Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:20]C)=[CH:15][CH:16]=2)[CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BrH:22]>C(O)(=O)C>[BrH:22].[CH2:2]([NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([OH:20])=[CH:15][CH:16]=2)[CH2:11]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc2c(c1)CC(NCc1ccccc1)CC2
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: Oc1ccc2c(c1)CC(NCc1ccccc1)CC2

Procedure:
A mixture of 25 g of 2-benzylamino-7-methoxytetraline hydrochloride, PREPARATION I (a), in 215 ml of a 33% hydrobromic acid solution in acetic acid and in the presence of 36 ml of 48% hydrobromic acid, is heated at reflux for 2 hours under stirring. After concentration under reduced pressure, the residue is taken up three times with 100 ml of absolute ethanol and dried every time. The product thus obtained is triturated with 150 ml of acetone, the mixture is filtered to give 25.3 g of 2-benzylamino-7-hydroxytetraline hydrobromide; m.p. 198°-200° C. The salt is dissolved in 1300 ml of hot water and, after cooling, there is added a concentrated ammonium hydroxide solution. The base is extracted with ethyl acetate, dried and a solid is obtained which after crystallization from 250 ml of toluene gives 14 g of 2-benzylamino-7-hydroxytetraline base; m.p. 161°-163° C.
Reaction SMILES: Br.[C:2]([C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:22]([O:33]C)[N:21]=2)=[CH:13]\[C@@H:14]2[NH:18][C:17](=[O:19])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].C(C1C=CC(/C(/C2C=CC=C(OC)N=2)=C\[C@@H]2NC(=O)CC2)=CC=1)(C)(C)C.O>O1CCOCC1>[C:2]([C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:20]2[NH:21][C:22](=[O:33])[C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)=[CH:13]\[C@H:14]2[CH2:15][CH2:16][C:17](=[O:19])[NH:18]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)ccc1Oc1ccccc1
Agent: Br
Agent: COc1cccc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)n1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(/C(=C\[C@H]2CCC(=O)N2)c2ccc(Oc3ccccc3)c(=O)[nH]2)cc1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
48% hydrobromic acid (2 mL) was added to a solution of the mixture of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(6-methoxy-5-phenoxypyridin-2-yl)ethenyl]pyrrolidin-2-one and (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one (61 mg) in 1,4-dioxane (1 mL), and the mixture was stirred at 65° C. for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire 19×150 mm 5 μm, rate: 20 mL/min, eluent: A=acetonitrile, B=0.1% trifluoroacetic acid solution, gradient: 10 to 90%) and solidified with ethyl acetate-hexane to give the title compound as a colorless amorphous (22 mg, 22% (two steps)). A crude product of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one (15 mg) was also obtained.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].CI.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1O>CC(C)=O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[O:4][CH3:1]
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(Cl)ccc1Cl
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
Anhydrous K2CO3 (21.9 g, 0.159 mol) and methyl iodide (10.8 mL, 0.178 mol) were added to a solution of 2,5-dichlorophenol (23.5 g, 0.144 mol) in 215 mL acetone. The reaction was allowed to stir at room temperature for 20 hours, then filtered through a celite pad. The filtrate was concentrated to a residue which was taken up in diethylether. The ether solution was washed with 10% NaHSO3, water, several portions of 1 M NaOH, and brine, then dried with anhydrous Na2SO4. Upon filtration and concentration, the residue was distilled (8 mm Hg, 110° C.) to yield 23.7 g (93.5%) of a light yellow oil.
Reaction SMILES: [CH:1]([OH:3])=O.[CH3:4][C:5]1[C:10](C#N)=[CH:9][N:8]=[C:7]([NH:13][CH2:14][CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[N:6]=1>[Ni].O>[CH3:4][C:5]1[C:10]([CH:1]=[O:3])=[CH:9][N:8]=[C:7]([NH:13][CH2:14][CH2:15][CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)[N:6]=1
Reactant: O=CO
Reactant: Cc1nc(NCCCC2CCN(C)CC2)ncc1C#N
Agent: [Ni]
Solvent: O
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1C=O
Temperature: 12.5 °C
Reaction time: 1 h

