Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]1.Cl[CH2:20][C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[O:24][CH:25]([CH3:30])[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:16][CH:15]([F:17])[N:12]1[C:13](=[O:14])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:20][C:21]3[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=3)[O:24][CH:25]([CH3:30])[C:26]([O:28][CH3:29])=[O:27])=[CH:7][C:2]=2[F:1])[N:10]=[C:11]1[CH3:18]
Reactant: Cc1nn(-c2ccc(O)cc2F)c(=O)n1C(F)F
Reactant: COC(=O)C(C)Oc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cccc(COc2ccc(-n3nc(C)n(C(F)F)c3=O)c(F)c2)c1
Yield: 89.8 %

Procedure:
By the method of Example 1, Step I, 1.0 g (0.0038 mole) of 1-(2-fluoro-4-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one (Example 1, Step F) and 1.72 g (0.0076 mole) of methyl 2-(3-chloromethylphenoxy)propionate were reacted in the presence of 0.79 g (0.0057 mole) of anhydrous potassium carbonate in 25 mL of N,N-dimethylformamide, yielding 1.54 g of methyl 2-[3-[4-(4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl)-3-fluorophenoxymethyl]phenoxy]propionate. The NMR and IR spectra were consistent with the proposed structure. NMR: 1.60 (d, 3H, JHH=8.0 Hz); 2.44 (s, 3H); 3.76 (s, 3H); 4.78 (q, 1H, JHH=8.0 Hz); 5.04 (s, 2H); 6.76-7.38 (m, 8H).
Reaction SMILES: C([O:3][C:4]([C:6]([OH:15])([CH3:14])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13])=[CH2:5])C.Cl.C([O-])(O)=O.[Na+]>CO>[CH3:14][C:6]([OH:15])([CH2:7][CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13])[C:4](=[O:3])[CH3:5]
Reactant: C=C(OCC)C(C)(O)CCCOCOC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COCOCCCC(C)(O)C(C)=O
Reaction time: 2 h
Yield: 58.7 %

Procedure:
To a solution of 2-ethoxy-3-hydroxy-6-methoxymethoxy-3-methyl-1-hexene (8.99 g. 41.2 mmol) in 50 mL of methanol was added dropwise 1 M HCl (100 mL, 100 mmol) at room temperature. The exothermic reaction was cooled by water bath and monitored by TLC. After being stirred for two hours, the resulting mixture was neutralized with NaHCO3, concentrated via rotary evaporation and extracted with 3×120 mL of dichloromethane. The combined organic layer was dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography using hexanes/ethyl acetate (2/1-1/1) as eluent to afford 4.6 g of 3-methyl-3-hydroxy-6-methoxymethoxy-2-hexanone (yield 59).
Reaction SMILES: CS(O[CH:6]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2)(=O)=O.[CH3:29][NH2:30]>>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([CH2:7][CH:6]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[NH:30][CH3:29])[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: CN
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccncc2)CCN(C)C1
Product: CNC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1

