example 1) was dissolved in 0.5 ml of toluene, to which 13.5 mg of 4-aminopyridine, 2 mg of palladium (II) acetate, 248 mg of potassium carbonate and 11 mg of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl were added, and stirred at 100° C. for 28 hours. After cooling, the insoluble substances were filtered off, the filtered product was washed with toluene, combined with the filtrate, and the solvent was evaporated. The residue obtained was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain 4.8 mg (yield 16%) of the title compound as a slight yellow crystalline powder.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:35][C@H:36]([C:49]([O:51]C(C)(C)C)=[O:50])[CH2:37][CH2:38][CH2:39][CH2:40][NH:41]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>>[NH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH:36]([NH:35][C:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=[CH:22]4)=[N:9][C:10]=2[CH:15]=1)=[O:17])[C:49]([OH:51])=[O:50]
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)ccc3c1)n2C1CCCCC1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NCCCCC(NC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)ccc3c1)n2C1CCCCC1)C(=O)O
Yield: 15 %

Procedure:
Compound 232 was synthesized from Compound 201 as described for Compound 235, except H-Lys(Boc)-OtBu was used instead of L-5-hydroxytryptophane. In the 3rd step the protected intermediate was treated with a mixture of TFA-anisol 8:2 for 2 hours then the product was precipitated with ether and purified on RP-HPLC. Yield 15%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].O>CC(C)=O>[CH2:21]([O:20][C:18](=[O:19])[C:17]([CH3:24])([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH3:23])[CH3:22]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 4-hydroxybenzaldehyde (20 g, 0.164 mol) in acetone (300 mL) was added K2CO3 (34 g, 1.5 equiv.) and the reaction was stirred at room temperature during 30 minutes. Ethyl 2-bromo-2-methylpropionate (36.2 mL, 1.5 equiv.) was added dropwise and the mixture was heated under reflux during 3 hours. K2CO3 (34 g, 1.5 equiv.) and ethyl 2-bromo-2-methylpropionate (36.2 mL, 1.5 equiv.) were added and the mixture was heated under reflux during 16 hours and then pourred into water and extracted with CH2Cl2 (3×300 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent evaporated to afford crude intermediate. After chromatography on silicagel, eluting with cyclohexane/CH2Cl2 (6/4, then 8/2) and then with CH2Cl2, the titled compound was obtained as an oil (27 g, 69.85%)
Reaction SMILES: C([O-])=O.[NH4+].Cl[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:8][C:7]=1[C:17]1[CH2:18][CH2:19][C:20](=[O:23])[NH:21][N:22]=1>[C].[Pd].CO>[NH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][CH:6]=[C:7]([C:17]2[CH2:18][CH2:19][C:20](=[O:23])[NH:21][N:22]=2)[CH:8]=1
Reactant: NCCCCc1ccc(Cl)c(C2=NNC(=O)CC2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: NCCCCc1cccc(C2=NNC(=O)CC2)c1
Yield: 74.1 %

Procedure:
1.0 g of 10% palladium carbon (Pd/C) and 9.0 g of ammonium formate were added to a methanol solution (100 ml) containing 2.0 g of 6-[2-chloro-5-(4-aminobutyl)phenyl]-4,5-dihydropyridazin-3(2H)-one. The resulting suspension was refluxed under heating for 12 hours. The suspension was left to stand for cooling and then filtered, and the filtrate was removed. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol-28% aqueous ammonia (50:10:1)) to obtain 1.3 g of 6-[5-(4-aminobutyl)phenyl]-4,5-dihydropyridazin-3(2H)-one.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[N:18][N:19]([CH2:21][CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=4)[S:15][C:8]=23)=[C:4]([F:34])[CH:3]=1.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1C=CN=C2C=C(C3C=CC(S(C)(=O)=O)=CC=3)SC=12.[CH3:75][O:76][C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][C:78]=1[CH2:83][C:84]([N:86]=[C:87]=[S:88])=[O:85]>>[F:34][C:4]1[CH:3]=[C:2]([NH:1][C:87]([NH:86][C:84](=[O:85])[CH2:83][C:78]2[CH:79]=[CH:80][CH:81]=[CH:82][C:77]=2[O:76][CH3:75])=[S:88])[CH:33]=[CH:32][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH:20]=3)[S:15][C:8]=12
Reactant: CN(CCn1cc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cn1)C(=O)OC(C)(C)C
Reactant: COc1ccccc1CC(=O)N=C=S
Agent: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1
Product: COc1ccccc1CC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4cnn(CCN(C)C(=O)OC(C)(C)C)c4)sc23)c(F)c1
Yield: 90 %

