Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][CH2:21][OH:22])[CH:15]=[CH:14]2)#[CH:10].C(NC(C)C)(C)C>C1COCC1.[Cu]I.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>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]#[C:9][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][CH2:21][OH:22])[CH:15]=[CH:14]3)=[N:3][CH:4]=1
Reactant: C#Cc1ccc2c(ccn2CCO)c1
Reactant: Brc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OCCn1ccc2cc(C#Cc3ccc(Br)cn3)ccc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Under an N2 atmosphere 29.4 g (124 mmol) 2,5-dibromo-pyridine, 241 mg (1.3 mmol) CuI and 888 mg (1.3 mmol) Pd(PPh3)2Cl2 are added to a solution of 23.0 g (124 mmol) 2-(5-ethynyl-indol-1-yl)-ethanol and 35 mL (248 mmol) diisopropylamine in 1150 mL THF and the reaction mixture is heated to 50° C. for 3.5 h. Another 241 mg CuI and 888 mg Pd(PPh3)2Cl2 and 9 g (38 mmol) 2,5-dibromo-pyridine are added, the mixture is stirred for a further 2.5 h at 50° C., 64 h at RT and a further 8 h at 60° C. The mixture is evaporated down i. vac., the residue is combined with 500 mL 3% NH3 solution and 800 mL EtOAc. The precipitate formed is filtered off, washed with water and dried at 50° C. The two phases of the filtrate are separated and the organic phase is evaporated down i.vac. The residue is stirred vigorously with 500 mL PE/diisopropylether (1:1) and suction filtered. The two product fractions are then combined.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][C@H:12]([CH3:16])[NH:13][C:14](=[O:15])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[CH:17]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>>[CH:17]([N:20]1[CH2:25][CH2:24][CH:23]([O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[CH2:11][C@H:12]([CH3:16])[NH:13][C:14](=[O:15])[C:6]4=[CH:5][C:4]=3[CH:3]=2)[CH2:22][CH2:21]1)([CH3:19])[CH3:18]
Reactant: C[C@H]1Cn2c(cc3cc(O)ccc32)C(=O)N1
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3C[C@H](C)NC2=O)CC1
Yield: 46 %

Procedure:
The title compound was synthesized in analogy to example 1, from (S)-8-hydroxy-3-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 1-isopropyl-piperidin-4-ol (commercially available), triphenylphosphine and di-tert-butyl-azodicarboxylate, to give the desired product as a light yellow solid (46%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].N12CCCN=C1CCCCC2.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][C:26](Cl)=[O:27]>ClCCl>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][C:26]([NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])=[O:27]
Reactant: CCOC(=O)CN
Reactant: O=C(Cl)Cc1cccs1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)Cc1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a suspension of glycine ethyl ester hydrochloride (21.77 g, 156 mmol) in anhydrous dichloromethane (260 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (55 mL, 368 mmol) was added under nitrogen, which addition turned the suspension clear. Then 2-thiopheneacetyl chloride (19.2 mL, 156 mmol) was added dropwise. After completion of the addition, the flask was warmed to room temperature and the mixture was stirred for 1 hour. Then it was washed with water (260 mL×3), dried and concentrated. A dark brown oil was obtained (31.77 g, yield 89%), which turned into a dark brown solid upon standing. 1H NMR (CDCl3, 500 MHz), δ=7.26 (dd, J=5.0, 1.0 Hz, 1H), 7.01-6.97 (m, 2H), 6.19 (s, 1H), 4.18 (q, J=7.0 Hz, 2H), 4.00 (d, J=5.0 Hz, 2H), 3.83 (s, 2H), 1.26 (t, J=7.0 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][OH:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O>C1COCC1>[CH2:3]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][O:16][CH2:22][C:23]([F:26])([F:25])[F:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OC[C@@H]1CCCN1Cc1ccccc1
Reactant: CS(=O)(=O)OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)COC[C@@H]1CCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.4 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 0.314 g, 7.84 mmol) in THF (20 mL) was added (S)-(1-benzyl-pyrrolidin-2-yl)-methanol (1.0 g, 5.23 mmol) and the reaction mixture was stirred at room temperature for 20 min. Then, 2,2,2-trifluoroethyl methanesulfonate (1.4 g, 7.84 mmol) was added and stirring was continued at room temperature over night. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (2×50 mL). Combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH(1% NH4OH)-DCM gradient to give the title compound (0.706 g, 37%) as a light yellow liquid. MS: 274.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([CH2:7][C:8]1[C:9]([CH3:22])=[N:10][C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:12][CH:13]=1)=[CH2:6])[CH3:2].CCOC(C)=O.[C:30]([OH:33])(=[S:32])[CH3:31]>>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([CH2:6][S:32][C:30](=[O:33])[CH3:31])[CH2:7][C:8]1[C:9]([CH3:22])=[N:10][C:11]([NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])=[CH:12][CH:13]=1)[CH3:2]
Reactant: C=C(Cc1ccc(NC(=O)OC(C)(C)C)nc1C)C(=O)OCC
Reactant: CC(O)=S
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CSC(C)=O)Cc1ccc(NC(=O)OC(C)(C)C)nc1C
Temperature: 25 °C
Reaction time: 64 h
Yield: 87 %