Procedure:
A solution of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethyl methanesulfonate (250 mg, 0.62 mmol) in methyl amine (3 mL, 40% in water) was stirred at 90° C. for 12 h. The progress of reaction was monitored by LCMS. The reaction mixture was extracted with EtOAc. The organic layer was dried and concentrated to get the crude product, which was purified by reverse phase HPLC to obtain the 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-N-methyl-1-(pyridin-4-yl)ethanamine. 1H NMR (CDCl3, freebase): δ (ppm): 8.59 d (2H), 7.3 d (2H), 7.29 d (1H), 7.23 s (1H), 7.03 d (1H), 4.19 m (1H), 4.03 m (2H), 3.66 dd (2H), 2.8 m (3H), 2.6 m (1H), 2.55 s (3H), 2.47 s (3H), 2.18 s (3H). Chiral HPLC provided enantiomers 151a and 151b.
Reaction SMILES: [C:1](=[O:8])([O-])[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[Si:9]([O:16][C@H:17]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:18]1[NH:22][CH:21]([CH2:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>>[NH2:28][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][CH:21]2[CH2:20][CH2:19][C@H:18]([C@H:17]([O:16][Si:9]([C:12]([CH3:13])([CH3:15])[CH3:14])([CH3:10])[CH3:11])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:22]2[C:1]([O:2][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:8])=[CH:30][CH:29]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H](c1ccccc1)[C@H]1CCC(Cc2ccc(N)cc2)N1
Reactant: CC(C)(C)OC(=O)[O-]
Product: CC(C)(C)OC(=O)N1C(Cc2ccc(N)cc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 121 mg (0.315 mmol) of 4-({(5R)-5-[(R)-([tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidin-2-yl}methyl)aniline in 5 mL of anhydrous THF (from Step B) was added tert-butyl carbonate (69 mg, 0.315 mmol), followed by TEA (44 μL, 0.315 mmol) and the resulting solution stirred at room temperature under nitrogen atmosphere overnight. The reaction mixture was put directly on a preparative plate (1500 μM) and eluted with 30% ethyl acetate in hexane to afford the title compound (100 mg, 64%). m/z (ES) 497 (MH)+, 397 (M-Boc)+. 1HNMR (500 MHz, CDCl3) δ: 7.40-7.30 (m, 5H), 6.75-6.68 (m, 2H), 6.56-6.51 (m, 2H), 5.52-5.48 (m, 1H), 5.32-5.28 (m, 1H), 4.16-4.06 (m, 2H), 3.88-3.82 (m, 1H), 3.76-3.70 (m, 1H), 3.55-3.48 (m, 2H), 2.74 (br d, J=11.8 Hz, 1H), 2.44 (br d, J=11.8 Hz, 1H), 2.05-1.94 (m, 1H), 1.90-1.82 (m, 1H), 1.60 (s, 9H), 1.50-1.42 (m, 1H), 1.32-1.22 (m, 2H), 1.10-1.02 (m, 1H), 0.95 (s, 9H), 0.08 (s, 3H), −0.15 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.Cl.[NH2:10][OH:11].[OH-].[Na+].Cl>C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[N:10]\[OH:11]
Reactant: O=Cc1ccccn1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O/N=C\c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
To a suspension of 2-pyridinecarboxaldehyde (53.6 g, 500 mmol) and hydroxylamine hydrochloride (38.2 g, 544 mmol) in ethanol (36 mL) and water (69 mL) was added ice (205 g). Then an aqueous solution of sodium hydroxide (32%, 115 mL, 1.24 mol) was added dropwise within a 10 min period (temperature rises from −8° C. to +7° C.) whereupon most of the solid dissolves. After 1 h stirring at room temperature the resulting mixture was then acidified with HCl (5 N). The mixture was then extracted with dichloromethane to afford the title compound (47.7 g, 78%) which was obtained as an off white solid. MS: m/e=123.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C(O)c1ncc(Br)cn1
Product: O=C(O)c1ncc(-c2ccc(F)cc2)cn1

Procedure:
Conducting the operations similar to those of Production Example 14 using 5-bromopyrimidine-2-carboxylic acid and 4-fluorophenylboronic acid, the title compound was obtained as white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:36])[N:18]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[C:17](=[O:36])[N:18]([CH2:28][C:29]([OH:31])=[O:30])[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:13][CH:14]=1)#[N:2]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(=O)OC(C)(C)C)c2ncnn12
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(=O)O)c2ncnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
A mixture of tert-butyl {6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}acetate (1.78 g) and trifluoroacetic acid (15 mL) was stirred at room temperature for 1 hr. The reaction mixture was diluted with toluene (15 mL) and the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.44 g, 92%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[CH2:24]([N:26]([CH2:30][CH2:31]Cl)[CH2:27][CH2:28]Cl)[CH3:25]>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:28][CH2:27][N:26]([CH2:30][CH3:31])[CH2:24][CH2:25]1)=[O:23])[CH3:2]
Reactant: CCN(CCCl)CCCl
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)cc1
Product: CCOC(=O)C1(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCN(CC)CC1

Procedure:
4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-1-ethyl-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(4-chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester (4 g, 11.3 mmol) and ethyl-bis-(2-chloro-ethyl)-amine (2.32 g, 16.9 mmol). Yield 3.36 g (66%); brown oil; MS: 452.0 (M+H)+
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:12]([CH3:14])([CH3:13])[O:11]/[C:10](=[C:15]2/[C:16](=[O:26])[NH:17][C:18]3[C:23]/2=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)/[CH:9]=1.[F:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[F:25])[NH:17][C:16](=[O:26])/[C:15]/2=[C:10]1/[O:11][C:12]([CH3:14])([CH3:13])[C:8]([C:31]2[CH:32]=[N:33][C:28]([F:27])=[CH:29][CH:30]=2)=[CH:9]/1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1Br
Reactant: OB(O)c1ccc(F)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1c1ccc(F)nc1
Temperature: 78 °C
Yield: 38.1 %

