Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([N+:13]([O-])=O)=[N:8][CH:9]=[C:10]([CH3:12])[CH:11]=1.Cl.O>[Fe].C(O)C>[NH2:13][C:7]1[C:6]([O:5][CH2:4][C:3]2[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:2]=2[CH3:1])=[CH:11][C:10]([CH3:12])=[CH:9][N:8]=1
Reactant: Cc1cnc([N+](=O)[O-])c(OCc2c(C)cccc2C)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cnc(N)c(OCc2c(C)cccc2C)c1
Yield: 92.1 %

Procedure:
A mixture of 3-(2,6-dimethylbenzyloxy)-5-methyl-2-nitropyridine (1.9 g, 6.99 mmol), iron powder (6.4 g), concentrated HCl (0.15 ml), water (1.5 ml) and 95% ethanol (35 ml) was refluxed for 1.0 h. The reaction mixture was filtered over celite and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, using methylene chloride:methanol (100:4) as eluent to give 1.56 g (92%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 37.9 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (962 mg, 0.005 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (3.3 g, 0.026 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-phenoxy-but-2-enoic acid ethyl ester (1.5 g, 0.005 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-(2-oxo-4-phenoxy-2,5-dihydro-pyrrol-1-yl)-propionic acid methyl ester (650 mg, 36%) as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11]([OH:19])([CH2:13]OS(C)(=O)=O)[CH2:10][C@H:9]1[C:20](=[O:31])[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[F:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([CH2:13][N:32]=[N+:33]=[N-:34])([OH:19])[CH2:10][C@H:9]1[C:20](=[O:31])[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[F:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1C[C@](O)(COS(C)(=O)=O)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@](O)(CN=[N+]=[N-])C[C@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of (2S,4S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-hydroxy-4-methanesulfonyloxy methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (580 mg, 1.21 mmol) (prepared as described Scheme B13) in DMF (20 mL) was added sodium azide (392 mL, 6.03 mmol) and the solution was stirred for 16 h at 80° C. The reaction mixture was diluted with EtOAc, washed with a saturated aqueous solution of NaHCO3 (3 times). The organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1) to give the desired material. MS (LC/MS): 430.1/432.1 [M+H]+, 374.1 [MH−tBu]+, 332 [MH−Boc]+; tR (HPLC conditions f): 2.22 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:56]=[CH:57][CH:58]=1)[O:5][C:6]1[CH:33]=[C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][C:41]3[CH2:46][CH2:45][C:44]([CH3:48])([CH3:47])[CH2:43][C:42]=3[C:49]3[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=3)[CH2:36][CH2:35]2)[CH:31]=[CH:30][C:7]=1[C:8]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[C:16]([N+:27]([O-:29])=[O:28])[CH:15]=1)(=[O:13])=[O:12])=[O:9].[CH:59]1([CH:62]=O)[CH2:61][CH2:60]1.CO>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:56]=[CH:57][CH:58]=1)[O:5][C:6]1[CH:33]=[C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][C:41]3[CH2:46][CH2:45][C:44]([CH3:48])([CH3:47])[CH2:43][C:42]=3[C:49]3[CH:50]=[CH:51][C:52]([Cl:55])=[CH:53][CH:54]=3)[CH2:36][CH2:35]2)[CH:31]=[CH:30][C:7]=1[C:8]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:62][CH:59]3[CH2:61][CH2:60]3)[CH2:23][CH2:22]2)=[C:16]([N+:27]([O-:29])=[O:28])[CH:15]=1)(=[O:12])=[O:13])=[O:9]
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCNCC5)c([N+](=O)[O-])c4)c(Oc4cccc(Cl)c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Reactant: O=CC1CC1
Solvent: ClCCl
Solvent: CO
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCN(CC6CC6)CC5)c([N+](=O)[O-])c4)c(Oc4cccc(Cl)c4)c3)CC2)=C(c2ccc(Cl)cc2)C1