Procedure:
TEA (0.556 mL, 3.99 mmol) was added to a solution of 2-(6-tert-butoxycarbonylamino-2-methyl-pyridin-3-ylmethyl)-acrylic acid ethyl ester (1.23 g, 3.84 mmol) in thioacetic acid (10 mL) at 0 ° C. under argon. The mixture was stirred at room temperature for 64 h. EtOAc was added and the solution was washed with Na2CO3 and brine, dried and concentrated under reduced pressure. Flash chromatography (toluene/EtOAc, 5:1→1:1) gave 2-acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-2-methyl-pyridin-3-yl)-propionic acid ethyl ester (1.33 g, 87%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([CH3:14])=[C:9]([C:12]#[CH:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.Cl[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([CH3:14])=[C:9]([C:12]#[C:13][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:18]=3)[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: C#Cc1cc2c(cc1C)SCCC2(C)C
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2cc3c(cc2C)SCCC3(C)C)nc1
Temperature: 55 °C

Procedure:
A mixture of 86 mg (0.4 mmol) of 4,4,7-trimethyl-6-ethynylthiochroman, 85 mg (0.46 mmol) of ethyl 6-chloronicotinate and 0.8 ml of triethylamine was degassed under nitrogen and then treated with a mixture of 10 mg (0.05 mmol) of cuprous iodide and 20 mg (0.03 mmol) of bis(triphenylphosphine) palladium (II) chloride. The reaction mixture was heated at 55° C. under a nitrogen atmosphere for 18 hours. The mixture was then extracted with 1.5 ml of 40% ethyl acetate in hexanes and purified by flash chromatography (silica; 10% ethyl acetate in hexanes) to give the title compound as a yellow solid.
Reaction SMILES: CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:23][C:24]([CH3:53])([CH3:52])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49][CH:50]=[CH2:51])[C@H:41]([O:46][CH2:47][CH3:48])[C:42]([O:44][CH3:45])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:27].[F:54][C:55]1[CH:56]=[C:57](Br)[CH:58]=[CH:59][C:60]=1[O:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:53][C:24]([CH3:23])([CH3:52])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49]/[CH:50]=[CH:51]/[C:57]1[CH:58]=[CH:59][C:60]([O:61][C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)=[C:55]([F:54])[CH:56]=1)[C@H:41]([O:46][CH2:47][CH3:48])[C:42]([O:44][CH3:45])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH3:30])=[O:27]
Reactant: Fc1cc(Br)ccc1Oc1ccccc1
Reactant: C=CC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C)[C@H](OCC)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCO[C@H](C(=O)OC)[C@@H](C/C=C/c1ccc(Oc2ccccc2)c(F)c1)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Yield: 60.4 %