Procedure:
A vessel at room temperature was charged with formic acid (800 mL) and 4-methyl-2-(3-(1-methylpiperidin-4-yl)propylamino)pyrimidine-5-carbonitrile (100 g) and the resulting mixture stirred to yield a clear solution, then cooled to 10-15° C. Water (200 mL) was added and the resulting mixture cooled to −2 to 0° C. To the resulting mixture was then added RANEY® nickel (160 g) maintaining the temperature at −2 to 0° C. and then stirred at this temperature for 2-3 hours. The resulting mixture was then filtered to remove the RANEY® nickel and the filtercake washed with water (100 mL). The filtrate was cooled to 0-5° C. and then slowly treated with 50% sodium carbonate solution in water (3.0 L) to adjust the pH of the solution to pH˜10. Toluene (400 mL) was added and the resulting mixture stirred at room temperature for about 30 minutes, then allowed to settle for about 1 hour. The resulting layers were separated and the aqueous layer washed with toluene (400 mL×2). The combined toluene layer and washed were distilled at 55-60° C. to remove the toluene, to yield the title compound as an oily residue.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].C1(P(O[NH2:50])(C2C=CC=CC=2)=O)C=CC=CC=1.O>O1CCCC1.C(OCC)(=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1[N:27]([NH2:50])[C:28]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:34]
Reactant: CC(C)(C)OC(=O)Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Cl
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(N)c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Cl
Reaction time: 0.33 h
Yield: 72.6 %

Procedure:
Sodium hydride (60% oily; 760 mg) was suspended in tetrahydrofuran (200 mL), and thereto was added dropwise a solution of tert-butyl {2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}carbamate (8.80 g) obtained by Reference Production Example 4 in tetrahydrofuran (50 mL) at room temperature, and then the mixture was stirred at the same temperature for 20 minutes. To the mixture was added O-(diphenylphosphoryl)-hydroxylamine (6.0 g) at room temperature, and the mixture was stirred at the same temperature for 15 hours. To the mixture were added water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain tert-butyl N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}carbazate (6.58 g).
Reaction SMILES: O.NN.[Cl:4][C:5]1[CH:22]=[CH:21][C:8]([O:9][N:10]2C(=O)C3=CC=CC=C3C2=O)=[CH:7][CH:6]=1>C(Cl)(Cl)Cl.CO>[Cl:4][C:5]1[CH:22]=[CH:21][C:8]([O:9][NH2:10])=[CH:7][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Oc1ccc(Cl)cc1
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NOc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Hydrazine hydrate (0.56 mL, 12 mmol) was added to a solution of Example 3A (820 mg, 3.0 mmol) in chloroform (37 mL) and methanol (4 mL). The suspension was stirred at room temperature for 22 hours. Silica gel (10 g) was added, and the mixture was concentrated to dryness. The residue was applied to the top of a flash chromatography column and eluted with hexanes-ethyl acetate (80:20) to provide the title compound as the free amine. The residue was dissolved in ethanol (5 mL) and treated with HCl/dioxane (4M, 1 mL). The solution was heated at reflux and diluted with gradual addition of ethyl acetate (50 mL). The mixture was cooled to room temperature and filtered to provide the title compound as a hydrochloride salt. 1H NMR (300 MHz, CD3OD) δ 7.15-7.22 (m, 2 H), 7.42-7.49 (m, 2 H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8]1([CH2:34][CH2:35][O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[S:12][C:11]2[CH:13]=[C:14]3[S:18][C:17]([CH2:26][CH2:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH2:19][CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:16][C:15]3=[CH:33][C:10]=2[S:9]1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[I:46]I.S(=O)(O)[O-].[Na+]>CCCCCC.O1CCCC1>[C:29]([O:28][CH2:27][CH2:26][C:17]1([CH2:19][CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:18][C:14]2[C:13]([I:46])=[C:11]3[S:12][C:8]([CH2:34][CH2:35][O:36][C:37]([CH3:40])([CH3:39])[CH3:38])([CH2:7][CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[S:9][C:10]3=[CH:33][C:15]=2[S:16]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: II
Reactant: CC(C)(C)OCCC1(CCOC(C)(C)C)Sc2cc3c(cc2S1)SC(CCOC(C)(C)C)(CCOC(C)(C)C)S3
Agent: O=S([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OCCC1(CCOC(C)(C)C)Sc2cc3c(c(I)c2S1)SC(CCOC(C)(C)C)(CCOC(C)(C)C)S3
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
A dry flask under argon was charged with 2,2,6,6-tetra(t-butoxyethyl)benzo[1,2-d:4,5-d']bis(1,3)dithiole (60.0 g, 95.08 mmol) and dry tetrahydrofuran (2000 ml). The mixture was cooled to -20° C. and n-Butyl lithium (76 ml of a 2.5M solution in hexane, 0.19 mol) was added over 3 minutes. The mixture was stirred for 20 minutes at -20° C. and then a solution of iodine (120 g, 0.475 mol) in tetrahydrofuran (500 ml) was added. The reaction mixture was poured into an aqueous sodium bisulphite solution and extracted with diethyl ether. The organic phase was washed once with an aqueous solution of sodium bisulphite and once with brine, dried (MgSO4) and evaporated. The product was purified by chromatography on silica gel using a mixture of CH2Cl2 and ethyl acetate as the eluent. Yield: 36.7 g (51 i).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:30]I.O>CN(C=O)C.C(OCC)(=O)C>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([N:23]([CH3:30])[S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1cccc(C=C2c3ccccc3CCc3ccccc32)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Dissolve N-[3-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenyl]-methanesulfonamide (10 mg, 0.265 mmol) in DMF (4 mL) and add NaH (13 mg of a 60% suspension in mineral oil, 0.318 mmol). Stir at room temperature for 50 min, then add MeI (33□L, 75 mg, 0.530 mmol). Stir at room temp for 1 h. Dilute reaction mixture with H2O and ethyl acetate. Separate layers, and wash organics with H2O. Dry organics (MgSO4) and concentrate to 101 mg (100%) of a pale yellow solid, mp 124.2° C. 1H NMR (CDCl3) δ 2.53 (s, 3H), 2.72-3.54 (br m, 4H), 6.74 (s, 1H), 6.78 (s, 1H), 6.91-7.43 (m, 11H); MS (ES) 412 (M+Na). HPLC shows 97% purity.
Reaction SMILES: C(OC(N1CCC[C@@H]1[C@H](C1C=CC(Cl)=CC=1)C(O)=O)=O)(C)(C)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]([C@H:51]2[CH2:55][CH2:54][CH2:53][NH:52]2)[C:32]([N:34]2[CH2:39][CH2:38][N:37]([C:40]3[C:41]4[C@H:48]([CH3:49])[CH2:47][C@@H:46]([OH:50])[C:42]=4[N:43]=[CH:44][N:45]=3)[CH2:36][CH2:35]2)=[O:33])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]([C@@H:51]2[CH2:55][CH2:54][CH2:53][NH:52]2)[C:32]([N:34]2[CH2:35][CH2:36][N:37]([C:40]3[C:41]4[C@H:48]([CH3:49])[CH2:47][C@@H:46]([OH:50])[C:42]=4[N:43]=[CH:44][N:45]=3)[CH2:38][CH2:39]2)=[O:33])=[CH:27][CH:26]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@H]4CCCN4)CC3)c21
Agent: CC(C)(C)OC(=O)N1CCC[C@@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4CCCN4)CC3)c21
Yield: 264 %