Procedure:
A suspension of EXAMPLE 187B (50 mg), cyclopropanecarbaldehyde (100 mg) and MP-CNBH3 resin (0.2 g, 2.43 mmol/g) in dichloromethane (4 mL)/methanol (3 mL) was shaken for 16 hours at room temperature. The product was filtered, washed with dichloromethane/methanol and concentrated. The crude product was purified by RP HPLC(C8, 30%-100% CH3CN/water/0.1% TFA) to yield the product. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 8.35 (s, 1H), 8.10 (s, 1H), 7.67-7.75 (m, 1H), 7.60 (d, 1H), 7.36 (d, 2H), 7.15 (t, 1H), 7.07 (d, 3H), 6.89 (d, 1H), 6.73 (dd, 1H), 6.63 (s, 1H), 6.60 (s, 1H), 6.40 (s, 1H), 3.86 (s, 1H), 3.12 (s, 5H), 2.71-2.80 (m, 3H), 2.13-2.28 (m, 9H), 1.98 (s, 3H), 1.79 (s, 1H), 1.41 (t, 2H), 0.99-1.11 (m, 2H), 0.94 (s, 6H), 0.84 (d, 1H), 0.63 (d, 2H), 0.33 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[CH:24])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1.N1CCCC1>Cl[Pd]Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:29]2[CH:30]=[CH:31][C:26]([Br:25])=[CH:27][CH:28]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Brc1ccc(I)cc1
Reactant: C#CCOc1ccc(OCC2CCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl[Pd]Cl
Solvent: C1CCNC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1COc1ccc(OCC#Cc2ccc(Br)cc2)cc1
Yield: 33.8 %

Procedure:
General procedure A was followed using the product from step 3 Example 1 (266 mg, 0.803 mmol), p-bromo iodobenzene (156.5 mg, 0.669 mmol), PdCl2 (2.5 mg, 0.014 mmol), pyrrolidine (0.277 mL, 3.34 mmol), water (0.844 mL) to give the title compound (110 mg, 33.8%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.[NH2:22][OH:23].O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:23][NH:22][C:19]([C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]3)[S:11][C:12]=2[CH:18]=1)=[NH:20]
Reactant: NO
Reactant: CC(C)N1CCN(c2nc3ccc(C#N)cc3s2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)N1CCN(c2nc3ccc(C(=N)NO)cc3s2)CC1
Yield: 71.6 %

Procedure:
To a solution of 2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carbonitrile (5.0 g, 17.5 mmol) in ethanol (50 mL) was added hydroxylamine hydrochloride (3.6 g, 52.4 mmol), water (8 mL) and potassium carbonate (7.2 g, 52.4 mmol). The reaction mixture was heated overnight at reflux. The mixture was allowed to cool and then concentrated in vacuo. The residue was dissolved into THF (30 mL) and then filtered. The filtrate was concentrated in vacuo to give 4 g of crude N-hydroxy-2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carboxamidine.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:7][C:8]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1Cl)=[CH:17][CH:16]=[C:15]([Cl:21])[CH:14]=2)=[O:9])[CH3:6].O>CN(C)C=O>[CH2:5]([O:7][C:8]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[N:1]=[N+:2]=[N-:3])=[CH:17][CH:16]=[C:15]([Cl:21])[CH:14]=2)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1cnc2cc(Cl)ccc2c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2cc(Cl)ccc2c1N=[N+]=[N-]
Reaction time: 18 h

Procedure:
Sodium azide (0.62 g; 0.009 M) was suspended in a solution of ethyl-4,7-dichloroquinoline-3-carboxylate E. F. Elslager, et al., J. Med. Pharm, Chem, 5, 550 (1962) (1.75 g; 0.006 M) in dry dimethyl formamide (20 ml) and this mixture stirred at ambient temperatures. After 18 hr. the mixture was poured into reapidly stirred water (200 ml), the resultant precipitate filtered off, dried at the pump and then recrystallised from ethanol (8 ml/g), 1.27 g (71%), m.p. 94.5° C., (Found: C, 51.7; H, 3.4; N, 20.2; Cl, 12.9% C12H9N4O2Cl requires C, 52.0; H, 3.3; N, 20.2; Cl, 12.8%); max (KBr) 2140, 1722, 1390, 1372, 1274, 1239, 1199 and 1058 cm-1, (CDCl3) 1.48 (t) and 4.55 (m) (CH3CH2), 7.59 (m), 8.11 (d), 8.32 (d) and 9.29 (s) (aromatic H's) m/e 276 (M+, 14%), 248 (9%), 218 (22%), 154 (29% 152 (100%).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BrH:11].Br.[CH3:13][N:14]([CH3:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH:21][NH2:22])=[NH:20]>C(O)C>[BrH:11].[BrH:11].[N+:1]([C:4]1[O:8][C:7]([CH:9]=[N:22][NH:21][C:19](=[NH:20])[NH:18][CH2:17][CH2:16][CH2:15][N:14]([CH3:23])[CH3:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: CN(C)CCCNC(=N)NN
Agent: Br
Solvent: CCO
Product: CN(C)CCCNC(=N)NN=Cc1ccc([N+](=O)[O-])o1