Procedure:
A mixture of palladium acetate (12 mg, 0.05 mmol) and tri-(2-methylphenyl)phosphine (30 mg, 0.10 mmol) in anhydrous acetonitrile (1 mL) was sonicated at room temperature for 1 min until a creamy-coloured suspension formed. This suspension was added via Pasteur pipette to a stirred solution of methyl (2S,3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-2-ethoxy-hex-5-enoate (415 mg, 0.96 mmol), 3-fluoro-4-phenoxy-bromobenzene (Preparation 10)(400 mg, 1.50 mmol), and triethylamine (280 μL, 2.0 mmol) in anhydrous acetonitrile (1 mL) under nitrogen. The mixture was purged with nitrogen, then heated at reflux for 16 h. After being cooled, the mixture was poured into ethyl acetate (70 mL) and washed with 5% aqueous citric acid (20 mL), saturated aqueous sodium chloride (50 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with dichloromethane:ethyl acetate) to give mainly methyl (2S,3R,5E)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-2-ethoxy-6-(3-fluoro-4-phenoxyphenyl)hex-5-enoate as a pale yellow foam (359 mg, 69%). 1H nmr suggested that two alkene isomers, the (5Z) and (4E) were also present. The mixture of alkenes was taken onto the next step (see c, below).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[C:9](Cl)(=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl>C(C(C)=O)C>[OH:8][C:3]1[CH:4]=[CH:5][C:6]([NH:7][C:9](=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:1][CH:2]=1
Reactant: CCCCCCCCCCCCCCCCC(=O)Cl
Reactant: Nc1ccc(O)cc1
Agent: Cl
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCCC(=O)Nc1ccc(O)cc1
Temperature: 70 °C
Yield: 78.9 %

Procedure:
Under a nitrogen atmosphere, p-aminophenol (109 g) was suspended in methyl ethyl ketone (2000 ml) and the suspension was heated to 70° C. Heptadecanoyl chloride (152 g) was added to the suspension with vigorous stirring, followed by refluxing with heating for 2 hours. A 5% aqueous hydrochloric acid solution (500 ml) was added to the resulting reaction mixture with vigorous stirring. The reaction mixture was cooled to room temperature to precipitate a white crystal. This crystal was filtered off under reduced pressure and recrystallized from methyl ethyl ketone to obtain 150 g of the desired product. Yield 80%; m.p. 137° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Br)=[C:9]([NH2:12])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[C:14]=2[F:22])[N:6]=1)=[O:4].[CH3:23][Si:24]([CH3:41])([CH3:40])[C:25]#[C:26][Sn](CCCC)(CCCC)CCCC>ClCCCl.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>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:26]#[C:25][Si:24]([CH3:41])([CH3:40])[CH3:23])=[C:9]([NH2:12])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[C:14]=2[F:22])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1Br
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1C#C[Si](C)(C)C
Temperature: 110 °C
Yield: 79.4 %