Procedure:
To 10 mL of 1,4-dioxane were added (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-5,6-difluoro-1,3-dihydro-2H-indol-2-one (150 mg, 0.44 mmol), 6-fluoropyridin-3-ylboronic acid (74 mg, 0.53 mmol), PdCl2(PPh3)2 (22 mg, 0.031 mmol), 2M Na2CO3 aqueous solution (0.6 mL, 1.2 mmol). The mixture was heated at 78° C. under N2 for 3 hours, cooled to room temperature and poured into 100 mL of water. The precipitates were filtered, washed with water and dried to give the crude product. Purification of the crude product through silica gel column with 1-3% MeOH/CHCl3 gave (3E)-5,6-difluoro-3-[4-(6-fluoropyridin-3-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as a yellow solid (yield: 60 mg, 38%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([Mg]Cl)[CH:6]=[CH:7][CH:8]=1.BrC1C=C(C(F)(F)F)C=CC=1.C([Mg]Cl)(C)C.C(OC([N:34]1[CH2:56][CH2:55][C:38]2[C:39]3[C:40](O)(C4C=CC=CC=4)[C:41]([F:47])([F:46])[CH2:42][C:43]=3[CH:44]=[CH:45][C:37]=2[CH2:36][CH2:35]1)=O)C>C1COCC1>[F:47][C:41]1([F:46])[CH:40]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=2)[C:39]2[C:38]3[CH2:55][CH2:56][NH:34][CH2:35][CH2:36][C:37]=3[CH:45]=[CH:44][C:43]=2[CH2:42]1
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(O)(c1ccccc1)C(F)(F)C3
Reactant: FC(F)(F)c1cccc([Mg]Cl)c1
Agent: CC(C)[Mg]Cl
Agent: FC(F)(F)c1cccc(Br)c1
Solvent: C1CCOC1
Product: FC(F)(F)c1cccc(C2c3c(ccc4c3CCNCC4)CC2(F)F)c1
Reaction time: 16 h

Procedure:
Example 18 was prepared in a similar fashion to Example 14, except (3-(trifluoromethyl)phenyl)magnesium chloride (prepared from 3-bromobenzotrifluoride (1 eq) in THF, followed by addition of isopropyl magnesium chloride (2M in THF, 1 eq) at room temperature and stirring for 16 hours was used instead of phenylmagnesium bromide (example 14, step (c)) 1H NMR (300 MHz, CDCl3) δ 7.55-7.53 (m, 1H); 7.42 (t, J=7.8 Hz, 1H); 7.29 (bs, 1H); 7.20-7.17 (m, 1H); 7.13-7.07 (m, 2H); 4.70 (d, J=19.2, 1H); 3.51-3.36 (m, 2H); 3.01-2.84 (m, 4H); 2.74-2.61 (m, 2H); 2.54-2.49 (m, 2H); 2.01 (bs, 1H); MS: ESI (positive): 368 (M+1).
Reaction SMILES: CC(OC1C=CC(C([C:18]2[CH:23]=[CH:22][C:21](OC(C)=O)=[CH:20]C=2)=C2CCCCC2)=CC=1)=O.[CH3:28][N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][CH:32]=[N:33][C:34]=2[NH2:38].C1(N)CCCC1.CN(C)C>C(O)C>[CH:21]1([NH:38][C:34]2[N:33]=[CH:32][N:31]=[C:30]3[C:35]=2[N:36]=[CH:37][N:29]3[CH3:28])[CH2:20][CH2:18][CH2:23][CH2:22]1
Reactant: CC(=O)Oc1ccc(C(=C2CCCCC2)c2ccc(OC(C)=O)cc2)cc1
Reactant: Cn1cnc2c(N)ncnc21
Agent: CN(C)C
Agent: NC1CCCC1
Solvent: CCO
Product: Cn1cnc2c(NC3CCCC3)ncnc21
Yield: 74 %

Procedure:
To prepare N6 -cyclopenyl-9-methyl Adenine the following additional steps were taken. A mixture of 6-chloro-9-methyl Adenine (0.82 g) , cyclopentylamine (0.52 ml) , trimethylamine (0.53 ml) and ethanol. (60 ml), was refluxed for 24 hours. The solution was concentrated in vacuo to a yellow syrup. The syrup was passed through a C-18 column to give 0.78 g or 74% yield of with m.p. 108°-109° C. 1HNMR(Me2SO-d6): δ1-2 (m, 9 H); 3.7 (S, CH3); 7.6(d,NH); 8.1(S,1H); 8.2(S,1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[C:19](Cl)(=[O:21])[CH3:20]>>[C:19]([N:16]1[CH2:15][CH2:14][N:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)[CH2:18][CH2:17]1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)C(N1CCNCC1)CCC2
Product: COc1ccc2c(c1)C(N1CCN(C(C)=O)CC1)CCC2