Procedure:
5-Nitro-2-furaldehyde (0.564 g, 4 mmole) and N-(3-dimethylaminopropyl)hydrazinecarboximidamide dihydrobromide (1.6 g, 5 mmole) are heated at reflux in 8 ml 95% ethanol for 1 hour. The title compound precipitates from solution on cooling and is recrystallized from ethanol, mp 131°-133° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[N:14]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:11]2=[N:12][CH:13]=1)=[O:7])#[N:2].N1C=CN=C1.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].C(OCC)(=O)C>CN(C)C=O>[C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])=[CH:19][CH:18]=3)[N:14]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:11]2=[N:12][CH:13]=1)=[O:7])#[N:2]
Reactant: N#CCCNC(=O)c1cnc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(C(=O)NCCC#N)cnc3n2C2CCCCC2)cc1
Temperature: 35 °C
Reaction time: 20 h
Yield: 82.5 %

Procedure:
To a solution of intermediate 60 (1.5 g, 3.85 mmol) in dimethylformamide (5 mL) was added imidazole (0.917 g, 13.5 mmol) and tert-butyldimethylsilyl chloride (0.870 g, 5.77 mmol). The reaction mixture was stirred at 35° C. for 20 h, and then ethyl acetate (100 mL) was added. The resulting organic phase was washed with water (4×20 mL) and brine (1×) and then dried (Na2SO4). After concentrating on a rotary evaporator the resulting residue was purified by column chromatography (silica gel, 1:1 hexanes/ethyl acetate-3:7 hexanes/ethyl acetate) to afford intermediate 61 as a white solid (1.6 g, 83%). ESI-MS m/e 504.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH:9]1[CH2:15]C(O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][OH:26])=[NH:24].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH:9]1[C:15]1[O:26][N:25]=[C:23]([C:22]2[CH:27]=[CH:28][CH:29]=[C:20]([Cl:19])[CH:21]=2)[N:24]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1CC(=O)O
Reactant: N=C(NO)c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1c1nc(-c2cccc(Cl)c2)no1
Temperature: 135 °C
Yield: 53.9 %

Procedure:
2-Carboxymethyl-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (1.87 g, 7.25 mmol), 3-chloro-N-hydroxy-benzamidine (1.36 g, 7.98 mmol), HOBt (1.08 g, 7.98 mmol) and EDCl (1.53 g, 7.98 mmol) in DMF (20 mL) were stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water (3 times), saturated sodium bicarbonate (2 times) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in DMF (20 mL) and then heated at 135° C. for 4 hours. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water (3 times) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification was performed by flash chromatography on silica gel using hexanes:dichloromethane (1:1) to afford the titled compound (1.48 g, 52%, white foam solid). 1H NMR (CDCl3) δ (ppm): 8.08 (m, 1H), 7.97 (m, 1H), 7.46 (m, 2H), 6.35 (m, 1H), 5.04 (m, 1H), 4.31 (m, 1H), 3.68 (m,1H), 3.50 ( m, 2H), 3.27 (m, 2H), 1.35 (bs, 9H).
Reaction SMILES: [NH2:1][C@H:2]([C:7](=[O:9])[NH2:8])[CH2:3][C:4]([OH:6])=[O:5].O.C(=O)(O)[O-].[C:15](O)(=[O:26])[C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.Cl>COCCOC>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[C:15]([NH:1][C@H:2]([C:7](=[O:9])[NH2:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:26]
Reactant: NC(=O)[C@@H](N)CC(=O)O
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: COCCOC
Product: NC(=O)[C@H](CC(=O)O)NC(=O)c1ccc2ccccc2n1
Yield: 69.1 %