Procedure:
6-Amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carboxylic acid methyl ester (1.0 g, 2.56 mmol), trimethyl((tributylstannyl)ethynyl)silane (1.98 g, 5.12 mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.18 g, 0.256 mmol) were combined in 1,2-dichloroethane (10 mL) and heated in a CEM microwave reactor at 110° C. for 15 min. The cooled reaction mixture was concentrated under vacuum then purified by flash chromatography on silica gel (dichloromethane/ethyl acetate gradient). A second purification by flash chromatography on silica gel (hexane/ethyl acetate gradient) yielded the title compound (0.829 g, 79% yield): mp 126-128° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:21][C:22]([O:24]CC)=[O:23])[CH:13]=3)[S:10][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28].[OH-].[Na+].Cl>COCCOC>[F:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:11][C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:21][C:22]([OH:24])=[O:23])[CH:13]=3)[S:10][C:6]=2[C:5]([F:27])=[CH:4][C:3]=1[F:28]
Reactant: CCOC(=O)Cn1cc(Cc2nc3c(F)c(F)cc(F)c3s2)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: O=C(O)Cn1cc(Cc2nc3c(F)c(F)cc(F)c3s2)c2ccccc21
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
A solution of give 3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid, ethyl ester (5.91 g, 14.6 mmol) in 1,2-dimethoxyethane (73 mL, 0.2 M) was cooled to 0° C. and treated with aq. NaOH (1.25 N, 58 mL, 73.1 mmol) in a dropwise manner over 15 min. After the addition was complete, the solution was stirred for an additional 30 min, acidified to pH 3 with 2N HCl, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and washed with sat'd. aq. NaCl (30 mL). The organic extract was dried over Na2SO4, filtered and concentrated. The resulting material was stirred as a supension in heptane, filtered and dried to give 3-(4,5,7-trifluorobenzothiazol-2-yl)methyl-indole-N-acetic acid (5.38 g, 98%) as a pale yellow solid: mp 177-178° C.; Rf 0.44 (20% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 7.74-7.65 (m, 1 H), 7.53 (d, J=7.5 Hz, 1 H), 7.46 (s, 1 H), 7.40 (d, J=8.1 Hz, 1 H), 7.15 (b t, J=6.9 Hz, 1 H), 7.03 (b t, J=7.2 Hz, 1 H), 5.03 (s, 2 H), 4.65 (s, 2 H); LRMS calcd for C18H11F3N2O2S: 376.4; found 375.0 (M−1)−. Anal. Calcd for C18H11F3N2O2S: C, 57.44; H, 2.95; N, 7.44; S, 8.52. Found C, 57.58; H, 2.99; N, 7.38; S, 8.51.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:12])=[N+:7]([O-])[CH:8]=[CH:9][N:10]=1)=[O:4].P(Cl)(Cl)([Cl:15])=O>CN(C=O)C>[Cl:15][C:8]1[N:7]=[C:6]([CH3:12])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:10][CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ncc[n+]([O-])c1C
Solvent: CN(C)C=O
Product: COC(=O)c1ncc(Cl)nc1C
Temperature: 100 °C
Reaction time: 1 h
Yield: 21.7 %

Procedure:
In a 1-L flask, the crude 3-(methoxycarbonyl)-2-methylpyrazine 1-oxide (step 2, 17.77 g, 106 mmol) was dissolved in DMF (300 mL). Neat phosphoryl trichloride (29.6 mL, 317 mmol) was added. The reaction mixture was heated to 100° C. After 1 h, the reaction mixture was concentrated to remove most of the DMF. The flask was cooled in an ice water bath, and 1 M aqueous Na2CO3 (300 mL) was added slowly, followed by 80% EtOAc-hexane (400 mL). The mixture was filtered through Celite. The resulting filtrate was partitioned and the aqueous phase was extracted further with 80% EtOAc-hexane (2×250 mL). The combined organic layers were dried over MgSO4 and concentrated. The material was purified through silica gel using 11% EtOAc-hexane to afford the title compound (4.29 g, 23 mmol, 22%). MS m/z=187 [M+H]+. Calculated for C7H7ClN2O2: 186. 1H NMR in CDCl3 δ: 8.51 (s, 1H), 4.01 (s, 3H), 2.86 (s, 3H).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[C:15]([Cl:28])[CH:14]=1.[CH:29](N1CCCCC1)=[O:30].[Cl-].[NH4+]>O1CCCC1>[Si:21]([O:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH:29]=[O:30])=[CH:14][C:15]=1[Cl:28])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: O=CN1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C=O)cc1Cl
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 72.8 %

Procedure:
A solution (1.6 M, 8.3 ml) of n-butyl lithium/hexane was added to a solution of 4-bromo-1-((tert-butyldimethylsilyloxy)methyl)-2-chlorobenzene (4.03 g) in tetrahydrofuran (10 ml) under a nitrogen atmosphere at −60° C. and the mixture was stirred for 45 min. The reaction mixture was once heated to 0° C. and then cooled to −40° C. and 1-formyl piperidine (1.63 g) was dropwise added over 3 min. Then, the reaction mixture was heated to 0° C. over 2 hr. Aqueous ammonium chloride was added to the reaction mixture and the resulting product was extracted twice with hexane. The organic layers were combined, washed successively with diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=30/1) to give the objective compound (2.49 g) as a colorless oil.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19]([O:21]C)=[O:20])=[CH:11][N:10]=1.CO.[OH-].[Na+].Cl>O1CCCC1>[C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[NH:8][C:9]1[N:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[C:12]([C:19]([OH:21])=[O:20])=[CH:11][N:10]=1
Reactant: COC(=O)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a mixture of methyl rac-2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-4-(trifluoromethyl)pyrimidine-5-carboxylate (5.2 g), methanol (25 mL), and tetrahydrofuran (25 mL) was added a 1 M aqueous sodium hydroxide solution (33 mL) at room temperature, followed by stirring at 60° C. for 2 hours. To the reaction mixture was added 1 M hydrochloric acid, followed by stirring at room temperature for 30 minutes, and then the precipitate was collected by filtration and washed with water to obtain rac-2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (4.9 g) as a white powder.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][CH3:8].[CH2:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][N:27]=2)=[CH:22][CH:21]=1)[CH2:12][CH3:13].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([O:9][C:1](=[O:10])[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][CH3:8])=[CH:28][N:27]=2)=[CH:24][CH:25]=1)[CH2:12][CH3:13]
Reactant: CCCC/C=C\CC(=O)O
Reactant: CCCOCCCCCc1ccc(-c2ccc(O)cn2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC/C=C\CC(=O)Oc1ccc(-c2ccc(CCCCCOCCC)cc2)nc1

