Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]([CH3:8])[CH3:7])(=[O:4])[C:2]#[CH:3].[Na+].[I-:10]>CC(O)=O>[I:10]/[CH:3]=[CH:2]\[C:1]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4]
Reactant: [I-]
Reactant: C#CC(=O)OC(C)C
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)OC(=O)/C=C\I
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 84.1 %

Procedure:
To a mixture of isopropyl propiolate (350 g, 3.1 moles) in AcOH (1300 mL) was added NaI (930 g, 6.2 moles) at 25° C. The reaction mixture was heated to 115° C. and stirred for 1.5 hrs. The reaction mixture was cooled to 25 to 30° C. and quenched with water followed by extraction with MTBE. The organic layer was washed with saturated bicarbonate, bisulfite and brine solution. The organic layer was dried over sodium sulfate and concentrated under vacuum to give the product (Z)-isopropyl 3-iodoacrylate (626 g; 83.5%). Product was confirmed by 1H NMR.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:23][C:24](=[O:39])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[N:34]2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([N:33]5[CH:37]=[CH:36][N:35]=[N:34]5)[CH:28]=4)[CH2:25][C:24](=[O:39])[NH:23][C:9]=3[CH:10]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnn3)c2)=Nc2ccc(C#Cc3ccc(F)cc3)cc2N1

Procedure:
Prepared from {4-(4-fluoro-phenylethynyl)-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example K82) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (53 mg).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:35]2[CH2:34][CH2:33][N:32]([C:26]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH2:37][CH2:36]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: COc1ccc(N2CCNCC2)cc1OC
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccc(OC)c(OC)c3)CC2)c(OC)nc1C
Yield: 69 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3,4-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH:17]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18]3)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:45]=[CH:44][CH:43]=[C:42]3[C:38]=2[CH:39]=[N:40][NH:41]3)O1>>[NH:41]1[C:42]2[C:38](=[C:37]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[S:10][C:9]([CH2:11][N:12]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:17]5[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18]5)=[CH:8][C:6]=4[N:7]=3)[CH:45]=[CH:44][CH:43]=2)[CH:39]=[N:40]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CN1CCC(N(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)S(C)(=O)=O)C1
Product: CN1CCC(N(Cc2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)S(C)(=O)=O)C1

Procedure:
N-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-N-(1-methyl-pyrrolidin-3-yl)-methanesulfonamide was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in General Procedure A to yield 195. NMR: (CDCl3): 1.96 (1H, m); 2.19 (2H, m); 2.33 (4H, m); 2.48 (1H, m); 2.90 (5H, m); 3.94 (4H, m); 4.10 (4H, m); 4.57 (1H, m); 4.90 (2H, s); 7.50 (1H, s); 7.53 (1H, d, J=7.4 Hz); 7.10 (1H, d, J=8.2 Hz); 8.30 (1H, d, J=7.1 Hz); 9.03 (1H, s); 10.14 (1H, br s). MS: (ESI+): MH+=528
Reaction SMILES: [C:1]1([N:7]([CH2:9][CH2:10][CH3:11])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].C(O)(C)C.[S:21]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:28](Cl)=[O:29])(=[O:24])(=[O:23])[NH2:22]>O>[CH2:9]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH:8][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:33]([Cl:34])=[C:25]([S:21](=[O:23])(=[O:24])[NH2:22])[CH:26]=1)[CH2:10][CH3:11]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: CCCN(N)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCCN(NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccccc1
Temperature: 25 °C

Procedure:
A vigorously stirred mixture of 14.0 g (0.1 mol) 1-phenyl-1-n-propylhydrazine, 8.4 g (0.1 mol) sodium bicarbonate, and 100 ml isopropanol was chilled to 0°-5° C., 23 g (0.09 mol) 3-sulfamoyl-4-chlorobenzoyl chloride was added in one portion, and the reaction mixture was allowed to stir for several hours, gradually warming to room temperature. Dilution with water and refrigeration overnight yielded solid material which was collected and recrystallized from acetone/water, mp. 102° C. (d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:5]=[CH:4][N:3]=1.[F:14][CH:15]([F:24])[CH2:16][N:17]1[CH:21]=[C:20](I)[N:19]=[C:18]1[CH3:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:20]2[N:19]=[C:18]([CH3:23])[N:17]([CH2:16][CH:15]([F:24])[F:14])[CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Reactant: Cc1nc(I)cn1CC(F)F
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1CC(F)F