Procedure:
Using procedures similar to those described in Example 1, Step 5, (S)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (144 mg, 0.424 mmol) was converted to (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-pyrrolidin-2-yl)ethanone (25 mg, 10%). LCMS (apci+) 456.0/458.0 [M+H]+; 1.93 minutes. Some (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone (66 mg, 28%) was also isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([OH:25])[CH2:23][CH3:24])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1.[H-].[Na+].[CH3:28]I>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([O:25][CH3:28])[CH2:23][CH3:24])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: CI
Reactant: CCC(O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(OC)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.1 %

Procedure:
To a solution of 1-[1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (350 mg, 0.930 mmol) in N,N-dimethylformamide (3.0 mL) was added sodium hydride (60% in oil, 44.8 mg, 1.12 mmol), and the mixture was stirred at room temperature for 5 min. To the mixture was added methyl iodide (657 mg, 4.65 mmol), and the mixture was stirred at room temperature for 1 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (76.5 mg, 0.196 mmol, 21%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21](O)=[O:22])[C:16]3=[O:24])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Br.[N:28]1[N:29]=[C:30]([NH2:36])[N:31]2[CH2:35][CH2:34][S:33][C:32]=12.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[N:28]1[N:29]=[C:30]([NH:36][C:21](=[O:22])[CH2:20][N:17]2[CH2:18][CH2:19][CH:15]([N:12]3[CH2:13][CH2:14][CH:9]([C:7](=[O:8])[C:6]4[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:10][CH2:11]3)[C:16]2=[O:24])[N:31]2[CH2:35][CH2:34][S:33][C:32]=12
Reactant: Nc1nnc2n1CCS2
Reactant: COc1ccc(C(=O)C2CCN(C3CCN(CC(=O)O)C3=O)CC2)cc1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)C2CCN(C3CCN(CC(=O)Nc4nnc5n4CCS5)C3=O)CC2)cc1
Temperature: 25 °C
Reaction time: 45 h
Yield: 34.4 %

