Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)(C)C.[CH:6]1([NH2:9])[CH2:8][CH2:7]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]3([C:30]4[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=4[OH:37])[CH2:29][CH2:28]3)[C:21]2=[O:38])[CH:14]=1.Cl>C1COCC1.O>[CH:6]1([NH:9][C:12](=[O:11])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]4([C:30]5[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=5[OH:37])[CH2:29][CH2:28]4)[C:21]3=[O:38])[CH:14]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)c1ccc(C)c(-n2ccnc(NC3(c4cc(F)ccc4O)CC3)c2=O)c1
Reactant: NC1CC1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3cc(F)ccc3O)CC2)c1=O
Reaction time: 1 h

Procedure:
Isopropylmagnesium chloride (5.86 mL of a 2M solution in THF) was added over 20 min to a solution of cyclopropylamine (2.066 mL) and 3-[3-[[1-(5-fluoro-2-hydroxyphenyl)cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoic acid methyl ester (Example 278c, 1.2 g) in THF (200 mL) at room temperature under nitrogen. The reaction mixture was stirred for 1 h. Water and 2M HCl were cautiously added and the aqueous layer extracted with dichloromethane (3×200 mL), dried (MgSO4) and the solvent removed to give the subtitle compound (1.22 g)
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)=[N:7][O:8][C:4]=2[C:3]=1[C:22]([OH:24])=O.CCN(C(C)C)C(C)C.[NH2:34][C:35]1[CH:36]=[N:37][C:38]([NH:41][C:42](=[O:44])[CH3:43])=[N:39][CH:40]=1>CN(C=O)C>[C:42]([NH:41][C:38]1[N:39]=[CH:40][C:35]([NH:34][C:22]([C:3]2[C:4]3[O:8][N:7]=[C:6]([NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:19])[F:18])[CH:11]=4)[C:5]=3[CH:20]=[CH:21][C:2]=2[Cl:1])=[O:24])=[CH:36][N:37]=1)(=[O:44])[CH3:43]
Reactant: CC(=O)Nc1ncc(N)cn1
Reactant: O=C(O)c1c(Cl)ccc2c(Nc3cccc(C(F)(F)F)c3)noc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ncc(NC(=O)c2c(Cl)ccc3c(Nc4cccc(C(F)(F)F)c4)noc23)cn1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A round-bottomed flask was charged with 6-chloro-3-(3-(trifluoromethyl)phenylamino)benzo[d]isoxazole-7-carboxylic acid (0.1 g, 0.28 mmol, made by the method described in Example 1), n,n-diisopropylethylamine (0.07 mL, 0.42 mmol), o-(7-azabenzotriazol-1-yl)-n,n,n′,n-tetramethyluronium hexafluorophosphate (0.15 g, 0.39 mmol), and DMF (1 mL). This mixture was stirred for 15 min before N-(5-aminopyrimidin-2-yl)acetamide (0.045 g, 0.29 mmol, Step B) was introduced. The reaction mixture was stirred at 60° C. for 16 h, then partitioned between EtOAc (15 ml) and brine (10 mL). The aqueous layer was back exacted with EtOAc (3×10 mL) and the combined EtOAc layer was dried (Na2SO4) and concentrated. The crude product was dissolved in DCM and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 0% to 4% of MeOH in CH2Cl2, to provide N-(2-acetamidopyrimidin-5-yl)-6-chloro-3-(3-(trifluoromethyl)phenylamino)benzo[d]isoxazole-7-carboxamide as an off-white solid. MS (ESI, pos. ion) m/z: 491 (M+1).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:26]#[N:27]>[OH-].[Na+]>[Br:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:26]#[N:27]
Reactant: Oc1cccc(Br)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2ncc(C#N)c(Oc3cccc(Br)c3)c2cc1OC
Temperature: 170 °C

