Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[N:11]([CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:13][CH:14]=1.[CH3:19][N:20]1[C:24]([CH3:25])=[C:23]([C:26](O)=[O:27])[C:22](=[O:29])[N:21]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:26]([C:23]2[C:22](=[O:29])[N:21]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:20]([CH3:19])[C:24]=2[CH3:25])=[O:27])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[N:11]([CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:13][CH:14]=1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: Nc1ccc(Oc2ccnn3cccc23)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnn4cccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 50 °C
Yield: 29.2 %

Procedure:
To a solution of 3-fluoro-4-(pyrrolo[1,2-b]pyridazin-4-yloxy)-phenylamine (50 mg, 0.206 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (32 mg, 0.137 mmol) dissolved in dimethylformamide (3 mL), HATU (78 mg, 0.206 mmol) and triethylamine (0.05 mL, 0.343 mmol) were sequentially added and heated at 50° C. for 7 hours. The resulting mixture was concentrated and the resulting residue was extracted with dichloromethane and water. After phase separation, the organic layer was washed with sodium chloride aqueous solution, dried with magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:hexane=1:3) to give the target compound as a white solid (16 mg, 0.04 mmol, 25% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[C:11]([O:15][C:16]([NH:18][CH:19]([C:21](O)=[O:22])[CH3:20])=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[OH:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[NH:1][C:21](=[O:22])[CH:19]([NH:18][C:16](=[O:17])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])[CH3:20]
Reactant: COc1ccc(O)c(N)c1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Product: COc1ccc(O)c(NC(=O)C(C)NC(=O)OC(C)(C)C)c1
Yield: 80.9 %

Procedure:
Using 2-amino-4-methoxyphenol (3.00 g, 21.6 mmol) and N-(tert-butoxycarbonyl)-D,L-alanine (4.08 g, 21.6 mmol), a method in the same manner as in Reference Example 13 was performed, and the obtained residue was triturated with ethyl acetate to give the title compound (5.42 g, yield 81%).
Reaction SMILES: C[Mg]Br.[CH3:4]COCC.[Cl:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:23]=[CH:22][N:21]([CH2:24][C@@H:25]([NH:27][C:28]([C:30]3[N:31]=[C:32]([CH3:40])[N:33]([CH2:35][CH2:36][C:37](=[O:39])[CH3:38])[CH:34]=3)=[O:29])[CH3:26])[N:20]=2)[CH:13]=[C:14]([F:18])[C:15]=1[C:16]#[N:17].[Cl-].[NH4+]>C1COCC1>[Cl:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:23]=[CH:22][N:21]([CH2:24][C@@H:25]([NH:27][C:28]([C:30]3[N:31]=[C:32]([CH3:40])[N:33]([CH2:35][CH2:36][C:37]([OH:39])([CH3:4])[CH3:38])[CH:34]=3)=[O:29])[CH3:26])[N:20]=2)[CH:13]=[C:14]([F:18])[C:15]=1[C:16]#[N:17]
Reactant: CCOCC
Reactant: CC(=O)CCn1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)nc1C
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1CCC(C)(C)O
Temperature: 45 °C
Reaction time: 5 h
Yield: 19.32 %

