Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:49][NH:50][O:51][CH3:52].O>C(Cl)Cl>[C:17]([O:16][C:14](=[O:15])[NH:1][CH:2]([C:11](=[O:13])[N:50]([O:51][CH3:52])[CH3:49])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of Boc-Phe(4-F)-OH (5.0 g, 17.7 mmol) in methylene chloride (89 ml), BOP reagent (9.39 g, 21.2 mmol), N,O-dimethylhydroxylamine hydrochloride (2.07 g, 21.2 mmol) and TEA (5.92 ml, 42.5 mmol) were added under cooling with ice and stirred for 30 min. The reaction mixture was mixed with water and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1), giving the titled compound (5.76 g, 100%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4]1.C(N(CC)CC)C.[C:23](=[S:25])=[S:24].[CH:26]([NH:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1)=[O:27]>CN(C)C=O.CS(C)=O>[OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][N:4]1[C:23]([S:25][CH2:33][C:32]1[CH:35]=[CH:36][C:29]([NH:28][CH:26]=[O:27])=[CH:30][CH:31]=1)=[S:24]
Reactant: OC[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: S=C=S
Reactant: O=CNc1ccc(CCl)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=CNc1ccc(CSC(=S)N2Cc3[nH]c4ccccc4c3C[C@H]2CO)cc1
Yield: 58 %

Procedure:
In the same manner as described in Example 29 by using (3S)-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (1.21 g), triethylamine (0.84 ml), CS2 (0.36 ml), 4-(N-formylamino)benzyl chloride (1.02 g) and dimethylsulfoxide (30 ml), there is prepared the title compound (1.43 g, 58%) as pale yellow powder, [α]D20 +120.2° (c=1.0, dimethylformamide); NMR (DMSO-d6, δ): 4.54 (s, 2H, ##STR12## Mass m/e: 244 (M+ -- ##STR13##
Reaction SMILES: O1CC=CC(=O)C1.C(N(CC)CC)C.CC(C)(O)C#N.[CH3:21][C:22]1([CH3:44])[O:27][C:26]([CH3:29])([CH3:28])[C:25](=O)[CH:24]([C:31](=[O:42])[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[N+:39]([O-:41])=[O:40])[C:23]1=O>C(#N)C.CCOCC>[CH3:21][C:22]1([CH3:44])[CH2:23][C:24]([C:31](=[O:42])[C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[N+:39]([O-:41])=[O:40])=[CH:25][C:26]([CH3:29])([CH3:28])[O:27]1
Reactant: CC1(C)OC(C)(C)C(=O)C(C(=O)c2ccc(Cl)cc2[N+](=O)[O-])C1=O
Agent: CC(C)(O)C#N
Agent: O=C1C=CCOC1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOCC
Product: CC1(C)C=C(C(=O)c2ccc(Cl)cc2[N+](=O)[O-])CC(C)(C)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 2,2,6,6.tetramethyl.5.(4.chloro.2.nitrobenzoyloxy)-3,6-dihydro-2H-pyran-3-one (5.97 g, 16.9 mmol) and triethylamine (4,70 ml, 33.8 mmol) in 30 ml of acetonitrile is added acetone cyanohydrin (0.5 ml), and the mixture is stirred at RT for 24 hours. The reaction mixture is diluted with ether and extracted with aqueous 5% K2CO3. The aqueous layer is made acidic with conc. HCl and extracted with ether. The combined organic layers are dried and evaporated to give light yellow crystals, which are purified to yield 2,2,6,6.tetramethyl-4-(4-chloro-2-nitrobenzoyl) -2H-pyran-3,5-(4H,6H)-dione (compound 8, Table A).
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][O:23][CH2:22][CH2:21][O:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.FC(F)(F)C(O)=O.[CH3:35][O:36][CH2:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:8]([N:41]3[CH2:42][CH2:43][CH:38]([CH2:37][O:36][CH3:35])[CH2:39][CH2:40]3)=[O:27])=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: COCC1CCNCC1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCC1CCN(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)CC1