Procedure:
A mixture of 0.16 g of 88% KOH and 1.73 g of 3-bromophenol at 50° C. was treated with 0.50 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile. The resulting mixture was heated to 170° C. during 30 min, cooled, and treated at 0° C. with 40 ml of 0.1N NaOH. The solid which resulted was filtered, washed with water, and dissolved in methylene chloride. The solution was washed with 0.5 N NaOH and water, dried, and concentrated. The resulting solid was recrystallized from methylene chloride-hexane to give 4-(3-bromophenoxy)-6,7-dimethoxy-3-quinolinecarbonitrile as a white solid, mp 187-190° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:29][CH2:28][CH2:27][C@H:9]1[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH:17]([OH:26])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:11])=[O:7])(C)(C)C.C(N(CC)CC)C.[O:37]([CH2:44]C(Cl)=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>Cl.O1CCOCC1.C(Cl)Cl>[OH:26][CH:17]([C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C:10](=[O:11])[C@@H:9]1[CH2:27][CH2:28][CH2:29][N:8]1[C:6](=[O:7])[CH2:44][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccccc1
Reactant: O=C(Cl)COc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(COc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
(2S)-1-[N-(tert-Butoxycarbonyl)-L-prolyl]-2-(1-hydroxy-2-phenoxyethyl)pyrrolidine (996 mg) was dissolved in 4N hydrochloric acid/1,4-dioxane (12 ml), and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated to dryness, and the residue obtained was dissolved in methylene chloride (10 ml). After triethylamine (0.68 ml) was added thereto under ice-cooling, phenoxyacetyl chloride (0.34 ml) was dropwise added. After stirring the mixture under ice-cooling for 0.5 hour, and then at room temperature for 1.5 hours, the reaction mixture was poured into ice-water, and extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium bicarbonate, and saturated brine successively, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluate: chloroform-methanol) to give 1.05 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([O:11][CH2:12][C:13]([F:26])([F:25])[C:14]([F:24])([F:23])[C:15]([F:22])([F:21])[C:16]([F:20])([F:19])[CH2:17][OH:18])=[C:5]([F:27])[C:4]=1[F:28].Cl[C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:32]=1[N+:40]([O-:42])=[O:41].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[CH3:1][N:2]([CH3:29])[C:3]1[C:4]([F:28])=[C:5]([F:27])[C:6]([O:11][CH2:12][C:13]([F:26])([F:25])[C:14]([F:23])([F:24])[C:15]([F:21])([F:22])[C:16]([F:19])([F:20])[CH2:17][O:18][C:35]2[CH:36]=[CH:31][C:32]([N+:40]([O-:42])=[O:41])=[CH:33][C:34]=2[N+:37]([O-:39])=[O:38])=[C:7]([F:10])[C:8]=1[F:9]
Reactant: CN(C)c1c(F)c(F)c(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO)c(F)c1F
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN(C)c1c(F)c(F)c(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)COc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])c(F)c1F
Yield: 73.2 %

