Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:5]([CH2:19][C:20]([OH:22])=[O:21])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:7])[CH:2]([CH3:4])[CH3:3].[CH2:23]=[C:24]([CH3:26])[CH3:25].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C(OCC)C.O>[CH2:1]([C@H:5]([CH2:19][C:20]([O:22][C:24]([CH3:26])([CH3:25])[CH3:23])=[O:21])[C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C[C@H](CC(=O)O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)C[C@H](CC(=O)OC(C)(C)C)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77 %

Procedure:
9.4 g of 1-(4-nitrobenzyl) hydrogen 2(R)-isobutylsuccinate were dissolved in 30 ml of dry diethyl ether and the solution was cooled in a dry-ice/acetone bath. There were then added 70 ml of isobutene, followed dropwise by 0.64 ml of concentrated sulfuric acid. The reaction flask was tightly topped and the mixture was stirred at room temperature for 2 days. The mixture was made basic with saturated sodium hydrogen carbonate solution and water was added. The organic phase was separated and the aqueous phase was extracted twice more with diethyl ether. The combined ethereal phases were washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to give 8.8 g (77%) of 4-tert.butyl 1-(4nitrobenzyl) 2(R)-isobutylsuccinate in the form of an oil. Rf (System A) 0.87.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)#[N:8]>O1CCCC1>[C:18]1([CH2:17][N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([CH2:7][NH2:8])=[CH:10][CH:11]=2)[CH3:24])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CN(Cc1ccccc1)Cc1ccc(C#N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)Cc1ccc(CN)cc1

Procedure:
To a suspension of 1.9 g (0.05 Mol) of lithium aluminium hydride in 70 ml of anhydrous tetrahydrofuran was added dropwise, at ambient temperature, a solution of 12.1 g (0.051 Mol) of 4-cyano-N-methyl-N-(phenylmethyl)benzenemethanamine in 30 ml of dry tetrahydrofuran and the mixture was then heated to 60° C. for 3 hours and refluxed for 2 hours. A further 0.5 g of lithium aluminium hydride were added and the mixture was refluxed for another 3 hours. After working up in the usual way and purification by column chromatography (Baker; 0.03-0.06 mm; dichloromethane/methanol/cyclohexane/conc. aqueous ammonia=68/15/15/2 (v/v/v/v)) 10.2 g (83% of theory) of a colourless oil were obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[CH3:11][N+:12]([CH3:14])=[CH2:13].[I-]>C1COCC1.CCOC(C)=O>[CH3:11][N:12]([CH2:14][C:8]1[N:6]2[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:13]
Reactant: Ic1ccc2nccn2c1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)Cc1cnc2ccc(I)cn12
Yield: 135.3 %

Procedure:
A stirred solution of 6-iodoimidazo[1,2-a]pyridine (2.0 g, 8.2 mmol) and Eschenmoser's salt (5.0 g, 2.7 mmol) in THF (50 mL) was heated to reflux for 24 h. The reaction mixture was then diluted with EtOAc (50 mL), washed with water (3×20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residual solid was triturated from Et2O, collected by filtration and dried to give the title compound (1.1 g, 45%) as a brown powder. δH (DMSO-d6) 8.67 (1H, m), 7.45 (1H, s), 7.43-7.41 (2H, m), 3.72 (2H, s), 2.14 (6H, s). LCMS (ES+) 302.2 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6](O)[CH2:5][C:4]1=[O:55])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]=[CH:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C=CC1=O)C(C)CC2OC
Yield: 87.7 %

Procedure:
A solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (210 mg) and a catalytic amount of p-toluenesulfonic acid in 40 ml of dry benzene was refluxed for 4 h under nitrogen atmosphere. The solvent was removed under reduced pressure and the dark brown residue was purified by column chromatography on silica gel (7% i-PrOH/CH2Cl2) to give 17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-14,18-diene-2,3,10,16-tetraone (180 mg) as a white solid. This material was dissolved in ethanol (20 ml) and treated with 5% Rh/C (40 mg). Hydrogen was introduced via balloon for 30 min and the mixture was filtered through celite. Removal of the solvent followed by column chromatography on silica gave 172 mg of the title compound (Mass, 1H and 13C NMR data were consistent with the desired structure).
Reaction SMILES: C(O[C@@H:5]([CH2:8][CH2:9][C@H:10]([OH:23])[CH2:11][O:12]S(C1C=CC(C)=CC=1)(=O)=O)[C:6]#[CH:7])(=O)C.C([O-])([O-])=O.[K+].[K+].[NH4+].[Cl-]>CO>[C:6]([C@H:5]1[O:23][C@H:10]([CH2:11][OH:12])[CH2:9][CH2:8]1)#[CH:7]
Reactant: C#C[C@H](CC[C@H](O)COS(=O)(=O)c1ccc(C)cc1)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: C#C[C@@H]1CC[C@@H](CO)O1
Reaction time: 3 h
Yield: 99.2 %