Procedure:
A mixture of 500 mg of 76.5% pure 2-(3-(4-(4-methoxybenzoyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)acetic acid (382 mg, 1.061 mmol) and 5,6-dihydrothiazolo[2,3-c][1,2,4]triazol-3-amine hydrobromide (237 mg, 1.061 mmol) was stirred in diisopropylethylamine (0.741 mL, 549 mg, 4.25 mmol) and dichloromethane (10 mL) before addition of HATU reagent (444 mg, 1.161 mmol). The reaction was stirred over 45 hours at room temperature. A small amount of off-white solid was removed by filtration. The filtrate was eluted through a silica gel column with 0 to 15% methanol/dichloromethane, then 15% to 30%, followed by 30%. The fractions containing contaminated product were concentrated down and eluted through a second silica gel column with 5% to 12% methanol/dichloromethane gradient followed by 12% to afford the title compound (177 mg) as a white solid. Calculated mass for C23H28N6O4S=484.57. HR-MS [m/z, (M+H)+]=485.1956. HPLC retention time=2.73 minutes (Agilent 1100 HPLC system; 3.0×100 nm 3 um C18 column; flow rate of 1.0 mL/min; gradient of 5-95% acetonitrile/water with 0.1% formic acid over 10 minutes). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.06 (br s, 1H), 7.94 (d, J=9.09 Hz, 2H), 7.03 (d, J=8.59 Hz, 2H), 3.92-4.21 (m, 6H), 3.83 (s, 3H), 3.39-3.51 (m, 1H), 3.21-3.37 (m, 3H), 2.99 (d, J=13.14 Hz, 1H), 2.64-2.84 (m, 2H), 2.28-2.42 (m, 1H), 2.03-2.18 (m, 1H), 1.85-2.02 (m, 1H), 1.65-1.78 (m, 2H), 1.44-1.60 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH2:9][CH2:8][CH:7]=[C:6]([CH3:10])[CH2:5][CH2:4][CH:3]=1.CC1CCC(C)=CCCC=1.[FH:21].C([O-])(=O)C.[K+]>O1CCCC1.CO.O>[CH3:10][C:6]12[CH:3]([F:21])[C:2]([CH3:1])([CH2:4][CH2:5]1)[CH2:9][CH2:8][CH2:7]2
Reactant: CC1=CCCC(C)=CCC1
Reactant: F
Agent: CC(=O)[O-]
Agent: CC1=CCCC=C(C)CC1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC12CCCC(C)(CC1)C2F
Yield: 86.5 %