Procedure:
This compound was prepared from (7-methoxytetralin-1-yl)piperazine and acetyl chloride by the method described in Example 11 above (pale yellow oil, 58%). Calc'd for C17H24N2O2 : C, 69.93%; H, 8.43%; N, 9.60%. Found: C, 69.94%; H, 8.18%; N, 9.45%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[Cl:27][C:28]1[C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:32][N:31]=[C:30]2[N:40]([CH2:49][CH2:50]O)[N:41]=[C:42]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:29]=12>C(Cl)Cl>[Cl:27][C:28]1[C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:32][N:31]=[C:30]2[N:40]([CH2:49][CH2:50][I:25])[N:41]=[C:42]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:29]=12
Reactant: II
Reactant: OCCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CCI
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
Triphenylphosphine (160 mg, 0.62 mmol), imidazole (42 mg, 0.62 mmol) and iodine (160 mg, 0.62 mmol) were added to a solution of 2-(4-chloro-3,5-diphenyl-1H pyrazolo[3,4-c]pyridazin-1-yl)ethanol (181 mg, 0.52 mmol) in CH2Cl2 (6 mL). After stirring at ambient temperature for 1 h the reaction was filtered and solvent removed in vacuo. Purification using chromatography (silica gel, gradient 10 to 60% ethyl acetate/isohexane) gave 4-chloro-1-(2-iodoethyl)-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine as a clear oil (202 mg) which was used as such in the subsequent step.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11]C)[CH:9]=2)[C:4](SC(C)(C)C)=[C:3]1[CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21].C(S)C.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH:4]=[C:3]1[CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2ccc(OC)cc2n1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: COC(=O)C(C)(C)Cc1cc2ccc(O)cc2n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold solution of 940 mg of the indole ester from Step B and 1.6 mL of ethanethiol in CH2Cl2 (50 mL) was added portion-wise 4.3 g of AlCl3. After complete addition, the mixture was stirred at R.T. for 2 h. The mixture was then cooled to 0° C. and carefully quenched with a solution of 0.5M Na,K tartrate (200 mL) and extracted with CH2Cl2. The organic layer was dried over Na2SO4 and evaporated to dryness to give a solid which was chromatographed on flash silica gel using ethyl acetate:hexane (30:70) as eluant to afford the title compound; m.p. 125°-126° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([OH:14])=[O:13])[NH:9]2)=[CH:5][CH:4]=1)#[N:2].[NH2:15][OH:16]>CCO>[NH2:2][C:1](=[N:15][OH:16])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([OH:14])=[O:13])[NH:9]2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: N#Cc1ccc2cc(C(=O)O)[nH]c2c1
Solvent: CCO
Product: NC(=NO)c1ccc2cc(C(=O)O)[nH]c2c1
Temperature: 60 °C
Yield: 104.2 %

Procedure:
A solution of 6-cyano-1H-indole-2-carboxylic acid (prepared according to J. Org. Chem. 1953, 18, 345-357, 1 g; 5.37 mmol; 1 eq.), hydroxylamine (50% in water; 1.77 mL; 26.86 mmol; 5 eq.) in EtOH (10 mL) was stirred at RT for 14 hours after which it was further heated at 60° C. for 28 hours. Solvents were removed under vacuum to give the title compound as a white powder (1.227 g; quantitative yield). 1H NMR (DMSO-d6) δ 11.75 (s, 1H), 7.72 (s, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.37 (dd, J=1.2, 8.5 Hz, 1H), 7.00 (d, J=1.2 Hz, 1H), 5.76 (bs, 2H), 3.44 (q, J=7.1 Hz, 2H), 1.05 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[CH:18]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:36])[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH3:29])[CH:23]=1)=O)[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].Cl.[NH2:38][OH:39].C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[CH:18]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:36])[CH2:19]/[C:20](=[N:38]\[OH:39])/[C:22]1[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH3:29])[CH:23]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10]
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Oc2cccc(C(=O)O)c2)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Oc2cccc(C(=O)O)c2)cc1F

Procedure:
In analogy to example 151, step 3, 3-{3-fluoro-4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-phenoxy}-benzoic acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as a colorless solid, MS (ESI+): m/z=501.2.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16]=O)[N:6]=1)([CH3:4])[CH3:3].Cl.NO.C([O-])(=O)C.[Na+].CC(C1C(O)=CN=C(C=[N:38][OH:39])N=1)(C)C>C(O)C.O>[CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16]=[N:38][OH:39])[N:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1nc(C=O)nc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1nc(C=NO)ncc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1nc(C=NO)nc(C(C)(C)C)c1O