Procedure:
Methylmagnesium bromide 3M in Et2O-solution (0.128 ml, 0.383 mmol) and dry THF (1 ml) were added into a flask and heated to 30° C. (S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-methyl-1-(3-oxobutyl)-1H-imidazole-4-carboxamide (35 mg, 0.077 mmol) of Example 286(b) dissolved in THF (5 ml) was added very slowly. The reaction mixture was heated to 45° C. and stirred for 5 h. Another batch of methylmagnesium bromide 3M in EtO2-solution (0.128 ml, 0.383 mmol) was added and the mixture was stirred at RT overnight. Next day the reaction mixture was poured into 10 ml of saturated ammonium chloride, THF was evaporated and the remaining water phase was extracted with ethyl acetate. The ethyl acetate phases were combined, dried and evaporated. The product was purified by flash-chromatography. Yield 19.32%. 1H-NMR (400 MHz; DMSO-d6): δ 1.06 (d, 3H), 1.12 (s, 6H), 1.69-1.77 (m, 2H), 2.34 (s, 3H), 3.92-3.98 (m, 2H), 4.25-4.46 (m, 4H), 7.01 (d, 1H), 7.50 (s, 1H), 7.85 (d, 1H), 7.92 (dd, 1H), 8.00 (s, 1H), 8.03 (d, 1H).
Reaction SMILES: Br[C:2]1[C:3]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:44]2[CH:45]=[N:46][N:47]([CH:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]3)[CH:48]=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:12]([N:8]1[C:9]2[C:4](=[C:3]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:2]([C:44]3[CH:45]=[N:46][N:47]([CH:49]4[CH2:50][CH2:51][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:53][CH2:54]4)[CH:48]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:6][C@@H:7]1[CH3:15])(=[O:14])[CH3:13]
Reactant: CC(=O)N1c2ccc(Br)c(Oc3ccccc3F)c2CC[C@@H]1C
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c(Oc3ccccc3F)c2CC[C@@H]1C
Temperature: 80 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
A 100-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen, and charged with 1-[(2S)-6-bromo-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (300 mg, 0.79 mmol), 1,4-dioxane (18 mL), water (3 mL), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (65 mg, 0.08 mmol), cesium carbonate (776 mg, 2.37 mmol), and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (378 mg, 1.00 mmol). The resulting mixture stirred for 12 h at 80° C. After cooling to room temperature, the reaction mixture was passed through a short pad of Celite and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 5:1, ethyl acetate/petroleum ether) to afford (S)-tert-butyl 4-(4-(1-acetyl-5-(2-fluorophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (370 mg, 85%) as yellow oil. MS (ESI, pos. ion) m/z 549 [M+H]+.
Reaction SMILES: [C:1]([C:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=1[CH2:13][CH3:14])(OCC)=O.C=O>>[CH2:13]([C:7]1[NH:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:6]=1[CH3:1])[CH3:14]
Reactant: CCOC(=O)c1c(CC)[nH]c(C)c1C
Agent: C=O
Product: CCc1[nH]c(C)c(C)c1C

Procedure:
3-Carbethoxy-4,5-dimethyl-2-ethyl-pyrrole was reductively alkylated with paraformaldehyde to yield 2-ethyl-3,4,5-trimethyl pyrrole. ##STR83##
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[N:5]1.C(N(C(C)C)CC)(C)C.[F:31][C:32]([F:44])([F:43])[C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>C(#N)C>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:6]2[CH:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:8][N:4]([CH2:3][CH2:2][NH:1][S:39]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([F:31])([F:43])[F:44])[CH:34]=3)(=[O:41])=[O:40])[N:5]=2)=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: NCCN1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=S(=O)(NCCN1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.3 %

Procedure:
Part C: To a solution of 1-(2-aminoethyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (0.56 gram, 1.87 mmol) and diisopropylethylamine in acetonitrile (20 ml) was added 3-(trifluoromethyl)phenylsulfonyl chloride (0.35 ml, 2.18 mmol) and the resulting solution was stirred at room temperature for 20 minutes. After concentration in vacuo the residue was dissolved in ethylacetate and washed with 2 N sodium hydroxide solution. The ethylacetate layer was concentrated in vacuo. The resulting oil was crystallised from a small amount of diisopropyl ether to afford crystalline N-[2-(3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazol-1-yl)ethyl]-3-(trifluoromethyl)benzenesulfonamide (0.44 gram, 46% yield). Melting point: 94-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:21])[CH2:9][C:10]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:11](OCC)=[O:12])=[C:4]([O:22][CH3:23])[C:3]=1[F:24].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+].C(O)(=O)C(C(C(O)=O)O)O>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:21])[CH2:9][C:10]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:11]=[O:12])=[C:4]([O:22][CH3:23])[C:3]=1[F:24]
Reactant: C=C(CC(O)(C(=O)OCC)C(F)(F)F)c1ccc(Cl)c(F)c1OC
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: C=C(CC(O)(C=O)C(F)(F)F)c1ccc(Cl)c(F)c1OC
Reaction time: 1 h
Yield: 29.3 %

