Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C-:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1)=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26].[OH-].[Na+]>C(O)C>[C-:16]1([C:14]([CH:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:1]2([OH:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:15])[CH:17]=[CH:18][CH:19]=[CH:20]1.[CH-:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[Fe+2:26]
Reactant: O=C(CCCCCC(=O)[c-]1cccc1)c1ccccc1
Agent: [Fe+2]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([c-]1cccc1)C1CCCCC1(O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Benzoylhexanoylferrocene [2.91g; 7.5 mmole] was dissolved in a solution of sodium hydroxide [0.3g; 7.5 mmole] in ethanol [100 ml] and stirred at room temperature for 16 hours.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:19]([NH2:21])=[O:20].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].Br[C:63]1[N:68]=[C:67]([CH:69]([N:72]2[CH2:77][CH2:76][O:75][CH2:74][CH2:73]2)[CH2:70][OH:71])[CH:66]=[CH:65][CH:64]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:71][CH2:70][CH:69]([C:67]1[N:68]=[C:63]([NH:1][C:2]2[S:6][C:5]([C:7]3[CH:8]=[N:9][C:10]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:11][CH:12]=3)=[N:4][C:3]=2[C:19]([NH2:21])=[O:20])[CH:64]=[CH:65][CH:66]=1)[N:72]1[CH2:77][CH2:76][O:75][CH2:74][CH2:73]1
Reactant: NC(=O)c1nc(-c2ccc(N3CCOCC3)nc2)sc1N
Reactant: OCC(c1cccc(Br)n1)N1CCOCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: NC(=O)c1nc(-c2ccc(N3CCOCC3)nc2)sc1Nc1cccc(C(CO)N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A sealed tube was charged with a stir bar, 5-amino-2-(6-morpholin-4-ylpyridin-3-yl)-1,3-thiazole-4-carboxamide (100 mg, 0.33 mmol), Pd2(dba)3 (30.0 mg, 0.033 mmol), X-PHOS (78 mg, 0.16 mmol), and potassium carbonate (50 mg, 0.36 mmol). The tube was evacuated and backfilled with argon (3×). 2-(6-Bromopyridin-2-yl)-2-morpholin-4-ylethanol (Enantiomer B) (Example 3, Step 1, chiral separation) (94 mg, 0.33 mmol) was placed in a separate vial which was also evacuated and backfilled with argon (3×). Fully degassed tert-amyl alcohol (1.5 mL) was added to the vial containing 2-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol (Enantiomer B) and the resulting solution was transferred to the sealed tube containing the rest of the reactants. This tube was then sealed and placed in an oil bath at 100° C. and stirred overnight. The reaction was cooled to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification via flash chromatography (silica, 0-15% methanol/ethyl acetate) afforded the title compound as a yellow powder. 1H NMR (500 MHz, d6-DMSO): δ 11.21 (s, 1H), 8.66 (d, 1H), 8.08 (dd, 1H), 7.72 (s, 1H), 7.69 (t, 1H), 7.59 (s, 1H), 7.05 (d, 1H), 6.96 (d, 1H), 6.93 (d, 1H), 4.53 (m, 1H), 3.99 (m, 2H), 3.70 (m, 4H), 3.66 (m, 1H), 3.54 (m, 8H), 2.51 (m, 4H). LRMS (APCI) calc'd for C24H30N7O4S [M+H]+ 512.2, found 512.1. τr=13.5 min using supercritical fluid chromatography supercritical fluid chromatography (CO2, AD-H column (1×25 cm, 5 um), isochratic, 40% Ethanol+0.25% isobutylamine modifier, 10 mL/min, 100 bar, 310 nM)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:29]=[C:30]([C:32]3([C:37]#[N:38])[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:31]=2)[C:26](O)=[O:27])=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:39][C:40]1[CH:45]=[CH:44][C:43]([C@H:46]([NH2:48])[CH3:47])=[CH:42][CH:41]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:29]=[C:30]([C:32]3([C:37]#[N:38])[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:31]=2)[C:26]([NH:48][C@@H:46]([C:43]2[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=2)[CH3:47])=[O:27])=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@](C)(Cc1ccccc1)c1nnc(-c2cc(C(=O)O)cc(C3(C#N)CCCC3)c2)o1
Reactant: C[C@@H](N)c1ccc(F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)cc(C2(C#N)CCCC2)c1)c1ccc(F)cc1

Procedure:
A solution of 3-(5-((2R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1-cyanocyclopentyl)benzoic acid (20 mg, 0.039 mmol), (R)-1-(4-fluorophenyl)ethanamine (0.017 mL, 0.13 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (24 mg, 0.05 mmol) and diisopropylethylamine (0.024 mL, 0.14 mmol) in 0.4 mL DMF was stirred at rt overnight. Purification by reverse phase preparative HPLC (5-95% MeCN/H2O containing 0.1% TFA, C18 PRO YMC 20×150 mm) gave 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(1-cyanocyclopentyl)-N—((R)-1-(4-fluorophenyl)ethyl)benzamide. 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.16 (m, 1H), 8.10 (d, J=1.5 Hz, 1H), 7.39 (m, 2H), 7.28 (m, 3H), 7.06 (m, 4H), 6.56 (d, J=7.5 Hz, 1H), 5.33 (m, 1H), 5.07 (bs, 1H), 3.59 (d, J=13.6 Hz, 1H), 3.40 (d, J=13.6 Hz, 1H), 2.55 (m, 2H), 2.16-1.98 (m, 6H), 1.72 (s, 3H), 1.64 (d, J=7.0 Hz, 3H), 1.41 (s, 9H).
Reaction SMILES: [CH2:1]([C:11]1[NH:15][N:14]=[N:13][N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(CC)CC)C.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(#N)C>[CH2:1]([C:11]1[N:12]=[N:13][N:14]([CH:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:24]=2)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCOC(=O)Cc1ccccc1Br
Reactant: CCCCCCCCCCc1nnn[nH]1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCCc1nnn(C(C(=O)OCC)c2ccccc2)n1
Yield: 33.9 %

Procedure:
The 5-decyl-1H-tetrazole, (4.0 g, 0.019 mol), triethylamine (2.9 mL, 0.021 mol) and ethyl 2-bromophenylacetate (5.09 g, 0.021 mol) were dissolved in 200 mL acetonitrile and heated to reflux for 2 hours. Cooled and concentrated in vacuo to give a yellow oil. Chromatography-to separate the regioisomers gave ethyl (±)-5-decyl-α-phenyl-2H-tetrazole-2-acetate as a clear oil (2.40 g, 34%).
Reaction SMILES: [CH2:1]([C:5]1[NH:9][C:8](=O)[CH2:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O=P(Cl)(Cl)[Cl:15]>>[CH2:1]([C:5]1[NH:9][C:8]([Cl:15])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCC1=NCC(=O)N1
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1ncc(Cl)[nH]1
Temperature: 100 °C

Procedure:
2-n-Butyl-3,5-dihydroimidazol-4-one (14.02 g, 0.1 mol) was added in portions for 15 minutes to POCl3 (50 ml) at 95° C. The solution was heated for 2 hours at 100° C., cooled and poured on 400 g of ice. The mixture was adjusted to pH 7 with 255 ml of 30 percent sodium hydroxide solution and extracted three times with 500 ml of ethyl acetate each. The combined organic phases were dried with MgSO4, filtered and concentrated by evaporation on a Rotavapor. After purification of the residue by column chromatography the title compound (5.52 g, 34.7 percent) was obtained in a high yield (>98 percent, according to GC and 1H-NMR). The product had a melting point of 85° to 87° C. Other data regarding the product was:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19]#[N:20])[CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=[O:34].[K+].[K+].OO>CS(C)=O.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19]([NH2:20])=[O:34])[CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc(OCc2ccccc2)cc2c(NCc3ccc(C(F)(F)F)cc3)ncnc12
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(OCc2ccccc2)cc2c(NCc3ccc(C(F)(F)F)cc3)ncnc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
To a solution of the 6-Benzyloxy-4-(4-trifluoromethyl-benzylamino)-quinazoline-8-carbonitrile (380 mg, 1 eq) in DMSO (20 mL) was added 10 wt % aqueous K2CO3 (6.68 mL, 5 eq) followed by 33% H2O2 (790 □L, 8 eq) at room temperature. The resulting light suspension was stirred for 12 h at room temperature and then diluted with water (˜20-40 mL). A white precipitate formed that was collected by filtration (crop A). The filtrate was then extracted with ethyl acetate (3×25 mL) and the combined organic layers were dried over sodium sulfate, concentrated to an oil and columned (50 to 90% ethyl acetate/heptane) to afford an off-white solid (crop B). The two crops of carboxamide product (A+B, each ˜90% pure by HPLC) were then combined in a 20 mL vial and triturated with minimal dichloromethane followed by ether. Trituration afforded a white solid (342.6 mg, 86%) LCMS (ESI) 453 (M+H)