Procedure:
The title compound, MS: m/e=282.0 (M+H+), was prepared in accordance with the general method of example A, step 2, from 2-chloro-4-trimethylsilanylethynyl-pyridine and 1-(2,2-difluoro-ethyl)-4-iodo-2-methyl-1H-imidazole.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH:11]([N:12]([CH3:23])S(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[C:3]1=[CH:26][CH2:27][OH:28].[Na].[ClH:31]>N>[ClH:31].[CH3:1][C:2]1([CH3:29])[CH:11]([NH:12][CH3:23])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[CH:3]1[CH2:26][CH2:27][OH:28]
Reactant: COc1ccc2c(c1)C(=CCO)C(C)(C)C(N(C)S(=O)(=O)c1ccc(C)cc1)C2
Agent: Cl
Agent: N
Agent: [Na]
Product: CNC1Cc2ccc(OC)cc2C(CCO)C1(C)C
Reaction time: 0.25 h

Procedure:
This compound, described already in Examples 12 and 13, can also be prepared as described in Example 13, however, starting from 2,2-dimethyl-1-(2-hydroxyethylidene)-7-methoxy-3-(N-methyl-p-toluenesulfonamido)1,2,3,4-tetrahydronaphthalene. In this case, both the reduction of the olefinic double bond and the reductive cleavage of the p-toluenesulphonamido group are effectuated by the sodium metal dissolving in liquid ammonia. The endpoint of the reduction is reached if the blue colour persists for some 15 minutes. In this case again, a mixture of two stereoisomers is obtained, the total yield being 87% of crystalline hydrochloride.
Reaction SMILES: [CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:13]4[N:14]=[N:15][N:16]([C:19]5[C:20](F)=[N:21][CH:22]=[CH:23][CH:24]=5)[C:17]=4[CH3:18])[CH:10]=3)[C:5]2=[O:26])[CH2:3][CH2:2]1.C(O)=[O:28]>>[CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:13]4[N:14]=[N:15][N:16]([C:19]5[C:20]([OH:28])=[N:21][CH:22]=[CH:23][CH:24]=5)[C:17]=4[CH3:18])[CH:10]=3)[C:5]2=[O:26])[CH2:3][CH2:2]1
Reactant: Cc1c(-c2ccc3c(c2)CN(C2CC2)C3=O)nnn1-c1cccnc1F
Reactant: O=CO
Product: Cc1c(-c2ccc3c(c2)CN(C2CC2)C3=O)nnn1-c1cccnc1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
180 mg of 4-(2-cyclopropyl-1-oxo-isoindoline-5-yl)-1-(2-fluoropyridine-3-yl)-5-methyl-1H-[1,2,3]triazole obtained in Example 49 was dissolved in 10 ml of formic acid, and the mixture was stirred for 5 hours. After cooling down to room temperature, the residues obtained by distilling out the solvents under reduced pressure were purified by silicagel column chromatography (chloroform:methanol=90:10) to obtain 112 mg of the above compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:21])[O:8][C:9]([C:14](=[O:20])[N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])([CH2:12][CH3:13])[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH3:22][N:23]([CH:25](N(C)C)N(C)C)[CH3:24]>CN(C)C=O.ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:21])[O:8][C:9]([C:14](=[O:20])[N:15]([CH2:16][CH3:17])[CH2:18][CH3:19])([CH2:12][CH3:13])[C:10]=1/[CH:11]=[CH:22]/[N:23]([CH3:25])[CH3:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)C(CC)(C(=O)N(CC)CC)OC1=O
Reactant: CN(C)C(N(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1=C(/C=C/N(C)C)C(CC)(C(=O)N(CC)CC)OC1=O
Reaction time: 17 h
Yield: 90.2 %