Procedure:
N,N-Dimethyl-4-(6-hydroxy-2,2,3,3,4,4,5,5-octafluorohexyloxy)-2,3,5,6-tetrafluorobenzeneamine (1.05 g) was treated with 1-chloro-2,4-dinitrobenzene (0.51 g) and potassium carbonate (0.35 g) in NMP (5 mL) at 80° C. for 21.5 hrs. The mixture was diluted with water and extracted with ethyl ether. The extracts were washed with water and brine, dried (K2CO3), and concentrated to an orange oil. The oil was purified by chromatography to give N,N-dimethyl-4-[6-(2,4-dinitrophenoxy)-2,2,3,3,4,4,5,5-octaflurohexyloxy]-2,3,5,6-tetrafluorobenzeneamine (1.05 g) as an oil.
Reaction SMILES: [CH:1]1([CH2:6][C:7](=[O:48])/[CH:8]=[CH:9]\[C@H:10]([CH3:47])[C@H:11]([O:39][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41])[C@@H:12]([CH3:38])/[CH:13]=[C:14](/[CH3:37])\[CH2:15][C@H:16]([CH3:36])[C@@H:17]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C@H:18]([CH3:27])[C@@H:19]([OH:26])[C@@H:20]([CH3:25])/[CH:21]=[CH:22]\[CH:23]=[CH2:24])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)[C:51]([N:53]=C=O)=[O:52]>C(Cl)Cl>[NH2:53][C:51]([O:26][C@@H:19]([C@@H:20]([CH3:25])/[CH:21]=[CH:22]\[CH:23]=[CH2:24])[C@@H:18]([CH3:27])[C@H:17]([O:28][Si:29]([C:32]([CH3:33])([CH3:34])[CH3:35])([CH3:30])[CH3:31])[C@@H:16]([CH3:36])[CH2:15]/[C:14](/[CH3:37])=[CH:13]\[C@H:12]([CH3:38])[C@@H:11]([O:39][Si:40]([C:43]([CH3:44])([CH3:45])[CH3:46])([CH3:42])[CH3:41])[C@@H:10]([CH3:47])/[CH:9]=[CH:8]\[C:7](=[O:48])[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:52]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\C(=O)CC1CCCC1
Solvent: ClCCl
Product: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\C(=O)CC1CCCC1
Temperature: 23 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
A solution of (3Z,5S,6S,7S,8Z,11S,12R,13R,14S,15S,16Z)-1-cyclopentyl-6,12-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-14-hydroxy-5,7,9,11,13,15-hexamethyl-3,8,16,18-nonadecatetraen-2-one (420 mg, 0.60 mmol, 1 eq) in CH2Cl2 (10 mL) is treated with trichloroacetyl isocyanate (135 mg, 0.72 mmol, 1.2 eq) at 23° C. (20 minutes). The solution is concentrated, and the residue dissolved in CH3OH (10 mL). To this solution is added K2CO3 (0.2 g) and the mixture is stirred at 23° C. (3 hours). The reaction mixture is concentrated and the residue dissolved in Et2O (20 mL). The organic solution is washed with H2O (1×10 mL) and brine (1×20 mL). The aqueous layer is extracted with Et2O (3×10 mL) and the combined extracts are dried (Na2SO4) and concentrated. Chromatography (SiO2, 30–50% EtOAc-hexanes gradient elution) provides (3Z,5S,6S,7S,8Z,11S,12R,13R,14S,15S,16Z)-14-[(aminocarbonyl)oxy]-1-cyclopentyl-6,12-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5,7,9,11,13,15-hexamethyl-3,8,16,18-nonadecatetraen-2-one (420 mg, 94%).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7].Br[CH2:9][CH2:10][CH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:12][CH2:11][CH2:10][CH2:9][N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7]
Reactant: OCCCBr
Reactant: O=C1CCC(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CCC(=O)N1CCCO
Yield: 32.8 %

Procedure:
A solution of pyrrolidine-2,5-dione (5 g, 50.5 mmol) and 3-bromopropan-1-ol (6.85 ml, 76 mmol) in acetonitrile (80 ml) containing potassium carbonate (14 g, 100 mmol) was refluxed overnight. After cooling, the mixture was filtered and the filtrate was evaporated. The residue was dissolved in methylene chloride and purified by column chromatography, eluting with ethylacetate/petroleum ether (4/1). After evaporation of the volatiles, the residue was distilled at 100-125° C. under about 0.1 mm Hg to give 1-(3-hydroxypropyl)pyrrolidin-2,5-dione (2.6 g, 34%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][C:33]1[O:34][C:35]([CH:38](O)[CH2:39][CH3:40])=[CH:36][CH:37]=1.[OH:42][C:43]1[C:50]([CH3:51])=[CH:49][C:46]([C:47]#[N:48])=[CH:45][C:44]=1[CH3:52]>C(Cl)Cl>[CH3:32][C:33]1[O:34][C:35]([CH2:38][CH2:39][CH2:40][O:42][C:43]2[C:50]([CH3:51])=[CH:49][C:46]([C:47]#[N:48])=[CH:45][C:44]=2[CH3:52])=[CH:36][CH:37]=1
Reactant: CCC(O)c1ccc(C)o1
Reactant: Cc1cc(C#N)cc(C)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(CCCOc2c(C)cc(C#N)cc2C)o1
Reaction time: 0.17 h
Yield: 80.7 %