Procedure:
From (+)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester with 4-methoxymethyl-piperidine trifluoroacetate and N-ethyldiisopropylamine in chloroform. [α]D20=+23.0° (c=1.04, CHCl3), ES-MS m/e (%): 422 (M+H+, 100).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[CH2:8]([C:10]1[S:14][C:13](C=O)=[CH:12][CH:11]=1)[CH3:9].N1CCCCC1.Cl>N1C=CC=CC=1.O>[CH2:8]([C:10]1[S:14][C:13](/[CH:1]=[CH:2]/[C:3]([OH:5])=[O:4])=[CH:12][CH:11]=1)[CH3:9]
Reactant: CCc1ccc(C=O)s1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCc1ccc(/C=C/C(=O)O)s1
Temperature: 80 °C
Reaction time: 17 h
Yield: 96.2 %

Procedure:
To a solution of malonic acid (5.9 g) and 5-ethyl-2-thiophenecarboxaldehyde (4.0 g) in dry pyridine (12 mL) was added piperidine (0.42 mL). The reaction mixture was stirred at 80° C. for 17 hours, chilled and diluted with water (70 mL). This mixture was acidified with concentrated HCl (14 mL) and the white precipitate was collected by filtration, washed with water (5×10 mL) and dried under vacuum giving (2E)-3-(5-ethyl(2-thienyl))prop-2-enoic acid (5.0 g). Yield=96%
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11](=O)[CH:12]=[CH:13][N:14]([CH3:16])C)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].N[C:19]1[C:23]([C:24]#[N:25])=C[NH:21][N:20]=1.C(N)(=O)C.C([BH3-])#N.[Na+]>C(O)(=O)C>[C:24]([C:23]1[CH:19]=[N:20][N:21]2[C:11]([C:7]3[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][CH:8]=3)=[CH:12][CH2:13][NH:14][C:16]=12)#[N:25]
Reactant: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Reactant: N#Cc1c[nH]nc1N
Agent: CC(N)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(C2=CCNc3c(C#N)cnn32)c1

Procedure:
A mixture of 7.0 g of 3'-actamido-3-(N,N-dimethylamino)acrylophenone and 3.3 g. of 3-amino-4-cyanopyrazole in 100 ml of acetic acid was heated at reflux for 8 hours. Crystals that formed on cooling were filtered and dried to give 7.4 g. of N-[3-(3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl)phenyl[acetamide, m.p. 254°-256° C. This was reacted with 14.8 g of sodium cyanoborohydride in 50 ml of acetic acid to give 3.0 g of N-[3-(3-cyano-4,5-dihydropyrazolo[1,5-a]pyrimidin-7-yl)phenyl]acetamide, m.p. 251°-254° C. This is reacted with chloroacetic anhydride and sodium carbonate in toluene as in Example 3 to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[N:5]=[CH:4][N:3]1[CH2:21][C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28]C(C)(C)C)=O)=[CH:24][CH:23]=1.C(Cl)(=O)C(Cl)=O.[NH3:41]>ClCCl.CN(C=O)C.O1CCOCC1>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)[N:5]=[CH:4][N:3]1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH2:41])=[O:28])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2cnc3ccc(C#CCc4ccccc4)cc3c2=O)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cn2cnc3ccc(C#CCc4ccccc4)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.1 g (0.254 mmol) of the compound of Example 18 is suspended in 50 ml of dichloromethane. 35.4 mg of oxalyl chloride (0.279 mmol) is added, followed by 1 drop of DMF. The reaction is refluxed under nitrogen for 2 hours, and stirred at room temperature for an additional 12 hours. Then an excess amount of 0.5 M ammonia in dioxane is added. The reaction is stirred at room temperature for 1 hour. The solvent is then removed in vacuum and the residue is washed with 1:1 water:methanol to yield 70 mg of an off-white powder as the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:24](O)([CH3:26])[CH3:25])[N:9]=2)=[CH:4][CH2:3]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:24]([CH3:26])([N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)[CH3:25])[N:9]=2)=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2nc(C(C)(C)O)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Reactant: CN1CCNCC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN1CCN(C(C)(C)c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCC(C)(C)CC3)n2)CC1