Procedure:
Starting from the amine 182, following the procedure described above for the synthesis of compound 50 (scheme 10, example 55) but replacing 2-phenylacetyl isothiocyanate with 2-(2-methoxyphenyl)acetyl isothiocyanate, title compound 183 was obtained in 90% yield. LRMS (M+1) 691.2 (100%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[C:9]([N:13]1[C:17](=[O:18])[C:16]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:15]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:14]1(=[O:33])=[O:32])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([N:13]1[C:17](=[O:18])[C:16]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:2][C:3]3[CH:7]=[C:6]([CH3:8])[O:5][N:4]=3)[CH2:22][CH2:21]2)=[C:15]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[S:14]1(=[O:33])=[O:32])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)N1C(=O)C(NC2CCNCC2)=C(c2ccccc2)S1(=O)=O
Reactant: Cc1cc(CBr)no1
Product: Cc1cc(CN2CCC(NC3=C(c4ccccc4)S(=O)(=O)N(C(C)(C)C)C3=O)CC2)no1
Yield: 17 %

Procedure:
The title compound was prepared as described for Example 104 from 3-(bromomethyl)-5-methylisooxazole and 2-tert-butyl-5-phenyl-4-(piperidin-4-ylamino)isothiazol-3(2H)-one 1,1-dioxide (Example 75) to give the title compound (0.021 g, 17%) as a solid. 1H NMR (500 MHz CDCl3): δ 7.52-7.48 (m, 2H), 7.48-7.42 (m, 3H), 5.92 (s, 1H), 5.18 (d, 1H), 3.40 (s, 2H), 2.98-2.88 (m, 1H), 2.70-2.62 (m, 2H), 2.40 (s, 3H), 1.74 (m, 9H), 1.79-1.60 (m, 4H), 1.42-1.32 (m, 2H); 13C NMR (125 MHz CDCl3): δ 169.7, 161.7, 159.9, 134.2, 131.8, 130.1, 128.9, 125.3, 106.9, 101.8, 61.8, 53.4, 52.0, 50.1, 32.5, 27.8, 12.5; Mass Spectrum M+H+ 459.
Reaction SMILES: [CH3:1][C@H:2]([NH:25][C:26](=O)[O:27]C(C)(C)C)[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:7][CH2:6]1.Cl.[C:34](OCC)(=O)C>>[CH3:1][C@H:2]([NH:25][C:26](=[O:27])[CH3:34])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([O:20][CH2:21][CH:22]([CH3:23])[CH3:24])[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:7][CH2:6]1
Reactant: CCOC(C)=O
Reactant: CC(C)COc1ccc2nc(N3CCC(OC[C@H](C)NC(=O)OC(C)(C)C)CC3)oc2c1
Agent: Cl
Product: CC(=O)N[C@@H](C)COC1CCN(c2nc3ccc(OCC(C)C)cc3o2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To tert-butyl [(1S)-1-methyl-2-({1-[6-(2-methylpropoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)ethyl]carbamate (97 mg) was added 4 M hydrogen chloride/ethyl acetate (5 mL), and the mixture was stirred at room temperature for 15 min and concentrated. To the residue were added pyridine (5 mL) and acetic anhydride (5 mL), and the mixture was stirred at room temperature for 15 min. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/methanol), and recrystallized from ethyl acetate/hexane to give the title compound (52 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][N:16]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1>C(O)C.[C].[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc(N)cn2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 77 %