Procedure:
Diethyl azodicarboxylate (DEAD, 11.9 mL; 75.6 mmol) was added dropwise over a 10 min period to a solution of triphenylphosphine (19.8 g; 75.6 mmol), (2-methyl-5-furanyl)propanol (ex 1a, 9c and 12a) (10.6 g; 75.6 mmol), and 4-hydroxy-3,5-dimethyl-benzonitrile (12.2 g; 83.2 mmol) in methylene chloride cooled in an ice-bath under nitrogen with stirring. After 10 min, a solid formed. Additional methylene chloride (50 mL) was added to the mixture and the resulting suspension was filtered. The filtrate was washed with water (2×100 mL) and brine (1×100 mL). The organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo to yield a brown oil which crystallized on standing. The solid product was chromatographed on silica gel eluting with ethyl acetate/hexane (2:8), and the appropriate fractions were concentrated in vacuo to afford 16.43 g (81%) of 2-methyl-5-[3-(2,6-dimethyl-4-cyanophenoxy)-propyl)furan. The cyano moiety is then elaborated to a suitably substituted 5-tetrazolyl moiety as in the preparation of Intermediates 5-6 or oxadiazolyl as in Intermediates 7-8, giving a compound of formula II wherein R3 is methyl, R4 is hydrogen, R1, R2 is 3,5-dimethyl Y is 1,3-propylene and R5 is as described.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])([CH2:12][CH2:13]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1.[CH3:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[CH3:27][C:28]1[N:33]=[CH:32][C:31]([O:1][C:2]2[CH:3]=[C:4]([C:8]34[CH2:15][CH2:14][C:11]([CH2:16][CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21])([CH2:12][CH2:13]3)[CH2:10][O:9]4)[CH:5]=[CH:6][CH:7]=2)=[CH:30][CH:29]=1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(O)c3)(CC1)OC2
Product: Cc1ccc(Oc2cccc(C34CCC(CCOCC(=O)O)(CC3)CO4)c2)cn1

Procedure:
Example 115 was synthesized using the same 2-step protocol as for the syntheses of Examples 39-45 from intermediate phenol 7F, but with 6-methylpyridin-3-ylboronic acid. LCMS, [M−H]+=396.2. 1H NMR (500 MHz, DMSO-d6) δ=8.18 (br. s, 1H), 7.35-7.25 (m, 3H), 7.11 (d, J=7.3 Hz, 1H), 7.00 (br. s, 1H), 6.83 (d, J=7.6 Hz, 1H), 3.95 (s, 2H), 3.58-3.43 (m, 2H), 2.44 (s, 3H), 2.06-1.96 (m, 2H), 1.81-1.72 (m, 2H), 1.68-1.54 (m, 4H), 1.40-1.34 (m, 2H), 1.28-1.20 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10]([OH:12])=[O:11].[CH2:14](O)[CH2:15][CH:16]=[CH2:17]>>[CH3:1][C:2]1([CH3:13])[C@H:4]([CH:5]=[C:6]2[CH2:9][CH2:8][CH2:7]2)[C@H:3]1[C:10]([O:12][CH2:17][CH2:16][CH:15]=[CH2:14])=[O:11]
Reactant: C=CCCO
Reactant: CC1(C)[C@H](C=C2CCC2)[C@H]1C(=O)O
Product: C=CCCOC(=O)[C@@H]1[C@@H](C=C2CCC2)C1(C)C

Procedure:
Using the procedure of Example 1, (1R,trans) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylic acid and 3-buten-1-ol were reacted to obtain 3-buten-1-yl (1R,trans) 2,2-dimethyl-3-cyclobutylidenemethyl-cyclopropane-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:13]2[C:18]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)(=[O:22])=[O:21])=[CH:17][C:16]([Cl:34])=[CH:15][N:14]=2)=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:35][N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:37].F[P-](F)(F)(F)(F)F.N(C)C.C1COCC1.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[C:10]([C:11]([C:13]2[C:18]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)(=[O:22])=[O:21])=[CH:17][C:16]([Cl:34])=[CH:15][N:14]=2)=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:36]([CH3:37])[CH3:35])=[O:6]
Reactant: O=C(O)c1cccc(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1Cl
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cccc(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1Cl
Temperature: 25 °C
Yield: 21.5 %