Procedure:
To a solution of 0.50 g (3.78 mmol) of L-isoasparagine in 5.0 mL H2O containing ~45 mg (1.5 eq) of solid bicarbonate. To this was added a suspension of 1.02 g (3.78 mmol) quinaldic acid, N-hydroxysuccinamide ester in ethylene glycol dimethylether, and the suspension was solubilized by the addition of 10 mL of dimethyfformamide. After 3 hours the solution was acidified by the addition of 5% HCl (aqueous) and the product was filtered and washed with water, dried under vacuum to yield 750 mg (70% yield) of N-(2-quinolinylcarbonyl)-L-isoasparagine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]#[N:7].[C:8](OC)(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[SH:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8](=[O:16])[N:7]=1
Reactant: N#Cc1nccs1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2nccs2)sc2ccccc12
Yield: 71.4 %

Procedure:
1,3-Thiazole-2-carbonitrile (0.32 g, 2.9 mmol) and methyl thiosalicylate (0.98 g, 5.8 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The reaction mixture was refluxed for 2 hrs. After cooling, the precipitates were collected by filtration and recrystallized from diisopropyl ether-ethanol to give the titled compound (0.51 g, 70%) as yellow crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH3:8])[CH:2]=1.Cl.[NH2:11][OH:12].C(=O)(O)[O-].[Na+]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[N:11][OH:12])[CH3:8])[CH:2]=1
Reactant: CC(=O)c1cccnc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=NO)c1cccnc1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
A mixture of 50 g (0.41 mol) of 1-(3-pyridinyl)ethanone and 29 g (0.42 mol) of hydroxylamine hydrochloride in 250 ml of methanol was heated under reflux for five hours. Upon cooling to room temperature, a white solid separated from the reaction mixture. This material was collected by filtration and the filtrate was concentrated to yield additional white solid. The combined solids were dissolved in water and the solution was made weakly basic by the addition of sodium bicarbonate solution while cooling. The white precipitate which formed was separated by filtration to yield 55.4 g of 1-(3-pyridinyl)ethanone oxime, mp 115°-117° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([C:11]#[C:12][CH2:13][OH:14])=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([C:11]#[C:12][CH2:13][O:14][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:8][C:6]=2[N:7]=1
Reactant: OCC#Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OCC#Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-prop-2-yn-1-ol (142 mg) in chloroform (10 ml) was added triethylamine (77 μL) and methanesulfonyl chloride (49 μL). Stir at room temperature for 2 hours then partition between chloroform and brine, the combined organics were dried (MgSO4). The solvents were removed in vacuo to yield methanesulfonic acid 3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-prop-2-ynyl ester (150 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2I)=[O:16])[CH2:4][O:3]1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.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>[CH3:1][C:2]1([CH3:25])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)=[O:16])[CH2:4][O:3]1
Reactant: OB(O)c1cccs1
Reactant: CC1(C)OC[C@H](NC(=O)Nc2ccccc2I)[C@H](c2ccccc2)O1
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: CCO
Solvent: COCCOC
Product: CC1(C)OC[C@H](NC(=O)Nc2ccccc2-c2cccs2)[C@H](c2ccccc2)O1
Temperature: 80 °C
Yield: 37.3 %

Procedure:
To a reaction flask charged with 10.6 mg (0.0092 mmol) of tetrakis(triphenylphosphine)palladium(0) in ethylene glycol dimethyl ether (1.8 mL) under nitrogen was added 104 mg (0.23 mmol) of the product from Example 6. The resulting yellow solution was stirred for 10-15 min before the addition of 34.5 mg (0.27 mmol) of 2-thiopheneboronic acid dissolved in ethanol (0.2 mL) and ethylene glycol dimethyl ether (0.2 mL) and the subsequent addition of 0.23 mL (0.46 mmol) of a 2 M sodium carbonate aqueous solution. The reaction mixture was heated at 80° C. for 24 h and then cooled to room temperature. The liquid was separated from the solid residue, and the residue was rinsed with dichloromethane, which was subsequently combined with the isolated liquid. The solvent was evaporated, and the crude product was partitioned between brine (˜4 mL) and dichloromethane (˜4 mL). The organic layer was washed with additional brine, dried over magnesium sulfate, and filtered. The solvent was evaporated, and the dark residue was purified by column chromatography (hexanes/ethyl acetate) to yield 35 mg (37%) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[N:26]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:25]=[CH:24]5)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:36]>CCOC(C)=O.O>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[N:26]([CH2:30][CH2:31][C:32]([O-:34])=[O:33])[CH:25]=[CH:24]5)[N:17]=3)[S:10][C:11]=2[C:12]([F:14])([F:15])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:36]
Reactant: O=C(O)CCn1ccc2cc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C([O-])CCn1ccc2cc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)ccc21