Procedure:
760 mg (2.67 mmol) of 1,1′-bi-2-naphthol are admixed with 2.68 ml (1.34 mmol) of a 0.5 M titanium tetraisopropoxide solution in toluene and the red solution is stirred at room temperature for an hour. 5.07 g (28.1 mmol) of 3-chloro-2-fluoro-6-(1-methyleneethyl)anisole and 3.25 ml (26.7 mmol) of ethyl trifluoropyruvate are added and the mixture is heated at 140° C. for 17 hours. After it has cooled it is immediately purified by column chromatography on silica gel (pentane/diethyl ether 25-40%) to give 1.47 g of ethyl 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate. 1.47 g (3.97 mmol) of ethyl 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate in 40 ml of diethyl ether are cooled to −15° C. and over 10 minutes 300 mg (7.9 mmol) of lithium aluminum hydride in solid form are added in portions. The mixture is stirred for 1 hour, during which it warms to 0° C., and is poured into saturated ammonium chloride solution. Saturated tartaric acid solution is added and the mixture is stirred for 30 minutes. The phases are separated and subjected to repeated extraction with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo. Separation by column chromatography on silica gel (hexane/ethyl acetate 0-50%) yields 0.38 g of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enal and 0.15 g of alcohol. 0.27 g of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pent-4-enal is dissolved in 14 ml of methanol and 0.3 ml of acetic acid, and 27 mg of palladium on carbon (10%) are added. The suspension is shaken for 2 hours under a hydrogen atmosphere under atmospheric pressure until the hydrogen uptake is 46 ml. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. Removal of the solvent gives 027 g of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal as a mixture of the diastereomers.
Reaction SMILES: [H-].[Na+].C(N(CC)CC)C.[O:10]=[C:11]1[NH:20][CH:19]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[C:18]2[C:17](=[O:29])[CH2:16][CH2:15][CH2:14][C:13]=2[N:12]1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>O1CCCC1>[CH3:40][S:41]([N:20]1[CH:19]([C:21]2[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=2)[C:18]2[C:17](=[O:29])[CH2:16][CH2:15][CH2:14][C:13]=2[N:12]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=2)[C:11]1=[O:10])(=[O:43])=[O:42]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% in mineral oil, 6 mg, 0.15 mmol) and triethylamine (26 μL, 182 μmol) are added to a solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 1, 25 mg, 61 μmol) in tetrahydrofuran (600 μL), and the mixture is stirred at room temperature for 15 min. Methanesulfonyl chloride (6 μL, 0.07 mmol) is added, and the mixture is stirred for 2.5 h and purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 13 mg; ESI mass spectrum [M+H]+=490; Retention time HPLC: 0.95 min (Z018_S04).
Reaction SMILES: [Na].O[CH:3]=[CH:4][C:5]#[N:6].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.S(=O)(=O)(O)O>C(O)C>[NH:7]1[CH2:11][CH2:10][CH:9]([CH:3]=[CH:4][C:5]#[N:6])[CH2:8]1
Reactant: N#CC=CO
Reactant: C1CCNC1
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCO
Product: N#CC=CC1CCNC1
Temperature: 50 °C
Reaction time: 7 h
Yield: 79.6 %

Procedure:
32.5 g (0.25 mol) of sodium-3-hydroxyacrylonitrile (content 70%) is added to a mixture of 17.8 g (0.25 mol) of pyrrolidine, 12.3 g (0.125 mol) of sulfuric acid and 200 ml of ethanol, and the mixture is stirred at 50° C. for 7 h. After working up as in Example 50, 24.3 g of 3-pyrrolidine acrylonitrile (79.6%) is obtained.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:19](=[O:21])[CH3:20])[CH:10]=[C:11]([S:13]([F:18])([F:17])([F:16])([F:15])[F:14])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br-:22].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(Cl)Cl>CO.C1COCC1>[Br:22][CH2:20][C:19]([C:9]1[CH:10]=[C:11]([S:13]([F:15])([F:14])([F:16])([F:17])[F:18])[CH:12]=[C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:8]=1)=[O:21]
Reactant: [Br-]
Reactant: CC(=O)c1cc(N2CCOCC2)cc(S(F)(F)(F)(F)F)c1
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CBr)c1cc(N2CCOCC2)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 27 h
Yield: 109.5 %

Procedure:
1-[3-Morpholin-4-yl-5-(pentafluorosulfanyl)phenyl]ethanone (O2.044; 1.1 g) was dissolved in methanol/THF (20/20 ml) and admixed while stirring with phenyltrimethylammonium tribromide (1.25 g). After stirring at RT for 27 h, 50 ml of 20% citric acid were added and the mixture was stirred for 1 h. After adding DCM (100 ml), the DCM phase was removed, dried and concentrated. The residue was dissolved in acetonitrile (100 ml), and 2 N sulfuric acid (20 ml) was added to the solution. After stirring at RT for 24 h, the mixture was admixed with water and extracted with EA. The EA phase was washed with saturated sodium hydrogencarbonate solution, dried and concentrated. The residue was purified using silica gel (80 g cartridge, n-heptane/EA gradient of 0-60% within 40 min). 866 mg of the title compound were obtained. LC-MS rt: 1.69 min [M+H]+: 410.0 (met. a)
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5](=[O:21])[CH2:6][NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C=O.[C:24]([BH3-])#N.[Na+]>>[ClH:1].[ClH:1].[CH3:3][O:4][C:5](=[O:21])[CH2:6][N:7]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)[CH3:24]
Reactant: [BH3-]C#N
Reactant: COC(=O)CNC1CCN(Cc2ccccc2)CC1
Agent: C=O
Agent: Cl
Agent: [Na+]
Product: COC(=O)CN(C)C1CCN(Cc2ccccc2)CC1