Procedure:
A solution of (3S,6S)-3-acetoxy-6-hydroxy-7-p-toluene sulfonyloxy-hept-1-yne 15 (3.67 g, 10.79 mmol) in MeOH (50 mL) at room temperature, was treated with K2CO3 (3.2 g, 23.7 mmol) and stirred for 3 h. It was further treated with NH4Cl solution, evaporated MeOH and residue extracted with EtOAc (3×50 mL). Organic layer was washed with water (2×25 mL), brine (25 mL), dried (Na2SO4), and evaporated. The residue obtained was purified by column chromatography (Si-gel, 20% EtOAc-hexane) to afford (2S,55)-5-ethynyl-2-(hydroxymethyl)-tetrahydrofuran 16 (1.35 g) in 90% yield as a colorless liquid. [α]D−15.07 (c 1.26, CHCl3); 1HNMR (CDCl3, 200 MHz): δ1.9-2.38 (m, 4H, H-3,4), 2.45 (d, 1H, J 2.1 Hz, H-7), 3.55 (dd, 1H, J 6.3, 12.75 Hz, H-1), 3.72 (dd, 1H, J 3.8, 12.75 Hz, H-1a), 4.0-4.18 (m, 1H, H-2), 4.55-4.65 (m, 1H, H-5); 13CNMR (CDCl3, 50 MHz): δ26.6, 29.64, 64.62, 68.33, 73.11, 80.7, 83.92.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:12]([N+:17]([O-])=O)[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:28][CH3:29])=[C:5]([CH3:30])[O:4][N:3]=1>C(OCC)(=O)C.CO.[Pd].O.CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH2:21][CH:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:28][CH3:29])=[C:5]([CH3:30])[O:4][N:3]=1
Reactant: COc1cc2c(NCC3CCOCC3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2c(NCC3CCOCC3)c(N)cnc2cc1-c1c(C)noc1C
Yield: 40.4 %

Procedure:
7-(3,5-Dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)quinolin-4-amine (for a preparation see Intermediate 16) (1.2 g, 2.91 mmol) was dissolved in a mixture of ethyl acetate (60 ml) and methanol (10 ml) and hydrogenated over Pd/C (0.310 g, 2.91 mmol, 5% w/w, 50% water, Type E101 NO/W) for 24 h at atmospheric pressure under a hydrogen burette. The mixture was filtered and evaporated and the residue was dissolved in DCM (3 ml) and loaded onto a 50 g silica column, then eluted with 0-15% 2M methanolic ammonia/DCM and product containing fractions evaporated in vacuo to give 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-((tetrahydro-2H-pyran-4-yl)methyl)quinoline-3,4-diamine (0.45 g, 1.177 mmol, 40.4% yield) as a pale yellow solid. LCMS (formate) Rt 0.68 min, MH+ 384
Reaction SMILES: Cl[C:2]1[C:3]([CH3:11])=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.CN(C=[N:16][S:17]([CH2:20][CH2:21][CH2:22][C:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][OH:25])(=[O:19])=[O:18])C>>[CH2:28]([C:23]([CH2:26][CH3:27])([CH2:22][CH2:21][CH2:20][S:17](=[O:19])(=[O:18])[NH2:16])[CH2:24][O:25][C:2]1[C:3]([CH3:11])=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1)[CH3:29]
Reactant: CCC(CC)(CO)CCCS(=O)(=O)N=CN(C)C
Reactant: Cc1cc2nccn2nc1Cl
Product: CCC(CC)(CCCS(N)(=O)=O)COc1nn2ccnc2cc1C