Procedure:
E1 (30 mg) was dissolved in EtOAc (1 ml), treated with 2M aqueous NaOH (40 ul), diluted with H2O (1 ml) and extracted with EtOAc (3×5 ml), using a small volume of brine during the third extraction to aid phase separation. The combined organics were evaporated to give the title compound (37 mg) as a green solid. δH (methanol-d4, 400 MHz): 2.68 (2H, t), 4.48 (2H, t), 6.55 (1H, d), 7.49 (1H, d), 7.45-7.56 (5H, m), 7.62 (1H, d), 7.92 (1H, d), 8.03 (1H, s), 8.35 (1H, s). MS (ES+): C24H16F3N3O3S requires 483; found 484 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[Cl:26][C:27]1[N:28]=[C:29]2[N:33]([C:34]=1[S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:31][S:30]2>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:35]([C:34]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[Cl:26])(=[O:36])=[O:37])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: O=S(=O)(Cl)c1c(Cl)nc2sccn12
Reactant: Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1)c1c(Cl)nc2sccn12
Yield: 64.1 %

Procedure:
The title compound was prepared using the method of example 94, starting with 3-chloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (92) (150 mg, 0.53 mmol), pyridine (Aldrich, 0.21 mL, 2.63 mmol) and 6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride (Maybridge, 149 mg, 0.58 mmol) in THF. 172 mg (65%) of 98 was obtained as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[N:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[P:17]([O:24][CH2:25][CH2:26][C:27]#[N:28])[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(Cl)Cl>[C:27]([CH2:26][CH2:25][O:24][P:17]([C:7]1[NH:6][N:5]=[C:4]([N+:1]([O-:3])=[O:2])[N:8]=1)[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)#[N:28]
Reactant: O=[N+]([O-])c1nc[nH]n1
Reactant: N#CCCOP(Cl)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCCOP(c1nc([N+](=O)[O-])n[nH]1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a stirred solution of 3-nitro-1,2,4-triazole (2.57 g, 22.57 mmol) and triethylamine (12.58 mL, 9.14 g, 90.28 mmol) in CH2Cl2 (40 mL) was added dropwise Chloro(2-Cyanoethoxy)morpholinophosphine (5.82 g, 22.57 mmol) at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was filtered to remove the resulting salt, and the solvent was removed under reduced pressure to give the crude product as a yellow oil (5.98 g, 79%). 31P NMR (CDCl3) δ 126.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:25][CH3:26])=[C:11]([CH:13]3[C:21](=[O:22])[CH:20]4[CH:15]([CH:16]5[O:23][CH:19]4[CH2:18][CH2:17]5)[C:14]3=[O:24])[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:25][CH3:26])=[C:11]([C:13]3[C:14](=[O:24])[CH:15]4[CH:20]([CH:19]5[O:23][CH:16]4[CH2:17][CH2:18]5)[C:21]=3[O:22][C:37]([CH:34]3[CH2:36][CH2:35]3)=[O:38])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: CCc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)C2C3CCC(O3)C2C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1sc(-c2ccc(Cl)cc2)nc1C1=C(OC(=O)C2CC2)C2C3CCC(O3)C2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 124.3 %

Procedure:
To a solution of 4-[2-(4-chloro-phenyl)-5-ethyl-thiazol-4-yl]-10-oxa-tricyclo[5.2.1.0*2,6*]decane-3,5-dione (100 mg, 0.18 mmol) in DCM (5 ml) and triethylamine (140 μl, 1 mmol) is added the cyclopropane carbonyl chloride (91 μl, 1 mmol) at room temperature. The reaction mixture is stirred overnight at room temperature. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give cyclopropanecarboxylic acid-4-[2-(4-chloro-phenyl)-5-ethyl-thiazol-4-yl]-5-oxo-10-oxa-tricyclo[5.2.1.0*2,6*]dec-3-en-3-yl ester (102 mg).