Procedure:
To a vial containing 2-chloro-3-[5-chloro-3-(4-chloro-3-trifluoromethylbenzenesulfonylamino)-pyridine-2-carbonyl]benzoic acid (24 mg, 0.04 mmol) were added HATU (19 mg, 0.05 mmol), DMF (0.5 mL), a 2.0 M solution of Me2NH in THF (40 μL, 0.08 mmol), and (i-Pr)2NEt (10 μL, 0.06 mmol). The solution was maintained at room temperature for 5 h. EtOAc (10 mL) was added, and the organic phase washed with saturated aqueous NaCl (1×5 mL), 0.1 N acetic acid in water (1×5 mL), and dried over MgSO4. The volatiles were removed in vacuo, and the resulting residue was purified by preparative HPLC (20→95% gradient of MeCN—H2O with 0.1% TFA) and the pure fractions lyophilized to afford the title compound (5 mg, 22% yield): HPLC retention time=2.90 minutes. MS (ES) [M+H]+ expected 580.0, found 579.9. 1H NMR (400 MHz, CDCl3) δ 10.94 (s, 1H), 8.17-8.20 (m, 3H), 7.98 (dd, J=2.4, 8.4 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.41 (d, J=4.4 Hz, 1H), 7.28-7.30 (m, 2H), 3.12 (s, 3H), 2.86 (s, 3H).
Reaction SMILES: [CH2:1]([CH:8]([C:11]#[N:12])[C:9]#[N:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:25][C:26]([F:29])([F:28])[F:27])(=O)=O>CN(C)C=O>[CH2:1]([C:8]([CH2:25][C:26]([F:29])([F:28])[F:27])([C:9]#[N:10])[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: N#CC(C#N)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(Cc1ccccc1)CC(F)(F)F
Yield: 55.5 %

Procedure:
Using 0.1 g of benzylmalononitrile, 5 ml of N,N-dimethylformamide, 0.073 g of cesium carbonate, and 0.1 g of 2,2,2-trifluoroethyl trifluoromethanesulfonate, and according to the process described in the Production Example 1, there was obtained 0.057 g of 2-benzyl-2-(2,2,2-trifluoroethyl)malononitrile (the present compound (3)).
Reaction SMILES: [C:1]1([C:7]2[C:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4([NH:34]C(=O)OC(C)(C)C)[CH2:33][CH2:32][CH2:31]4)=[CH:26][CH:25]=3)=[N:22][C:10]3[O:11][CH2:12][C:13]4[N:14]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O>[C:1]1([C:7]2[C:23]([C:24]3[CH:25]=[CH:26][C:27]([C:30]4([NH2:34])[CH2:33][CH2:32][CH2:31]4)=[CH:28][CH:29]=3)=[N:22][C:10]3[O:11][CH2:12][C:13]4[N:14]([C:15]([C:18]([F:20])([F:19])[F:21])=[N:16][N:17]=4)[C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3C(F)(F)F)CO4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3C(F)(F)F)CO4)cc2)CCC1
Reaction time: 0.01 h
Yield: 27 %

Procedure:
Tert-butyl (1-(4-(8-phenyl-1-(trifluoromethyl)-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (7 mg, 0.012 mmol) was dissolved in TFA (1 ml) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure. This was repeated three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The residue was then slurred in n-hexane (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and the residue was dried to give the desired product as an off-white solid (1.5 mg, 26% yield). LCMS (Method D): RT=0.877 min, M+1=465. 1H-NMR (500 MHz, CD3OD) δ 8.02 (1H, s), 7.50 (2H, d), 7.43 (2H, d), 7.38-7.36 (3H, m), 7.25 (2H, m), 5.77 (2H, s), 2.75-2.69 (2H, m), 2.55-2.42 (2H, m), 2.29-2.17 (1H, m), 2.05-1.90 (1H, m).
Reaction SMILES: [C:1]([C:3]1([C:37]([O:39]C(C)(C)C)=[O:38])[CH:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][N:26]=5)[C:21](=[O:28])[C:20]([C:29]([NH:31][CH:32]5[CH2:34][CH2:33]5)=[O:30])=[CH:19]4)[CH:13]=3)=[CH:8][CH:7]=2)[C:4]1([CH3:36])[CH3:35])#[N:2]>C(Cl)Cl.FC(C(O)=O)(F)F.CSC>[C:1]([C:3]1([C:37]([OH:39])=[O:38])[CH:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][N:26]=5)[C:21](=[O:28])[C:20]([C:29]([NH:31][CH:32]5[CH2:34][CH2:33]5)=[O:30])=[CH:19]4)[CH:13]=3)=[CH:8][CH:7]=2)[C:4]1([CH3:36])[CH3:35])#[N:2]
Reactant: CC(C)(C)OC(=O)C1(C#N)C(c2ccc(-c3cccc(-n4cc(C(=O)NC5CC5)c(=O)c5cccnc54)c3)cc2)C1(C)C
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)C(c2ccc(-c3cccc(-n4cc(C(=O)NC5CC5)c(=O)c5cccnc54)c3)cc2)C1(C#N)C(=O)O