Procedure:
The title compound is prepared from 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-6-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-amide (as prepared in Example 56, step (e)), N-methylpiperizine and thionyl chloride in DCM solvent according to the procedure in Example 14, step (e).
Reaction SMILES: [CH:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)=[CH2:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.CN(C)C=O>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:16]2[CH:15]=[CH:14][C:13]([CH:2]=[CH:1][C:3]3([OH:11])[CH:8]4[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]4)[CH2:4]3)=[CH:18][CH:17]=2)[CH:20]=1
Reactant: C=CC1(O)CN2CCC1CC2
Reactant: Brc1ccc(-c2cccnc2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: OC1(C=Cc2ccc(-c3cccnc3)cc2)CN2CCC1CC2
Temperature: 130 °C
Reaction time: 4 h
Yield: 29.7 %

Procedure:
A mixture of 3-ethenyl-3-hydroxyquinuclidine (673 mg), 3-(4-bromophenyl)pyridine (1.08 g), bis-(triphenylphosphine)-palladium (II) chloride (140 mg), copper (I) iodide (70 mg), and dimethylformamide (10 ml) was stirred at 130° C. under an atmosphere of argon for 4 hours. The mixture was evaporated and the residue was paritioned between aqueous 2M sodium hydroxide solution (10 ml) and dichloromethane (10 ml). The organic layer was separated, washed with dichloromethane (2×10 ml), dried (MgSO4) and evaporated. The residue was crystallised from acetonitrile to give 3-[2-(4-[3-pyridyl]phenyl)ethenyl]-3-hydroxyquinuclidine (400 mg) as a solid, m.p. 195°-198° C.; microanalysis, found: C, 76.4; H, 7.2; N, 8.6%; C20H22N2O.0.5H2O requires: C, 76.2; H, 7.3; N, 8.9%; NMR (DMSO-d6 +CD3COOD): 1.7-2.15(4H, m), 2.35(1H, m), 3.15-3.4(5H, m), 3.5(1H, d), 6.7(1H, d), 6.9(1H, d), 7.5-7.8(7H, m), 8.15(1H, d); m/Z 307 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:12]([C:13]([N:15]3[CH2:20][CH2:19][C:18]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)([CH2:21][N:22]4[C:26]([CH3:28])([CH3:27])[CH2:25][O:24][C:23]4=[O:29])[CH2:17][CH2:16]3)=[O:14])[CH2:11][C@@H:10]([N:36]([CH3:52])S(C3C=CC([N+]([O-])=O)=CC=3[N+]([O-])=O)(=O)=O)[CH2:9]2)=[CH:4][CH:3]=1.C(N)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:9][C@H:10]([NH:36][CH3:52])[CH2:11][C@H:12]2[C:13]([N:15]2[CH2:20][CH2:19][C:18]([CH2:21][N:22]3[C:26]([CH3:27])([CH3:28])[CH2:25][O:24][C:23]3=[O:29])([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[CH2:17][CH2:16]2)=[O:14])=[CH:4][CH:3]=1
Reactant: CN([C@@H]1C[C@@H](C(=O)N2CCC(CN3C(=O)OCC3(C)C)(C3CCCCC3)CC2)[C@H](c2ccc(Cl)cc2)C1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCCN
Product: CN[C@@H]1C[C@@H](C(=O)N2CCC(CN3C(=O)OCC3(C)C)(C3CCCCC3)CC2)[C@H](c2ccc(Cl)cc2)C1
Temperature: 25 °C
Yield: 31.4 %

Procedure:
A 10 mL round bottom flask equipped with a magnetic stir bar was charged with 0.184 g (0.24 mmol) of the product of Step G dissolved in 2 mL of methylene chloride and the reaction mixture was stirred at room temperature. Propylamine (50 μL, 0.49 mmol) was added via syringe and the reaction mixture developed an intense yellow color. Stirring was continued an additional 15 min, at which point TLC analysis (75% ethyl acetate-hexanes) revealed complete reaction of the starting material. The reaction mixture was concentrated in vacuo, and the residue was applied to two 1000 micron preparative TLC plates. Elution of the plates with a mixture of methylene chloride-methanol-14.8 N aqueous ammonium hydroxide (90:9:1) followed by recovery of the product band from the silica gel afforded 0.040 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][C:14]=3[Cl:22])[C:9]([CH3:11])=[N:10][C:5]2=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:29](I)([CH3:31])[CH3:30].O>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([O:21][CH:29]([CH3:31])[CH3:30])=[O:20])=[CH:15][C:14]=3[Cl:22])[C:9]([CH3:11])=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1nc2ccc(Br)nc2n1Cc1ccc(C(=O)O)cc1Cl
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccc(Br)nc2n1Cc1ccc(C(=O)OC(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.7 %