Procedure:
0.5 g of (Z)-3-octenoic acid, 1.0 g of 2-[4-(5-[propyloxy]-1-pentyl)phenyl]-5-hydroxypyridine, 07 g of N,N'-dicyclohexyl-carbodiimide, 0.04 g of (dimethylaminio)pyridine and 50 ml of dichloromethane were reacted in an analogous manner to Example 1 to give 2-[4-(5-[propyloxy]-1-pentyl)phenyl]-5-([(Z)-3-octenoyl]oxy)pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]O)[CH:24]=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: OCc1cccnc1
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2Cc1cccnc1

Procedure:
Compound IIn was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and pyridin-3-ylmethanol following the general procedure for the Mitsunobu reaction.
Reaction SMILES: [CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][N:10]=2)[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:25]([O:32][C:33]([C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][N:51]([C:54](=[O:57])[CH2:55]Br)[CH2:50][CH2:49]2)=[C:44]([CH:58]=[CH:59][CH3:60])[CH:43]=1)([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C=O>[CH2:25]([O:32][C:33]([C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][N:51]([C:54](=[O:57])[CH2:55][N:4]3[C:3](=[O:8])[C:2]([C:9]4[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][N:10]=4)([CH3:1])[NH:6][C:5]3=[O:7])[CH2:50][CH2:49]2)=[C:44](/[CH:58]=[CH:59]\[CH3:60])[CH:43]=1)([C:34]([F:35])([F:36])[F:37])[C:38]([F:39])([F:40])[F:41])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)nc1
Reactant: CC=Cc1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)CN2C(=O)NC(C)(c3ccc(OC(C)C)cn3)C2=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.9 %

Procedure:
5-Methyl-5-[5-(1-methylethoxy)pyridin-2-yl]imidazolidine-2,4-dione (7.7 mg, 0.0309 mmol) was dissolved in N,N-dimethylformamide (2.8 mL), added potassium carbonate (9.3 mg, 0.0674 mmol) under ice-cold conditions, and the mixture was stirred at room temperature for 5 minutes. Then, under ice-cold conditions, 1-(4-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-2-(prop-1-en-1-yl)phenyl}piperazin-1-yl)-2-bromoethanone (16 mg, 0.0281 mmol) was added, and stirred at room temperature overnight. Then, the mixture was stirred at 60° C. for 10 hours. Under ice-cold conditions, the reaction solution was added water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone), and the title compound (17 mg (yield 80%)) was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][C:20]([CH3:39])([CH3:38])[CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:30][C:25]=2[N:24]=[CH:23]1>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][C:20]([CH3:39])([CH3:38])[CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][C:29]([C:31]4[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=4)=[CH:30][C:25]=3[N:24]=[CH:23]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Reactant: CC(C)(N)Cn1cnc2cc(C3=NNC(=O)CC3)ccc21
Product: CC(C)COCCc1ccc(OCC(O)CNC(C)(C)Cn2cnc3cc(C4=NNC(=O)CC4)ccc32)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isobutoxyethyl)-phenoxy]-2,3-epoxypropane and 6-[1-(2-amino-2,2-dimethylethyl)benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.