Procedure:
To a solution of 500.0 mg of compound (12) as obtained from example 5 (22.73 mmol) in 3.0 mL dimethyl formamide were added at room temperature 3.0 mL tris(dimethylamino)methane (17.3 mmol, 10.3 eq). The color of the reaction mixture changed from orange to brown and further to green. After 17 h, the mixture was diluted with 50 mL dichloromethane, washed with 25mL aqueous hydrochloric acid (1.0 M) and washed again three times with 50 mL brine. The organic phase was dried over 2 g sodium sulfate and was filtered. The filter cake was washed with 4 mL dichloromethane. After evaporation of the solvent in a rotary evaporator (50° C., 5 mbar), the crude product was obtained as an orange oil (627.0 mg, 106% by weight), which was liberated from residual dimethyl formamide in a high vacuum rotary evaporator (50° C., 0.5 mbar) yielding the title product (536.0 mg, 1.517 mmol, 90% by weight) as orange crystals.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:14](OC(C)(C)C)=[O:15]>CCO>[N:14]([C:10]1[CH:9]=[N:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]=1[NH2:12])=[O:15]
Reactant: Nc1ccnn1-c1ccccc1
Reactant: CC(C)(C)ON=O
Agent: Cl
Solvent: CCO
Product: Nc1c(N=O)cnn1-c1ccccc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To a solution of 2-phenyl-2H-pyrazol-3-ylamine (250 mg, 1.57 mmol) in EtOH (3 mL) is added HCl (4N in dioxane, 1.15 mL, 4.6 mmol). The mixture is then cooled down to −10° C., tert-butyl nitrite (178 mg, 1.73 mmol) is added drop wise. After addition, the mixture is stirred at 0° C. for 1 h. The precipitate is collected by filtration to provide 4-nitroso-2-phenyl-2H-pyrazol-3-ylamine (180 mg, 60%) as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C@@H:23]([C:37]([OH:39])=O)[CH2:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[C:28]([NH2:35])=[C:27]([Cl:36])[CH:26]=4)=[O:21])[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:40]=1.[CH2:41]([O:43][C:44](=[O:58])[CH2:45][N:46]1[CH2:51][CH2:50][N:49]([CH:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[CH2:48][CH2:47]1)[CH3:42]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C@H:23]([CH2:24][C:25]4[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[C:28]([NH2:35])=[C:27]([Cl:36])[CH:26]=4)[C:37]([N:55]4[CH2:56][CH2:57][CH:52]([N:49]5[CH2:50][CH2:51][N:46]([CH2:45][C:44]([O:43][CH2:41][CH3:42])=[O:58])[CH2:47][CH2:48]5)[CH2:53][CH2:54]4)=[O:39])=[O:21])[CH2:18][CH2:19]3)[CH2:9][CH2:8][C:7]=2[CH:40]=1
Reactant: CCOC(=O)CN1CCN(C2CCNCC2)CC1
Reactant: COc1ccc2c(c1)CCN(C1CCN(C(=O)O[C@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)C(=O)O)CC1)C(=O)N2
Product: CCOC(=O)CN1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5cc(OC)ccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 9 from 100 mg (0.17 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 49 mg (0.19 mmol) ethyl(4-piperidin-4-yl-piperazin-1-yl)-acetate.
Reaction SMILES: [CH:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[NH2:20]>>[CH3:16][O:17][C:18](=[O:23])[C:19]([NH:20][C:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:12]=1)=[O:15])([CH3:22])[CH3:21]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1cccc(C2CCCCC2)n1
Product: COC(=O)C(C)(C)NC(=O)c1cccc(C2CCCCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclohexyl-pyridine-2-carboxylic acid and 2-methyl-alanine methyl ester as starting materials, MS (LC/MS): 305.1 (M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([NH:13][C:14]([C:16]3[CH:17]=[N:18][C:19](S(C)(=O)=O)=[N:20][CH:21]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[N:27]1[C:28]([CH2:36][OH:37])=[CH:29][N:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=12.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([NH:13][C:14]([C:16]3[CH:17]=[N:18][C:19]([O:37][CH2:36][C:28]4[N:27]=[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][N:30]5[CH:29]=4)=[N:20][CH:21]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: OCc1cn2ccccc2n1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cnc(S(C)(=O)=O)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cnc(OCc2cn3ccccc3n2)nc1
Temperature: 67 °C
Yield: 23.3 %