Procedure:
To a solution of 5-bromo-3-(2-chloro-4-carboxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (400 mg) in N,N-dimethylformamide (4 ml) were successively added potassium carbonate (218 mg) and isopropyl iodide (197 mg), and the mixture was stirred at room temperature for 24 hr. Water and ethyl acetate were added for partitioning. The organic layer was successively washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Hexane was added to the residue and the mixture was heated and allowed to cool. The precipitated crystals were collected by filtration. The crystals were dried under reduced pressure and by heating to give the objective compound (394 mg) as gray-brown crystals.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH3:14])[N:8]=1.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18].O>CCCCC.C(OCC)C>[CH2:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH3:18])[N:8]=1)[CH3:14]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCc1cccc(Br)n1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Solvent: CCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(CC)n1
Temperature: 25 °C
Yield: 94 %

Procedure:
Add under nitrogen a solution of tert-butyllithium in pentane (1.5; M, 80.3; mL, 120.5; mmol) dropwise over 1; hour to a cooled solution of 2-bromo-6-ethyl-pyridine (10.19; g, 54.77; mmol) in anhydrous diethyl ether (101.9; mL) at −78° C. at a rate so that the internal reaction temperature does not exceed −75° C. Stir 15; min and add tri-n-butyltin chloride (16.25; mL, 57.51; mmol) dropwise at a rate so that the internal reaction temperature does not exceed −70° C. Warm to room temperature, add water and separate the layers. Extract the aqueous phase once with diethyl ether. Dry the combined organic layers over sodium sulfate, filter and concentrate to give the title compound as a pale yellow liquid (24.05; g, 94%) that is subsequently used without further purification. 1H NMR (CDCl3) δ 0.88; (t, 9H), 1.09; (m, 6H), 1.32; (m, 9H), 1.56; (m, 6H), 1.57; (m, 6H), 2.80; (q, 2H), 6.95; (m, 1H), 7.17; (d, 1H), 7.38; (t, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C:11]3([NH:19][C:18](=[O:20])[C:17]4[CH:21]=[C:22](/[CH:25]=[CH:26]/[C:27]([NH:29][O:30]C5CCCCO5)=[O:28])[CH:23]=[CH:24][C:16]=4[O:15]3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(N1CCCC2(NC(=O)C3C=C(/C=C/C(O)=O)C=CC=3O2)C1)C1C=CC=CC=1>C(Cl)Cl.O1CCOCC1>[C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C:11]3([NH:19][C:18](=[O:20])[C:17]4[CH:21]=[C:22](/[CH:25]=[CH:26]/[C:27]([NH:29][OH:30])=[O:28])[CH:23]=[CH:24][C:16]=4[O:15]3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(CCc3ccccc3)C1)O2)NOC1CCCCO1
Agent: Cl
Agent: O=C(O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3ccccc3)C1)O2
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(CCc3ccccc3)C1)O2)NO
Yield: 73.6 %

Procedure:
(±)-(E)-3-{1′-(2-Phenyl-ethyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (150 mg, 0.30 mmol) in DCM (5 ml) was treated with 4 M HCl in dioxane (1 ml) as described in Example 30, STEP C to give (±)-(E)-3-{1′-(2-phenyl-ethyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-hydroxy-acrylamide (90 mg) as a pale yellow solid (hydrochloride salt).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[CH2:13]([N:20]1[C:25](=[O:26])[C:24]([O:27][CH3:28])=[C:23](Br)[CH:22]=[N:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[C:25](=[O:26])[C:24]([O:27][CH3:28])=[C:23]([C:4]2[CH:5]=[CH:6][C:7]([S:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[CH:22]=[N:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1c(Br)cnn(Cc2ccccc2)c1=O
Reactant: CSc1ccc(B(O)O)cc1F
Product: COc1c(-c2ccc(SC)c(F)c2)cnn(Cc2ccccc2)c1=O
Yield: 91 %