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:43][C@@H:42]([CH2:44][CH2:45][NH2:46])[CH2:41][O:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:43][C@H:42]([CH2:41][OH:40])[CH2:44][CH2:45][NH:46][C:35]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Br:8])[CH:10]=2)[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:33])([CH3:34])[CH3:32])[NH:17]1)=[O:36]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Br)c2)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Br)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 53.9 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 66c (0.5 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.49 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.26 g, 55%).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[OH-:18].[Na+].OO>C1COCC1>[CH2:11]([O:10][CH2:9][CH2:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([CH2:1][OH:18])[CH2:3][CH2:4]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=C1CCC(CCOCc2ccccc2)CC1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OC[C@H]1CC[C@H](CCOCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0 C) solution of ((2-(4-methylenecyclohexyl)ethoxy)methyl)benzene (9.68 g, 41.66 mmol) in THF (200 mL) was added B2H6Me2S complex (2M in THF, 41.66 mL, 83.32 mmol) under N2. After being stirred at 0° C. for 2 h and at rt for another 2 h, the solution was cooled to 0° C. and added a mixture of 3M aqueous NaOH solution (34 ml) and 30% hydrogen peroxide solution (34 mL) dropwise. The resulting mixture was stirred at 0° C. for 1 h and at rt for 1.5 h. Aqueous workup and purification by flash column chromatography (eluent: 40% EtOAc in hexanes) gave the product as yellow oil (7.04 g, 68%). LC/MC: 249.1 (MH)
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[C:22]1(C)C=CC=CC=1.[OH-].[Na+]>CO.C(OCC)(=O)C.O>[CH3:22][O:10][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=[C:15]([N+:16]([O-:18])=[O:17])[C:7]=1[CH3:6]
Reactant: Cc1c(C(=O)O)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C
Reaction time: 8 h
Yield: 84 %

Procedure:
Concentrated sulfuric acid (0.5 mL) was added slowly at ambient temperature with stirring to 2-methyl-3,5-dinitro-benzoic acid (5.22 g, 23.06 mmol) in anhydrous methanol (200 mL). After refluxing overnight under an argon atmosphere, the reaction was determined to be about 50% complete. Toluene (100 mL) was used to azeotrope the H2O generated from the reaction, and fresh anhydrous methanol (300 mL) and H2SO4 (0.5 mL) were added and the mixture was again refluxed overnight under an argon atmosphere at which point the volatile components were reduced in vacuo. Ethyl acetate and 5% aqueous NaOH were added with stirring, and the product was extracted into the ethyl acetate. The ethyl acetate was then washed twice each with 5% aqueous NaOH and saturated aqueous NaHCO3, once with brine and dried with Na2SO4 to give Intermediate 2(a) (4.65 g, 19.37 mmol) as a white solid in 84% yield.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:16])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[N:11][CH:10]=2)=O)C.[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23].C(=O)(O)[O-].[Na+]>>[NH:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:24]=[C:4]1[C:6]1[C:7](=[O:16])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[N:11][CH:10]=2
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)c1cc2ccncc2[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Product: O=c1[nH]c2cnccc2cc1-c1nc2ccccc2[nH]1
Temperature: 200 °C

Procedure:
A mixture of 6-3 (300 mg, 1.37 mmol, 1 equiv) and 1,2-phenylenediamine (223 mg, 2.06 mmol, 1.5 equiv) in polyphosphoric acid (8 mL) was heated at 200° C. for 3 h. The hot rxn mixture was poured into ice water (50 mL), and the resulting mixture was allowed to stand until all polyphosphoric acid had dissolved. The acidic suspension was neutralized with saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate (5×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (EtOAc) to afford 3-(1H-benzoimidazol-2-yl)-1H-[1,7]naphthyridine-2-one (6-4) as a yellow solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.75 (s, 1H), 12.71 (s, 1H), 9.13 (s, 1H), 8.79 (s, 1H), 8.43 (d, 1H, J=5.2 Hz), 7.91 (d, 1H, J=5.2 Hz), 7.74 (m, 1H), 7.68 (m, 1H), 7.24 (m, 2H). HRMS (electrospray FT/ICR) calculated for C15H11N4O [M+H]+ 263.0933, found 263.0930.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1cc(F)c(C(F)(F)F)cc1N

Procedure:
The title compound was prepared from (5-fluoro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A2) (3.34 g, 10.3 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a yellow solid (2.93 g, 97%).
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[CH:19]([OH:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:53])=[CH:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH:47]([O:51][CH3:52])[CH2:46]2)[CH:8]([CH3:54])[CH:7]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[CH2:6][C:5]1=[O:63])[CH:2]=[CH2:3].C(=O)([O-])O.[Na+]>C(O)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:53])=[CH:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH:47]([O:51][CH3:52])[CH2:46]2)[CH:8]([CH3:54])[CH:7]([O:55][Si:56]([C:59]([CH3:60])([CH3:61])[CH3:62])([CH3:57])[CH3:58])[CH2:6][C:5]1=[O:63])[CH:2]=[CH2:3]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(C)CC2OC)C(O)C(=O)N2CCCCC2C(=O)OC(C(C)=CC2CCCC(OC)C2)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CC(=O)O
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCCC(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 80 °C
Yield: 47.2 %

Procedure:
A solution of the product of step (b) (85 mg) in glacial acetic acid (10 ml) containing copper (II) acetate (1 g) was heated at 80° C. for 5 minutes. The cooled reaction mixture was then poured into saturated aqueous sodium hydrogen carbonate solution and this was extracted with diethyl ether. The ether extracts were then dried (MgSO4), filtered and concentrated to an oil in vacuo. Chromatography on silica eluting with acetone/hexane [2:5] then gave the subtitle compound as a foam (40 mg).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:25])[C:13]([N:22]([CH3:24])[CH3:23])([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:14])=[CH:8][CH:7]=1.Br[CH2:27][C:28](=[CH2:33])[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:32][O:31][C:29](=[O:30])[C:28]([CH2:33][S:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:25])[C:13]([N:22]([CH3:23])[CH3:24])([CH3:14])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1)=[CH2:27]
Reactant: C=C(CBr)C(=O)OC
Reactant: CN(C)C(C)(Cc1ccccc1)C(=O)c1ccc(SCCCS)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C=C(CSCCCSc1ccc(C(=O)C(C)(Cc2ccccc2)N(C)C)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.5 g (4.0 mmol) of 1-[4-(3-mercaptopropylthio)phenyl]-2-dimethylamino-2-benzyl-propan-1-one are dissolved in 100 ml of methanol. To the solution are successively added 0.86 g (4.8 mmol) of methyl 2-(bromomethyl)acrylate and 0.55 g (4.0 mmol) of potassium carbonate, and the resulting reaction mixture is stirred at room temperature for 10 min. The reaction mixture is added to water and extracted with ethyl acetate. The organic phase is washed with water, and dried over MgSO4. After distilling off the ethyl acetate, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:7) as an eluent, and an oily product is obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:13]1[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=1)[C:11]#[N:12].C([O-])(=O)C.[Na+]>C(O)(=O)C.[Pd]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][N:14]=1)[C:11]#[N:12]