Procedure:
A mixture of N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-(methylsulfonyl)pyrimidine-5-carboxamide (120 mg, 0.32 mmol), imidazo[1,2-a]pyridine-2-methanol (48 mg, 0.32 mmol) and potassium carbonate (44 mg, 0.32 mmol) in THF (5 mL) was heated to 67° C. for 3.5 h. The mixture was cooled to room temperature and partitioned between DCM and water and the layers separated. The aqueous layer was extracted with DCM and the combined organic extracts dried (MgSO4), filtered and concentrated at reduced pressure to give a yellow oil. This material was purified by silica column chromatography, eluting with a gradient of 0 to 8% methanol in DCM to give the title compound as a white solid (33 mg, 23%); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.67 (m, 2H), 2.27 (s, 3H), 2.83 (m, 1H), 5.70 (s, 2H), 7.26 (t, 1H), 7.35 (d, 1H), 7.66 (m, 2H), 7.78 (d, 1H), 7.83 (d, 1H), 8.30 (s, 1H), 8.38 (d, 1H), 8.75 (d, 1H), 9.17 (s, 2H), 10.16 (s, 1H); Mass Spectrum: m-H− 441, 443.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:12](Cl)=[N:13][OH:14])=[C:6]2[C:10]=1[O:9][C:8]([CH3:11])=[N:7]2.[Cl:16][C:17]1[CH:22]=[C:21]([C:23]([C:25]([F:28])([F:27])[F:26])=[CH2:24])[CH:20]=[C:19]([Cl:29])[CH:18]=1.C(=O)([O-])O.[Na+]>CC(O)C>[Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])=[N:7][C:6]=2[C:5]([C:12]2[CH2:24][C:23]([C:21]3[CH:20]=[C:19]([Cl:29])[CH:18]=[C:17]([Cl:16])[CH:22]=3)([C:25]([F:26])([F:28])[F:27])[O:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc2c(C(Cl)=NO)ccc(Br)c2o1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1nc2c(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc(Br)c2o1
Temperature: 65 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
To a solution of 7-bromo-N-hydroxy-2-methyl-benzo[d]oxazole-4-carbimidoyl chloride (3.63 g) in 2-propanol (100 ml) was added 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (preparation described in, for example, EP 1,731,512) (3.43 g) and sodium hydrogen carbonate (1.44 g). The reaction mixture was stirred at 65° C. for 16 hours. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (eluent: 2-25% v/v ethyl acetate in heptane) to give 7-bromo-4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl)-2-methyl-benzo[d]oxazole (3.7 g). 1H-NMR (400 MHz, CDCl3): 7.71-7.42 (m, 5H), 4.50 (d, 1H), 4.06 (d, 1H), 2.73 (s, 3H) ppm.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)=[O:16])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: NCCc1ccc(O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCc1ccc(O)cc1)O2
Yield: 72.8 %

Procedure:
Following the amide coupling procedure described in protocol A, 500 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.0 mmol), 356 mg CDI (2.2 mmol) and 548 mg tyramine (4.0 mmol) produced 537.8 mg of 6-hydroxy-N-(4-hydroxyphenethyl)-2,5,7,8-tetramethylchroman-2-carboxamide as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C:8](=[O:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.O>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]([OH:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)COC(=O)c1ccccc1
Reactant: [H][H]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)COC(=O)c1ccccc1
Temperature: 50 °C
Yield: 89 %

Procedure:
To (S)-6-benzoyloxy-3-oxo-5-hydroxyhexanoic acid tert-butylester (161 mg, 0.50 mmol) and RuBr2(R)-BINAP (4.4 mg, 0.0050 mmol) (BINAP was 2,2′-bisdiphenylphosphino-1,1′-binaphthyl), 2 mL of a methanol-water (10/1) solution was added to completely dissolve the (S)-6-benzoyloxy-3-oxo-5-hydroxyhexanoic acid tert-butylester and RuBr2(R)-BINAP in an argon atmosphere. Hydrogen replacement at −78° C. was performed three times. After the temperature of the resulting mixture had increased to 50° C., the mixture was allowed to react for twenty hours under a hydrogen pressure of 5.0 kg/cm2. After extraction of hydrogen, the mixture was condensed and purified by silica gel column chromatography. As a result, 144.4 mg (89%) of (3R, 5S)-6-benzoyloxy-3,5-dihydroxyhexanoic acid tert-butylester was obtained. The diastereomer ratio determined by high performance liquid chromatography (HPLC) analysis was (3R, 5S):(3S, 5S)=93.5/6.5 (Chiralcel-AD, hexane/isopropanol=95/5, 1.0 mL/min, UV=210 nm. Retention time: (3R, 5S) 28.2 min, (3S, 5S) 42.9 min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[CH3:9][OH:10]>OS(O)(=O)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:8])[N:5]=[C:6]([CH2:9][OH:10])[CH:7]=1
Reactant: Cc1cc(Br)ccn1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(Br)cc(CO)n1
Reaction time: 2 h