Procedure:
3-Fluoro-4-(methylthio)benzeneboronic acid and 2-benzyl-4-methoxy-5-bromo-3(2H)-pyridazinone were coupled according to the method of Example 83C to provide 2-benzyl-4-methoxy-5-[3-fluoro-4-(methylthio)phenyl]-3(2H)-pyridazinone as a yellow solid (yield: 4.98 g, 91%). 1H NMR (300 MHz, CDCl3) ? 7.76 (s, 1H), 7.47 (m, 2H), 7.39–7.21 (m, 7H), 5.34 (s, 2H), 4.13 (s, 3H), 2.51 (s, 3H). MS (DCI/NH3) m/z 357 (M+H)+, m/z 374 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].FC(F)(F)C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:30]([N:37]1[CH2:42][CH2:41][CH:40](O)[CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH:40]1[CH2:39][CH2:38][N:37]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:42][CH2:41]1)=[O:5]
Reactant: Nc1ncccc1C(=O)O
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Nc1ncccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
0.14 g (0.00101 mol) of 2-amino-nicotinic acid was suspended in 50 ml of THF and treated with 0.077 ml (0.00101 mol) of trifluoroacetic acid. The mixture was stirred at room temperature for 1 hr., whereby a solution resulted. To this was added 0.25 g (0.0015 mol) of carbonyidiimidazole and the mixture was stirred at room temperature for 2 hrs. Subsequently, 0.34 g (0.00178 mol) of 1-benyl-4-hydroxy-piperidine was added and the mixture was stirred at 60° for 72 hrs. After removing the solvent the residue was chromato-graphed over silica gel with ethyl acetate/hexane (1:1) as the eluent. 0.105 g (31%) of 1-benzyl-piperidin-4-yl 2-amino-nicotinate was obtained as white crystals. MS: me/e (% basic peak)=311 (C18H21N3O2+, 7.5), 173 (42), 91 (100), 82 (86).
Reaction SMILES: C[N:2](C)C=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:15](=[O:22])[C@@H:14]([CH2:23][C:24]([OH:26])=O)[O:13][C@H:12]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=3[O:35][CH3:36])[C:11]=2[CH:37]=1.[Cl-].[NH4+].C(OP(C#N)(=O)OCC)C>C(N(CC)CC)C>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]([CH2:17][C:18]([CH3:19])([CH3:21])[CH3:20])[C:15](=[O:22])[C@@H:14]([CH2:23][C:24]([NH2:2])=[O:26])[O:13][C@H:12]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[C:28]=3[O:35][CH3:36])[C:11]=2[CH:37]=1
Reactant: COc1cccc([C@H]2O[C@H](CC(=O)O)C(=O)N(CC(C)(C)C)c3ccc(Cl)cc32)c1OC
Reactant: CN(C)C=O
Agent: CCOP(=O)(C#N)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Product: COc1cccc([C@H]2O[C@H](CC(N)=O)C(=O)N(CC(C)(C)C)c3ccc(Cl)cc32)c1OC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A dimethylformamide solution of (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2, 3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid (2.0 g), ammonium chloride (1.2 g) and triethylamine (1.0 ml) was cooled in ice bath. To the solution were added diethylcyanophosphonate (0.85 g) and triethylamine (0.5 ml). The mixture was stirred for further 20 minutes, to which was added ice-water, followed by extraction with ethyl acetate. The organic layer was washed with water, which was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from diethyl ether to give 1.0 g of (3R,5S)-7-chloro-5-(2, 3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide as colorless crystals, m.p. 170-172° C.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][CH2:5][NH:6][C:7]([C@H:9]1[O:13][C@@H:12]([N:14]2[C:18]3[N:19]=[C:20]([C:24]#[C:25][CH2:26][CH:27]4[CH2:32][CH2:31][CH:30]([C:33](OC)=[O:34])[CH2:29][CH2:28]4)[N:21]=[C:22]([NH2:23])[C:17]=3[N:16]=[CH:15]2)[C@H:11]([OH:37])[C@@H:10]1[OH:38])=[O:8]>>[CH2:5]([NH:6][C:7]([CH:9]1[CH:10]([OH:38])[CH:11]([OH:37])[CH:12]([N:14]2[CH:15]=[N:16][C:17]3[C:18]2=[N:19][C:20]([C:24]#[C:25][CH2:26][CH:27]2[CH2:32][CH2:31][CH:30]([C:33](=[O:34])[NH:3][CH2:1][CH3:2])[CH2:29][CH2:28]2)=[N:21][C:22]=3[NH2:23])[O:13]1)=[O:8])[CH3:4]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)nc(C#CCC4CCC(C(=O)OC)CC4)nc32)[C@H](O)[C@@H]1O
Reactant: CCN
Product: CCNC(=O)C1CCC(CC#Cc2nc(N)c3ncn(C4OC(C(=O)NCC)C(O)C4O)c3n2)CC1
Temperature: 60 °C
Reaction time: 80 h
Yield: 73 %