Reactant: N#CC(c1ccnc(Cl)n1)c1nc2ccccc2s1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#CC(c1ccncn1)c1nc2ccccc2s1
Temperature: 70 °C
Yield: 13.6 %

Procedure:
To a solution of 1 (0.1 g, 0.35 mmol) in acetic acid was added sodium acetate (29 mg, 0.35 mmol) and palladium on charcoal (20 mg). The suspension was heated up to 70° C. under hydrogen at 3.5 bar for 3 h. After cooling to rt., the suspension was filtered through celite and the acetic acid evaporated. The bright yellow powder was taken up in ethyl acetate and aqueous sodium hydroxide 10%. After 3 extractions the organic phases were thoroughly washed with brine then dried over MgSO4 and concentrated to dryness. After purification by preparative HPLC and drying under vacuum at 50° C., 12 mg (13%) of the title compound were obtained as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([N:12]2[C@@H:19]3[C@@H:14]([CH2:15][CH2:16][NH:17][CH2:18]3)[CH2:13]2)[CH:3]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[N:36]1[N:37]([C:41]2[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=2[C:43](O)=[O:44])[N:38]=[CH:39][CH:40]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[N:5]=[C:4]([N:12]2[C@@H:19]3[C@@H:14]([CH2:15][CH2:16][N:17]([C:43]([C:42]4[CH:46]=[CH:47][CH:48]=[CH:49][C:41]=4[N:37]4[N:38]=[CH:39][CH:40]=[N:36]4)=[O:44])[CH2:18]3)[CH2:13]2)[CH:3]=1
Reactant: O=C(O)c1ccccc1-n1nccn1
Reactant: Cc1cc(N2C[C@@H]3CCNC[C@@H]32)nc(C(F)(F)F)n1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: Cc1cc(N2C[C@@H]3CCN(C(=O)c4ccccc4-n4nccn4)C[C@@H]32)nc(C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(6-methyl-2-trifluoromethyl-pyrimidin-4-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 9) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 14) for 2-thiophen-2-yl-benzoic acid. Additionally, the reaction time was shortened to 30 minutes. MS (ESI) mass calcd. for O21H20F3N7O, 443.43; m/z found 444.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.16-5.81 (m, 7H), 4.84-1.60 (m, 13H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.[C:28](=[O:30])=[O:29]>C(OCC)C.O>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:28]([OH:30])=[O:29])=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cnccc1C(=O)O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Pyridin-3-yl-carbamic acid tert-butyl ester (6.20 g) was dissolved in anhydrous diethyl ether (260 mL), cooled to −78° C. and N,N,N′,N′-tetramethylethylendiamine (14.4 mL) was added. A solution of n-butyl lithium (1.6 M in hexane, 60 mL) was added slowly over a time period of 10 minutes. After the addition of the reagent was completed, the reaction mixture was allowed to warm to −10° C. and stirred at this temperature for 2 hours. The reaction mixture was then re-cooled to −78° C. and slowly poured on a stirred mixture of dry ice in diethyl ether. After stirring for 30 minutes, water was added to the reaction mixture and the layers were separated after complete dissolution of solid materials. The aqueous layer was washed 2× with diethyl ether and the pH-value of the aqueous layer was adjusted to 5-6. The organic layer was extracted 2× with MTB-ether. The combined organic layer was washed with a small amount of brine, dried over MgSO4 and concentrated in vacuum. The residue was washed with hexane to remove oily by-products and dried in vacuum to afford 1.19 g of the title compound as beige solid. The aqueous washing was concentrated on a rotary evaporator to approx. 50 mL, inorganic salts were filtered off and MTB-ether was added to the mother liquor. 6N hydrochloric acid was slowly added into the well-stirred mixture until the pH-value was adjusted to −3. The layers were separated, the aqueous layer was washed 2× with MTB-ether and 2× with chloroform. The combined organic layer was dried over MgSO4 and dried in vacuum to give another 2.03 g of beige solid. Together, the first organic extract and 3.22 g of the title compound of the formula