Procedure:
A solution of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carboxaldehyde (1.5 g, 6.3 mmol) , hydroxylamine hydrochloride (2.2 g, 32.7 mmol), and sodium acetate (2.9 g, 34.9 mmol) in ethanol (20 mL) is heated at reflux for 12 hours. The reaction mixture is poured over water (150 mL) and the precipitate is collected by filtration. Recrystallization from ether/hexane gives the desired 4,6-his (1,1-dimethylethyl) -5-hydroxy-2-pyrimidine carboxaldehyde oxime as a mixture of isomers (0.62 g, 39%); mp 205°-220° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.[CH:40]12[N:46]([C:47](=O)[CH2:48]Br)[CH:43]([CH2:44][CH2:45]1)[CH2:42][CH2:41]2>>[CH:43]12[N:46]([CH2:47][CH2:48][O:39][C:38]3[CH:37]=[CH:36][C:4]([CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]4[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=4[C@@H:16]4[CH2:25][CH2:24][C:23]5[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=5[CH2:17]4)=[CH:3][C:2]=3[F:1])[CH:40]([CH2:45][CH2:44]1)[CH2:41][CH2:42]2
Reactant: O=C(CBr)N1C2CCC1CC2
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3C4CCC3CC4)c(F)c2)C(C)C)c1
Yield: 65.3 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 1-(7-azabicyclo[2.2.1]hept-7-yl)-2-bromoethanone (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (13 mg) was obtained.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C:6](=[O:8])[CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][C@H:3]1[C:17]1[C:22]([F:23])=[CH:21][CH:20]=[C:19]([F:24])[C:18]=1[F:25].C(O[K])(C)(C)C>O>[CH3:1][C@H:2]1[NH:7][C:6](=[O:8])[C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:15])[CH3:13])[CH2:4][C@H:3]1[C:17]1[C:22]([F:23])=[CH:21][CH:20]=[C:19]([F:24])[C:18]=1[F:25]
Reactant: C[C@H]1NC(=O)C(NC(=O)OC(C)(C)C)C[C@H]1c1c(F)ccc(F)c1F
Agent: CC(C)(C)O[K]
Solvent: O
Product: C[C@H]1NC(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1c1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of crude cis and trans mixture 20 in a mixture of iPAc and iPA (1.83 wt %, 9.9 kg; 181 g assay as a mixture) was concentrated in vacuo and dissolved in 2-Me-THF (3.6 L). To the solution was added tert-BuOK (66.6 g, 0.594 mol) at room temperature. The suspension was stirred at room temperature for 2 h. The mixture was poured into water (3.5 L) and the organic layer was separated, washed with 15 wt % of aqueous NaCl (3.5 L), dried over Na2SO4, and concentrated to dryness. The residue was suspended with iPAc (275 mL) and heptane (900 mL) at 60° C. The suspension was slowly cooled down to 1° C. The solid was filtered and rinsed with iPAc and heptane (1:3), dried to afford 21 (166 g, 93 wt %; 85%) as crystals. Mp 176-179° C.; 1H NMR (CDCl3, 500 MHz): δ 7.06 (m, 1H), 6.84 (m, 1H), 5.83 (broad s, 1H), 5.58 (broad s, 1H), 4.22 (m, 1H), 3.88-3.79 (m, 2H), 2.77 (m, 1H), 2.25 (m, 1H), 1.46 (s, 9H), 1.08 (d, J=6.4 Hz, 3H); 19F NMR (CDCl3, 376 MHz): δ −117 (d, J=14 Hz), −135 (d, J=20 Hz), −142 (dd, J=20, 14 Hz); 13C NMR (CDCl3, 100 MHz): δ 171.1, 156.6 (ddd, J=245, 6.4, 2.8 Hz), 155.8, 149.3 (ddd, J=248, 14.4, 8.8 Hz), 147.4 (ddd, J=245, 14.2, 3.8 Hz), 118.0 (dd, J=19.3, 14.5 Hz), 115.9 (dd, J=19.2, 10.4 Hz), 111.0 (ddd, J=26.4, 6.0, 4.3 Hz), 79.8, 51.4, 49.5, 34.1, 29.3, 28.3, 18.0; HRMS: m/z calcd for C17H21F3N2O3 381.1396 (M+Na). found 381.1410.