Procedure:
To a sealed tube containing 5 mL of freshly distilled ethylamine was added 10 mg (0.02 mmol) of ATL146e. The flask was sealed and allowed to stir at 60° C. for 80 hours. After this time the reaction was only about 50% complete by HPLC. The vessel was cooled to 0° C., opened, and the ethylamine was removed in vacuo to yield 4.5 mg (73%) of JR3037 as a white solid and the recovery of 4.0 mg of starting material after the residue was purified by RP-HPLC. 1H NMR (CD3OD-d4) δ. 13C NMR (CD3OD-d4) δ. APCI m/z (rel intensity) 500.8 (MH+, 100), 327.4 (3).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH:15]1[CH:19]=[CH:18][CH:17]=[N:16]1>>[N:15]1([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=2[C:11]([F:14])([F:13])[F:12])[CH:19]=[CH:18][CH:17]=[N:16]1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: c1cn[nH]c1
Product: Nc1ccc(-n2cccn2)c(C(F)(F)F)c1

Procedure:
The title compound is obtained in a similar manner as Example 71a using 1-fluoro-4-nitro-2-trifluoromethyl-benzene (Aldrich, Buchs, Switzerland) and pyrazole (Fluka, Buchs, Switzerland). Title compound: ES-MS: 228 (M+H)+; analytical HPLC: tret=4.58 minutes (Grad 2).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:4]=1[Cl:11].[NH2:12][C:13]1[N:18]=[C:17]([SH:19])[N:16]=[C:15]([OH:20])[CH:14]=1.C(N(CC)CC)C>C(O)C>[NH2:12][C:13]1[N:18]=[C:17]([S:19][CH2:2][C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([Cl:10])[C:8]=2[Cl:9])[N:16]=[C:15]([OH:20])[CH:14]=1
Reactant: Nc1cc(O)nc(S)n1
Reactant: Clc1ccc(Cl)c(CBr)c1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1cc(O)nc(SCc2c(Cl)ccc(Cl)c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
A mixture of 2-(bromomethyl)-1,3,4-trichlorobenzene (580 mg, 2.1 mmol), 6-amino-2-sulfanylpyrimidin-4-ol (290 mg, 1.8 mmol), and triethylamine (280 μL, 2.0 mmol) in absolute ethanol (10 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The solid product was suspended in water (50 mL). The solid material was recovered by filtration, washed with water (1×20 mL) and diethyl ether (2×20 mL), and dried in vacuo, affording the title compound (325 mg, 54% yield); 1H NMR (400 MHz, DMSO-d6): δ 4.64 (s, 2H), 5.03 (s, 1H), 6.57 (s (br), 2H), 7.54 (d, 1H, J=8.8 Hz), 7.64 (d, 1H, J=8.8 Hz); M+ 337; HPLC purity: 95.5%.