Procedure:
Prepared from N-[1-benzyl-4-piperidinyl]glycine methyl ester dihydrochloride, paraformaldehyde and sodium cyanoborohydride.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][CH:28]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:29][N:30]([CH3:32])[CH3:31])(C(C)(C)C)(C)C>C1COCC1>[CH3:31][N:30]([CH3:32])[CH2:29][CH:28]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:27][OH:26]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOC(CO[Si](C)(C)C(C)(C)C)CN(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\CCCCCCCCOC(CO)CN(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TBAF (1.0 M in THF, 0.5 mL, 0.50 mmol, 1.2 equiv) was added in one portion to a dry THF (100 μL) solution of 3-(tert-butyldimethylsilyloxy)-N,N-dimethyl-2-((9Z,12Z)-octadeca-9,12-dienyloxy)propan-1-amine (0.2 g, 0.42 mmol, 1.0 equiv) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated and the residue was partitioned between EtOAc (15 mL) and aqueous saturated ammonium chloride solution (10 mL). The layers were separated and the aqueous layer was extracted with 2 additional portions of EtOAc (10 mL). The combined extracts were dried (MgSO4), filtered, and concentrated to give crude 3-(dimethylamino)-2-((9Z,12Z)-octadeca-9,12-dienyloxy)propan-1-ol, a thick, beige oil, which was used without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[Cl:31])=[N+]=[N-].N#N.CO>C1COCC1.O>[Cl:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[CH2:23][NH2:20]
Reactant: [N-]=[N+]=NCc1ccc(F)cc1Cl
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
Add triphenylphosphine (129.9 g, 495 mmol) to a solution of 1-azidomethyl-2-chloro-4-fluoro-benzene (61.2 g, 330 mmol) in THF (500 mL) and water (30 mL). Stir at RT until no more N2 is evolved. Add 100 mL MeOH and stir at RT overnight. Concentrate; acidify to pH 1 with 1N HCl solution, wash with CH2Cl2 (3 times). Basify aqueous layer with 5N NaOH solution, extract with CH2Cl2 (3 times), dry over MgSO4. Concentrate to afford the title compound (38.5 g, 73%) as a clear liquid. MS(IS) 160 (M+1). 1H NMR (400 MHz, CDCl3): 3.90 (s, 2H); 6.96 (t, 1H, J=6.4 Hz); 7.11 (d, 1H, J=8.3 Hz); 7.36 (t, 1H, J=6.4 Hz).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C:7]1[S:8][C:9]2[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:10]=2[N:11]=1>N1C=CC=CC=1.C(OCC)(=O)C>[O:16]=[C:15]1[C:9]2[S:8][C:7]([NH:6][C:2](=[O:3])[O:4][CH3:5])=[N:11][C:10]=2[CH2:12][CH2:13][CH2:14]1
Reactant: COC(=O)Cl
Reactant: Nc1nc2c(s1)C(=O)CCC2
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)Nc1nc2c(s1)C(=O)CCC2
Temperature: 50 °C
Reaction time: 15 h

Procedure:
572 μl of methyl chloroformate (7.3 mmol) are added to a solution of 500 mg of 2-amino-5,6-dihydro-4H-benzothiazol-7-one (2.4 mmol) in 5 ml of pyridine. The reaction mixture is stirred at 50° C. for 15 h and then diluted with ethyl acetate; the mixture is then extracted by shaking, in each case 2×, with water and cold 1 N hydrochloric acid. The organic phase is dried and evaporated. Yield: 290 mg
Reaction SMILES: C([S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[CH:8][C:7]=1[C:19]([F:22])([F:21])[F:20])(C)(C)C.[ClH:23]>>[ClH:23].[CH3:18][C:14]1[CH:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([SH:5])=[C:7]([C:19]([F:22])([F:20])[F:21])[CH:8]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Cc1cc(-c2ccc(SC(C)(C)C)c(C(F)(F)F)c2)ccn1
Agent: Cl
Product: Cc1cc(-c2ccc(S)c(C(F)(F)F)c2)ccn1
Temperature: 100 °C
Yield: 93.9 %