Procedure:
To a solution of the above-mentioned crude product tert-butyl{3-[(5-nitropyridin-2-yl)oxy]phenyl}carbamate in ethanol (80 mL)/tetrahydrofuran (20 mL) was added 10% palladium-carbon (1.54 g), and the mixture was stirred at room temperature for 7 hr under a hydrogen atmosphere (1.0 pressure). The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from methanol to give the title compound (3.35 g, 77%) as brown crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH:4]2[CH2:5][C:6]3[C:10]([CH:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12]([NH:14][NH:15][C:16](=O)[C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([CH2:24][CH3:25])[CH:18]=1)=[O:13].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.CC(=O)OCC>[CH2:24]([C:19]1[CH:18]=[C:17]([C:16]2[O:13][C:12]([C:7]3[S:8][C:9]([CH3:11])=[C:10]4[C:6]=3[CH2:5][C@H:4]3[C:2]([CH3:27])([CH3:1])[C@H:3]34)=[N:14][N:15]=2)[CH:22]=[C:21]([CH3:23])[N:20]=1)[CH3:25]
Reactant: CCc1cc(C(=O)NNC(=O)c2sc(C)c3c2CC2C3C2(C)C)cc(C)n1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc(-c2nnc(-c3sc(C)c4c3C[C@@H]3[C@H]4C3(C)C)o2)cc(C)n1
Temperature: 110 °C
Yield: 8.8 %

Procedure:
A mixture of crude 2-ethyl-6-methyl-isonicotinic acid N′-(1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carbonyl)-hydrazide (350 mg, ca. 0.5 mmol) and Burgess Reagent (385 mg, 1.62 mmol) in THF (5 mL) is heated at 110° C. for 3 min in a microwave oven. The mixture is diluted with EA (10 mL) and extracted with sat. aq. Na2CO3 (2×5 mL). The organic phase is dried (Na2SO4), filtered and evaporated to give crude product (50.9 mg) that is purified by HPLC to give 2-ethyl-6-methyl-4-[5-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine (16 mg) as a light yellow powder; LC-MS: tR=0.91 min, [M+1]=366.21.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[F:9])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:26][CH2:27]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3F)CC2)c1
Reactant: Oc1ccc(F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(F)cc3)c3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-fluorophenol and N-(3-(1-[6-(2-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 7.72-6.72 (m, 12H), 5.42-5.34 (m, 1H), 3.68-3.58 (m, br, 2H), 3.02-2.92 (m, 2H), 2.80-2.46 (m, 6H), 2.05-1.78 (m, 6H), 1.68-1.56 (m, 1H), 1.56-1.38 (m, 3H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 535.1 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=O)[C:7]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:6]=2[O:5]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>C(#N)C.C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:21])[C:7]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:6]=2[O:5]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1CC(CCCl)Oc2ccc([N+](=O)[O-])cc2C1=O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CN1CC(CCCl)Oc2ccc([N+](=O)[O-])cc2C1=S
Reaction time: 2 h
Yield: 173.5 %

Procedure:
To 2.0 g (0.007 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-7-nitro-1,4-benzoxazepin-5(4H)-one in 35 ml of acetonitrile was added 1.0 g (0.0023 mole) of phosphorus pentasulfide and the mixture heated to reflux for 2 hr. Another 0.4 g (0.001 mole) of phosphorus pentasulfide was added and heating continued for 2 hr. After cooling, the reaction mixture was diluted with 100 ml of toluene and filtered. The filtrate was washed with 3×50 ml of saturated sodium bicarbonate and 100 ml of water, dried over sodium sulfate, filtered, charcoaled, filtered, and concentrated by rotary evaporation. The crude oil was crystallized from isopropyl ether/toluene to give 1.2 g (57%) of yellow crystals, m.p. 153°-155° C.
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrN1C(=[O:20])CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([C:8]1[C:9](=[O:13])[CH2:10][CH:11]([OH:20])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC=C1Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1CC(O)C=C1Cc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 2-benzylcyclopent-2-en-1-one and N-bromosuccinimide in dry carbon tetrachloride (150 ml) is refluxed for 1 hour, cooled and filtered. The filtrate is concentrated under reduced pressure to approx. 100 ml, and mixed with a stirred suspension of silver acetate (5 g) in acetic acid (150 ml). The resulting mixture is heated to 50° C. for 30 minutes and then stirred at room temperature overnight. The mixture is filtered, poured onto H2O (50 ml) and extracted with methylene chloride (150 ml×3). The combined extracts are washed with water ag. sodium bicarbonate, ag. sodium chloride, dried and concentrated under reduced pressure. (b.pt. is 128°-132° at 0.05 mmHg). The crude acetate is added to a solution of KOH (1.1 g) in 10% aqueous MeOH (100 ml) and stirred at room temperature for 40 minutes, poured onto dil.HCl and extracted with Et20 (×3). The combined extracts are washed with water dried, concentrated under reduced pressure and finally distilled. The ketone has b.pt 150°-154° C. at 0.04 mmHg and nD 1.5562.