Procedure:
A mixture of 13.6 g (0.1 mol) 1,5-dimethyl-1,5-cyclooctadiene and 1,6-dimethyl-1,5-cyclooctadiene (ratio 80/20 was dissolved in a mixture of tetrahydrofuran (15 ml) and methanol (5 ml). The resulting mixture was added dropwise under stirring and cooling to 50 ml anhydrous hydrogen fluoride. The temperature was kept at about -10° C. during the addition (45 min). After the addition, the reaction mixture was stirred for a further period of 15 minutes at 0° C. and then poured into a cooled saturated solution of potassium acetate in water. The upper layer was then decanted and the aqueous layer was extracted several times with pentane. The upper layer and the pentane solutions were combined and washed with water and an aqueous diluted solution of sodium bicarbonate (5%). The pentane layer was then treated as described in Example 1a which resulted in 10.8 g of 1,5-dimethyl-8-fluorobicyclo-[3,2,1]octane (b.p. 68°-69° C./22 mm Hg) or a yield of 86.5% based on the starting 1,5-dimethyl-1,5-cyclooctadiene. The purity of the product according to gas-liquid chromatography was more than 98%.
Reaction SMILES: P(=O)(O)(O)O.[C:6]([O:10][C:11]([NH:13][CH:14]([C:22](=[O:32])[NH:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:15]([OH:21])[C:16](OCC)=[O:17])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(C(C(C(OCC)=O)O)O)(OCC)=O.[BH4-].[Na+].[Na+].[Cl-]>O1CCCC1>[C:6]([O:10][C:11]([NH:13][CH:14]([CH:15]([OH:21])[CH2:16][OH:17])[C:22]([NH:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:32])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CCOC(=O)C(O)C(NC(=O)OC(C)(C)C)C(=O)NOCc1ccccc1
Agent: CCOC(=O)C(O)C(O)C(=O)OCC
Agent: O=P(O)(O)O
Agent: [BH4-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)NOCc1ccccc1)C(O)CO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To solution of tetrahydrofuran (THF, 6 L) and phosphoric acid buffer (0.025 M, KH2PO4/Na2HPO4; ratio 1/1, 2 L) containing ethyl 3-[(tert-butoxy)carbonylamino]-2-hydroxy-3-[N-(phenylmethoxy) carbamoyl]propanoate (compound prepared from diethyl tartrate according to the procedures described in Org. Synth., Coll. Vol. 1998, 220, J. Org. Chem. 1983, 3556 and U.S. Pat. No. 4,794,108) (120 g, 31.38 mmol), sodium borohydride (59.35 g, 156.9 mmol) was added portion wise at 0° C. over 1 h. The resulting mixture was stirred at 0° C. for an additional 1 h and at room temperature for 2 h. The micxture was cooled at 0° C. before addition of 1M aqueous solution containing H3PO4 until the pH reach 8. NaCl (100 g) was added to the mixture and the organic layer was separated. Extraction with ethyl acetate (3×1.5 L) was performed and the combined organic phases were washed with brine (1 L), dried over MgSO4 and evaporated under vacuo. The residue as purified by column chromatography using hexane/acetone as eluent to get 50 g of white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([OH:11])=O)[CH:3]=1.[NH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1>>[NH:14]1[C:13]([NH:12][C:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=2)=[O:11])=[N:17][N:16]=[N:15]1
Reactant: Nc1nnn[nH]1
Reactant: Cc1cc(C)nc(C(=O)O)c1
Product: Cc1cc(C)nc(C(=O)Nc2nnn[nH]2)c1
Yield: 40.2 %

Procedure:
0.81 g of 4.6-dimethyl-2-pyridinecarboxylic acid, 0.86 g of N,N'-carbonyldiimidazole and 0.54 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and ethanol, whereby 0.47 g of N-(5-tetrazolyl)-4,6-dimethyl-2-pyridinecarboxamide is obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH:21]1([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:28]3[CH2:29][CH2:30][N:25]([CH2:24][CH:21]4[CH2:23][CH2:22]4)[CH2:26][CH2:27]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: C1CN(CC2CC2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCN(CC2CC2)CC1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 1-(cyclopropylmethyl)piperazine (57184-25-5) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=407.6 [MH+].
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:15]([NH2:18])(=[O:17])=[O:16])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1.CC(C)([O-])C.[K+].[CH2:25]([SH:27])[CH3:26]>C(O)(C)(C)C>[CH2:25]([S:27][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([S:15]([NH2:18])(=[O:17])=[O:16])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=2)[N:7]=1)[CH3:26]
Reactant: NS(=O)(=O)c1c(C(F)(F)F)nc2ccc(Cl)nn12
Reactant: CCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCSc1ccc2nc(C(F)(F)F)c(S(N)(=O)=O)n2n1
Temperature: 25 °C

Procedure:
6-Chloro-2-trifluoromethylimidazo[1,2-b]pyridazin-3-ylsulfonamide (1.00 g, 3.33 mmol) was suspended in t-butyl alcohol (20.0 ml) and stirred at room temperature, during which potassium t-butoxide (80%, 1.40 g, 9.98 mmol) and ethanethiol (0.54 ml, 7.29 mmol) were added thereto. After the mixture was heated for 4 hours under reflux, the reaction solution was left and cooled to room temperature, poured into ice-water (200 ml) and adjusted to pH 3. The precipitated crystals were filtered and washed with water to give the title compound as colorless crystals. The yield was 0.54 g (50.0%).