Procedure:
Using 0.8 g of 6-chloro-7-methylimidazo[1,2-b]pyridazine and 1.52 g of 5-(N,N-dimethylaminomethylene)aminosulfonyl-2,2-diethyl-1-pentanol, 0.84 gof the title compound was obtained in the same manner as in Example 14.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][C:6]=1OS(C(F)(F)F)(=O)=O)=[O:4].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][SH:34])=[CH:29][CH:28]=1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>O1CCOCC1.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(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][C:6]=1[S:34][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=1)=[O:4]
Reactant: COc1ccc(CS)cc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)cnc2ccc(OC)cc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1c(SCc2ccc(OC)cc2)cnc2ccc(OC)cc12
Yield: 88.4 %

Procedure:
A mixture of 6-methoxy-3-trifluoromethanesulfonyloxy-quinoline-4-carboxylic acid methyl ester (3.69 g, 10.10 mmol, 1.0 eq), (4-methoxy-phenyl)-methanethiol (3.43 g, 22.22 mmol, 2.2 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (409 mg, 0.71 mmol, 0.07 eq), tris(dibenzylideneacetone)dipalladium(0) (925 mg, 1.01 mmol, 0.1 eq) and N,N-diisopropylethylamine (3.46 mL, 20.20 mmol, 2.0 eq) in dioxane (40 mL) is heated under reflux for 16 hours, then filtered through decalite and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford 6-methoxy-3-(4-methoxy-benzylsulfanyl)-quinoline-4-carboxylic acid methyl ester as an off-white solid (3.30 g, 88% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.C1(CN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CCC1.[NH2:43][CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1>>[CH:2]1([CH2:1][N:8]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][C:15]([C:19]([NH:43][CH2:44][C:45]4[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[C:9]2=[O:22])[CH2:7][CH2:6][CH2:5]1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(CC3CCC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CC3CCC3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 32 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(cyclobutylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 32% yield: mp 136-137° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.53-8.41 (m, 2H), 7.63-7.61 (m, 1H), 7.20-7.16 (m, 1H), 6.51-6.17 (m, 1H), 4.60-4.46 (m, 2H), 4.08-3.93 (m, 2H), 3.53-3.41 (m, 2H), 3.39-3.20 (m, 2H), 2.60-2.45 (m, 4H), 2.03-1.98 (m, 2H), 1.88-1.79 (m 2H), 1.74-1.65 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.7, 157.5, 155.5, 153.5, 149.2, 148.7, 135.5, 134.0, 123.5, 116.7, 49.3, 42.5, 42.0, 41.3, 33.7, 26.2, 18.3, 17.2; MS (ES+) m/z 386.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:13](=[O:14])[CH:12](C(OC)=O)[C:11](=[O:19])[C:10]3([CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[CH2:9]2)=[CH:5][CH:4]=1.O>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13](=[O:14])[CH2:12][C:11](=[O:19])[C:10]3([CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH2:20]3)[CH2:9]2)=[CH:32][CH:33]=1
Reactant: COC(=O)C1C(=O)N(Cc2ccc(OC)cc2)CC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Solvent: O
Solvent: CC#N
Product: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)C(=O)CC2=O)cc1

Procedure:
Crude product A3 was dissolved in acetonitrile (50 mL) and water (50 mL) and stirred for 4 h at 80° C. The acetonitrile was evaporated off and the solids were filtered off, washed with water and taken up in DCM. The organic phase was dried over Na2SO4 and concentrated in vacuo. The product A4 (1.57 g) was obtained as a white solid. Overall yields (A2 to A4) are 70%. 1H NMR (400 MHz, CDCl3, 300K): δ=1.23 (2H, m), 1.41 (9H, s), 1.76 (2H, m), 3.13 (2H, m), 3.26 (2H, s), 3.37 (2H, m), 3.39 (2H, s), 3.81 (3H, s), 4.58 (2H, s), 6.87 (2H, d, J=8.6 Hz), 7.22 (d, J=8.6 Hz). 13C NMR (100 MHz, CDCl3, 300K): δ=28.8, 30.0, 46.3, 47.1, 49.8, 51.7, 55.7, 80.2, 114.6, 128.4, 130.5, 154.9, 159.8, 166.4, 206.8. MS (ES) C22H30N2O5 requires: 402. found: 425.2 [M+Na]+.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1.[Li+].CC([N-]C(C)C)C.[CH:29](=[O:36])[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C(O)(=O)C>C1COCC1.CO.CCOC(C)=O>[F:13][C:14]1[C:19]([CH:29]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[OH:36])=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1
Reactant: O=Cc1ccncc1
Reactant: Fc1cccc(F)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CO
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: OC(c1ccncc1)c1ccc(F)nc1F
Temperature: 25 °C