Procedure:
A solution of 4-bromo-2-methyl-pyridine (735 mg, 4.14 mmol) in methanol (80 mL) and H2SO4 (20 μL) is heated to reflux. A solution of (NH4)2S2O8 (3.78 g, 16.6 mmol) in water (6.5 mL) is added dropwise to the stirred mixture. Upon completion of the addition, refluxing is continued for 2 h. The mixture is cooled and the reaction is quenched by adding 1 M aq. NaS2O3 solution. The mixture is further diluted with sat. aq. NaHCO3 solution and extracted twice with EA (2×300 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 3:2 to give (4-bromo-6-methyl-pyridin-2-yl)-methanol (156 mg) as a white solid; LC-MS: tR=0.32 min, [M+1]+=201.93.
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2Br)[CH:6]=1)C.C(=O)([O-])[O-].[K+].[K+].[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(COC)OC>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:12]1[CH2:13][CH2:14][CH2:15][C:11]=1[C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1ccccc1OCc1ccccc1
Reactant: CCOC(=O)c1cccc(C2=C(Br)CCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=C(O)c1cccc(C2=C(c3ccccc3OCc3ccccc3)CCC2)c1

Procedure:
3-(2-Bromo-cyclopent-1-enyl] benzoic acid ethyl ester (0.148 g, 0.0005 mol), tetrakis-triphenylphosphine palladium (o) (30 mg), potassium carbonate (0.200 g) and (2-benzyloxyphenyl) boronic acid (0.110 g, 0.5 mmol) in dimethoxyethane (5 mL) were refluxed for 17 h under nitrogen. The reaction mixture was then filtered through Keiselghur and evaporated down to an oil. Purification was carried out on a Waters separation pack (10 g) cartridge with dichloromethane/iso hexane giving the product (120 mg).
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C(O)=O)(F)(F)F>C(Cl)Cl>[NH:12]1[CH2:13][CH2:14][C@H:10]([O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OC(=O)c2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O[C@H]1CCNC1)c1ccccc1
Yield: 191.9 %

Procedure:
tert-Butyl(3S)-3-(benzoyloxy)pyrrolidine-1-carboxylate (635 mg, 2.18 mmol) was treated with 20% CF3CO2H in CH2Cl2 (20 mL) overnight at room temperature. The volatiles were removed in vacuo to give the subtitled compound (800 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)=[O:11])#[N:2].Cl.[CH3:25][N:26](C)[CH2:27]CCN=C=NCC.ON1C2C=CC=CC=2N=N1.CNC.Cl>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:26]([CH3:27])[CH3:25])=[O:17])=[CH:14][CH:13]=1)=[O:11])#[N:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: N#Cc1cccc(OCCCC(=O)c2ccc(C(=O)O)cc2)c1
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(C(=O)CCCOc2cccc(C#N)c2)cc1

Procedure:
240 mg (0.78 mmol) of 4-[4-(3-cyanophenoxy)butyryl]benzoic acid, 150 mg (0.78 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 121 mg (0.78 mmol) of 1-hydroxybenzotriazole (hydrous, 87%) and 100 mg of 50% aqueous dimethylamine solution were stirred together in 5 ml of dimethylformamide at room temperature overnight. 1 N hydrochloric acid was added to the resultant mixture. After the extraction with dichloromethane, the extract was washed with saturated aqueous sodium hydrogencarbonate solution and then with saturated aqueous NaCl solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was purified by the silica gel chromatography with ethyl acetate as the eluent to obtain the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[C:24]([F:32])[CH:23]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6]C=CC=1.Br[CH2:34]C=C(C)C>>[CH3:6][C:7]([CH3:34])=[CH:2][CH2:1][N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:29])=[O:30])=[C:24]([F:32])[CH:23]=2)[CH:10]=[N:9]1
Reactant: CC(C)=CCBr
Reactant: NS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1F
Product: CC(C)=CCn1ncc(-c2ccc(S(N)(=O)=O)c(F)c2)c(-c2ccc(F)cc2)c1=O
Yield: 30 %

Procedure:
2-Benzyl-4-(4-fluorophenyl)-5-[3-fluoro-4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone, prepared according to the method of Example 68, was N-debenzylated according to the method of Example 11. The intermediate was N-alkylated according to the method of Example 20, substituting 1-bromo-3-methyl-2-butene in place of 4-fluorobenzyl bromide, to provide the title compound (yield: 50 mg, 30%). mp 134-136° C. 1H NMR (300 MHz, CDCl3) δ 1.79 (s, 3H), 1.86 (s, 3H), 4.78 (s, 2H), 4.85 (d, J=7.5 Hz, 2H), 5.48 (t, J=6 Hz, 1H), 6.96 (t, J=9 Hz, 2H), 7.18 (dd, J=9 Hz, 6 Hz, 2H), 7.28 (d, J=9 Hz, 2H), 7.83 (s, 1H), 7.85 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 414 (M+H)+. Anal. calc. for C21H20FN3O3S: C, 61; H, 4.87; N, 10.16. Found: C, 60.98; H, 4.66; N, 9.95.