Procedure:
4-(4-tert-Butylsulfanyl-3-trifluoromethyl-phenyl)-2-methyl-pyridine (65.1 g, ˜200 mmol) was dissolved in 5 M HCl (800 mL) and the yellowish solution was warmed up and stirred at 100° C. under reflux for 22 h. After cooling (˜1 h) and stirring at room temperature for 0.5 h, the beige suspension was filtered and the filter cake was washed with deionized water (400 mL) and acetone (200 mL) and then dried (50° C./≧10 mbar/24 h) to give 57.4 g (93.9%) of the title compound as an off-white, crystalline powder, mp. >270° C. (dec.). 1H NMR (CDCl3+2 drops TFA, 400 MHz) δ 2.96 (s, 3H), 4.06 (q, J=3.3 Hz, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.74 (dd, J1=8.3 Hz, J2=2.1 Hz, 1H), 7.84 (d, J=1.9 Hz, 1H), 7.93 (dd, J1=6.3 Hz, J2=1.9 Hz, 1H), 7.97 (d, J=1.9, 1H), 8.79 (d, J=6.2 Hz, 1H), 9.96 (s, 14H, TFA), 15.18 (br s, 1H). ESI-MS (m/z) [M−HCl]− 270 (100).
Reaction SMILES: C[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14](O)=[O:15])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:56][CH:57]([CH2:62][OH:63])[C:58]([O:60][CH3:61])=[O:59]>CN(C=O)C>[C:8]1([C:5]2[N:6]=[N:7][CH:2]=[C:3]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[C:14]([NH:56][CH:57]([CH2:62][OH:63])[C:58]([O:60][CH3:61])=[O:59])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1nnc(-c2ccccc2)c(C(=O)O)c1-c1ccccc1
Reactant: COC(=O)C(N)CO
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: CN(C)C=O
Product: COC(=O)C(CO)NC(=O)c1c(-c2ccccc2)cnnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.8 %

Procedure:
The solution of compound 6 (50 mg, 1.81 mmol) in DMF (0.5 mL), DIPEA (93 mg, 0.72 mmol), HATU (138 mg, 0.36 mmol) were sequentially added and stirred for 10 min at rt. Then methyl 2-amino-3-hydroxypropanoate (84 mg, 0.54 mmol) was added and stirred overnight at rt. Reaction was quenched by addition of ice cold water. The precipitated solid was filtered, washed with hexane, dried over anhydrous Na2SO4 and azeotroped with toluene to furnish methyl 2-(3,5-diphenylpyridazine-4-carboxamido)-3-hydroxypropanoate (20 mg, 29%) as an off white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12](Cl)=[O:13].[NH2:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]2[N:22]([CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)[N:23]=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([O:32][CH3:33])[CH:26]=3)[C:17]=12>ClCCl.N1C=CC=CC=1>[NH2:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]2[N:22]([CH:34]3[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH2:39]3)[N:23]=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:12](=[O:13])[C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=4[F:1])=[C:27]([O:32][CH3:33])[CH:26]=3)[C:17]=12
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Reactant: COc1cc(-c2nn(C3CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.9 %

Procedure:
2-Fluoro-4-(trifluoromethyl)-1-benzenecarbonyl chloride (3.05 mL, 20.2 mmol) in dichloromethane (25 mL) was added to a solution of tert-butyl 4-[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (8.77 g, 20.0 mmol) in pyridine (50 mL) at 0° C. After 5 minutes, the ice water bath was removed and the reaction mixture stirred at room temperature for 1 hours. 2-Fluoro-4-(trifluoromethyl)-1-benzenecarbonyl chloride (0.5 mL, 3.31 mmol) was added and the reaction mixture was stirred for addition 30 minutes. The solvent was evaporated and the residue was dissolved in dichloromethane. The organic layer was washed with water, brine then dried over MgSO4. The solvent was evaporated and the residue was purified by flash column chromatography using ethyl acetate/dichloromethane (80:20 to 100:0) as mobile phase to give tert-Butyl 4-[4-amino-3-(4-[2-fluoro-4-(trifluoromethyl)benzoyl]amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (11.2 g, 89%). 1H NMR (CDCl3-d) δ 1.48 (s, 9H), 2.04 (m, 2H), 2.30 (m, 2H), 2.98 (m, 2H), 4.05 (s, 3H), 4.32 (m, 2H), 4.95 (m, 1H), 5.89 (bs, 2H), 7.33 (m, 2H), 7.51 (d, J=11.62 Hz, 1H), 7.61 (d, J=8.21 Hz, 1H), 8.36 (m, 2H), 8.72 (d, J=8.18 Hz, 1H), 9.32 (d, J=14.39 Hz, 1H).