Procedure:
The ester from step 3 (1 eq) in CH2Cl2-TFA-DMS (3:2:1, 0.2M) was stirred at rt for 48 h. The volatiles were evaporated, the residue triturated in ether and then isolated by filtration to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH:10]([F:12])[F:11])[NH2:5].C(N(CC)CC)C.[CH3:20][C:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:24]([C:21]2([CH3:20])[CH2:23][CH2:22]2)=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([F:11])[F:12]
Reactant: Nc1ccc(OC(F)F)c(Cl)c1
Reactant: CC1(C(=O)Cl)CC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C(=O)Nc2ccc(OC(F)F)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of 3-chloro-4-difluoromethoxyaniline (1.95 g) in methylene chloride (50 ml), triethylamine (1.1 g) was added, and a solution of 1-methylcyclopropanecarbonyl chloride (1.2 g) in methylene chloride was dropwise added while cooling with ice-water. The reaction mixture was stirred at room temperature for 1 hour, admixed with water and extracted with ether. The extract was washed with 1 N hydrochloric acid, sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to give crude crystals (2.6 g). Recrystallization from ethanol gave N-(3-chloro-4-difluoromethoxyphenyl)-1-methylcyclopropanecarboxamide (2.2 g). M.P., 59°-60° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:18]([NH:20][CH2:21][CH2:22][O:23][CH3:24])[CH3:19]>>[Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][O:23][CH3:24])=[O:17])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C(O)C1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: CCNCCOC
Product: CCN(CCOC)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1

Procedure:
300 mg (1.12 mol) (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 31b) were transformed in analogy to example 3 using N-ethyl-2-methoxyethanamine to give after working up and purification 317 mg (80%) of the title compound.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([NH:10][C:11](=[O:13])[CH3:12])[CH2:4][C:3]1([CH3:15])[CH3:14].[C:16]1([CH3:23])[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1>>[CH3:23][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[CH2:22][O:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([NH:10][C:11](=[O:13])[CH3:12])[CH2:4][C:3]1([CH3:15])[CH3:14]
Reactant: CC(=O)NC1CC(C)(C)N(O)C(C)(C)C1
Reactant: Cc1cccc(C)c1
Product: CC(=O)NC1CC(C)(C)N(OCc2cccc(C)c2)C(C)(C)C1
Temperature: 133 °C
Yield: 25.3 %

Procedure:
A mixture of 10.67 g (0.05 mol) of 1-oxyl-4-acetamido-2,2,6,6-tetramethylpiperidine and 106.17 g (1.0 mol) of m-xylene under a nitrogen atmosphere is heated at 133° C. for 67 hours. The reaction mixture is filtered to remove the hydroxylamine, and the filtrate is washed with 10 w/v % ascorbic acid (3×33 mL) and distilled water (2×50 mL). The organic phase is dried over anhydrous sodium sulfate and the volatiles are removed in vacuo. The residue is recrystallized from acetonitrile to give 4.03 g (51% yield) of a white solid melting at 163-164.5° C.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:26])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:25])[C:19](=[O:24])[CH2:20][CH2:21][CH:22]=O)[CH2:12][CH2:11]1.[NH2:33][C:34]1[CH:46]=[CH:45][C:37]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[CH:36][CH:35]=1>>[C:1]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:25])[C:19](=[O:24])[CH2:20][CH2:21][CH2:22][NH:33][C:34]2[CH:46]=[CH:45][C:37]([C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])=[CH:36][CH:35]=2)[CH2:12][CH2:11]1)=[O:26]
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCC=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCNc1ccc(C(=O)OC(C)(C)C)cc1
Yield: 82.7 %

Procedure:
The compound (130 mg, 0.297 mmol) obtained in Example 33b and tert-butyl 4-aminobenzoate (92 mg, 0.475 mmol) were used to give the title compound (151 mg; yield, 83%) as a white solid according to the method described in Example 18b.