Procedure:
To diisopropylamine (9.3 mL, 66.1 mmol) in THF (100 mL) at −78° C. was added n-BuLi (23.1 mL of a 2.5 M solution in hexanes, 57.8 mmol) dropwise via syringe. 2,6-difluoropyridine (5.0 mL, 55.1 mmol) in THF (100 mL) at −78° C. was added to the above prepared LDA solution dropwise via canula to give a clear yellow-green solution. isonicotinaldehyde (6.3 mL, 66.1 mmol) was added causing a white precipitate to form. The reaction mixture was warmed to room temperature and then glacial acetic acid (3.3 mL, 57.8 mmol) was added. Silica gel was added and the volatiles removed on a rotary evaporator. Flash chromatography (80-100% EtOAc/hexanes-3-5-7% MeOH/EtOAc) gave 8.48 g (69%) of as an off white solid. Rf=0.38 (5% MeOH/EtOAc); MS m/z 223 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 5.91 (d, J=4.41 Hz, 1 H) 6.49 (d, J=4.41 Hz, 1 H) 7.20 (dd, J=8.31, 2.54 Hz, 1 H) 7.36 (m, 2 H) 8.19 (m, 1 H) 8.53 (m, 2 H); Found: 223, 221; Anal calcd for C11H8F2N2O: C, 59.46; H, 3.63; N, 12.61. Found: C, 59.45; H, 3.66; N, 12.62.
Reaction SMILES: [OH-].[Na+].O1CCOCC1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20][CH:19]([CH2:27][C:28]([O:30]CC)=[O:29])[C:18]2=[O:33])=[C:12]([F:34])[CH:11]=1.Cl>>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20][CH:19]([CH2:27][C:28]([OH:30])=[O:29])[C:18]2=[O:33])=[C:12]([F:34])[CH:11]=1
Reactant: CCOC(=O)CC1Sc2ccccc2N(Cc2ccc(Br)cc2F)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CC1Sc2ccccc2N(Cc2ccc(Br)cc2F)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To 8 ml of 1 N sodium hydroxide-dioxane (1:1) mixture was added 700 mg of the compound of Example 20. After the mixture had been stirred at room temperature for 2 hours, it was acidified with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water dried, and concentrated. The resulting crude product was recrystallized from ethyl acetate-isopropyl ether to give 620 mg of 2-[4-(4-bromo-2-fluorophenylmethyl)-3,4-dihydro-3-oxo-2H-1,4-benzothiazin-2-yl]acetic acid. The structural formula and physical data of this compound are shown in Table 36.
Reaction SMILES: [N:1]1([CH:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7]([O-:9])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:30][C:31]1([O:44][CH3:45])[C:38](=[O:39])[N:37]2[CH:32]1[S:33][CH2:34][C:35]([CH3:43])=[C:36]2[C:40]([OH:42])=[O:41]>O1CCCC1>[C:10]([CH:6]([N:1]1[CH:2]=[CH:3][CH:4]=[CH:5]1)[C:7]([NH:30][C:31]1([O:44][CH3:45])[C:38](=[O:39])[N:37]2[CH:32]1[S:33][CH2:34][C:35]([CH3:43])=[C:36]2[C:40]([OH:42])=[O:41])=[O:9])([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C(=O)[O-])n1cccc1
Reactant: COC1(N)C(=O)N2C(C(=O)O)=C(C)CSC21
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)NC1(OC)C(=O)N2C(C(=O)O)=C(C)CSC21)n1cccc1
Temperature: 0 °C

Procedure:
2-(1-Pyrryl)propanedioic acid, 3-ethyl ester, 1 equivalent and 1 equivalent of triethylamine is added to tetrahydrofuran (THF) which is cooled to 0° C. While stirring, iso-butyl chloroformate, 1 equivalent, is added and the temperature is maintained at 0° C. for about 15 minutes. A cold solution of 7-amino-7-methoxy-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 1 equivalent, and triethylamine, 1 equivalent, in 50% aqueous THF is added with stirring to the previous solution.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]([NH:12][NH2:13])=[C:6]2[CH:5]=[N:4]1)[CH3:2].N/[C:20](/[CH3:24])=[CH:21]\[C:22]#[N:23]>C(O)CCC>[C:22]([CH2:21][C:20](=[N:13][NH:12][C:11]1[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][N:8]=[C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=12)[CH3:24])#[N:23]
Reactant: C/C(N)=C/C#N
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NN
Solvent: CCCCO
Product: CCOC(=O)c1cnc2c(cnn2CC)c1NN=C(C)CC#N
Reaction time: 24 h

Procedure:
249 g of 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]-pyridine-5-carboxylic acid, ethyl ester (1 mol) and 82 g of 3-aminocrotononitrile (1 mol) are heated together in 1.5 liters of butyl alcohol with stirring for 24 hours. The solvent is removed in vacuo and the residual 4-[2-(2-cyano-1-methylethylidene)hydrazino]-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester is recrystallized from alcohol, yield 309 g (80%); m.p. 190°-191°.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:36])[CH2:34][OH:35])[NH:28][C:27](=[O:37])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:36])[CH2:34][OH:35])[NH:28][C:27](=[O:37])/[C:26]/2=[CH:20]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C(CO)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3cc(NC(=O)CO)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Yield: 76 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c obtained from step 3 of Example 28 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-acetamide 27b obtained from step 2 of Example 27 as starting materials to obtain (Z)—N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-acetamide 31 (50 mg, yield 76%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([CH3:14])([CH3:13])[O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[C:4]([Cl:15])[C:3]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1.[OH:29]O>>[Cl:1][C:2]1[C:7]2[C:8]([CH3:13])([CH3:14])[O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[C:4]([Cl:15])[C:3]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][S:21]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)=[O:29]
Reactant: Cc1ccc(SCCCCOc2c(Cl)cc3c(c2Cl)C(C)(C)OC(=O)N3)cc1
Reactant: OO
Product: Cc1ccc(S(=O)CCCCOc2c(Cl)cc3c(c2Cl)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 5,7-dichloro-6-[4-(4-methyl-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [ClH:1].[CH2:2]([C:9]#[N:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:11]([O:13]CC)[CH3:12]>>[ClH:1].[C:3]1([CH2:2][C:9](=[NH:10])[O:13][CH2:11][CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOCC
Reactant: N#CCc1ccccc1
Agent: Cl
Product: CCOC(=N)Cc1ccccc1
Reaction time: 12 h

Procedure:
Hydrogen chloride was blown into a solution of benzyl cyanide (5.8 ml) in diethyl ether (10 ml) with ice-cooling, and the mixture was stood at room temperature for 12 hours. After completion of the reaction, the solvent was evaporated. The obtained solid was washed with diethyl ether, collected by filtration and dried under reduced pressure to give the title compound (9.43 g).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:16](=[O:31])[N:17]([CH2:19][C:20]3[C:21]([CH3:30])=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=3)[N:18]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:2]2[C:3]3[N:4]([C:16](=[O:31])[N:17]([CH2:19][C:20]4[C:21]([CH3:30])=[N:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=4)[N:18]=3)[CH:5]=[CH:6][C:7]=2[C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:36][CH:35]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(-c3ccc(C#N)cc3)ccn2c1=O
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(-c2c(-c3ccc(C#N)cc3)ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4C)nc23)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
Into a flame-dried reaction vessel under argon was placed 4-(8-bromo-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)benzonitrile (49 mg, 0.1 mmol), 4-methoxyphenylboronic acid (46 mg, 0.3 mmol), K3PO4 (64 mg, 0.3 mmol), Pd(dppf)Cl2.CH2Cl2 (17 mg, 0.02 mmol) and anhydrous THF (1.5 mL). The suspension was degassed with argon bubbling, and the reaction vessel was sealed and stirred at 90° C. for 16 h. Analysis by HPLC/MS indicated the reaction was complete. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The EtOAc layer was washed with water, then saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of EtOAc (0-70%) in hexanes to afford the desired product (90% pure). The product was further purified by preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 70% to 100% B over 10 min (A=90% water, 10% methanol and B=90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue obtained was dissolved in acetonitrile, frozen and lyophilized to afford 18 mg of the title compound as a light yellow powder. HPLC/MS: retention time=3.71 min, [M+H]+=516.8.