Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N-:12]=[N+]=[N-].[Na+].OS(O)(=O)=O>C(Cl)(Cl)Cl.O>[NH:12]1[C:1](=[O:11])[CH2:2][CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]1=2
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCCc2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1CCCc2ccccc2N1
Temperature: 40 °C
Yield: 65.8 %

Procedure:
A suspension of 3,4-dihydronaphthalen-1(2H)-one (2.0 g, 13.68 mmol) and sodium azide (1.11 g, 17.10 mmol) in a mixture of 14 mL CHCl3 and 3 mL H2O was heated at 40° C. then treated with H2SO4 dropwise over 20 minutes. The mixture was diluted with 50 mL H2O and filtered. The solid was slurried in hot H2O, cooled and filtered to give a gray solid (1.45 g, 65.6%). 1H-NMR (DMSO-d6) δ 9.49 (s, 1H), 7.25-7.22 (m, 2H), 7.19-7.21 (m, 1H), 6.95 (d, J=7.8 Hz, 1H), 2.70-2.65 (m, 2H), 2.15-2.07 (m, 4H). MS (EI): 161 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[CH3:25][Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.CI.[Na+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[N:12]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C@:11]([CH3:25])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)[C@@H]1CC[C@H](c2cncc(F)c2)N1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CI
Product: CCOC(=O)[C@]1(C)CC[C@H](c2cncc(F)c2)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of (2S,5R)-1-tert-butyl 2-ethyl 5-(5-fluoropyridin-3-yl)pyrrolidine-1,2-dicarboxylate (250 mg, 0.739 mmol) in THF (10 mL) was cooled to −78° C. and 0.5 M KHMDS in toluene (1.77 mL, 0.885 mmol) was added dropwise. The reaction was stirred for 1 hour at −78° C. and MeI (59.9 μL, 0.960 mmol) was added. The reaction was allowed to warm to ambient temperature and saturated aqueous NaCl (20 mL) was added. The mixture was extracted with EtOAc (2×50 mL) and the combined organic extracts were filtered and concentrated to afford (2S,5R)-1-tert-butyl 2-ethyl 5-(5-fluoropyridin-3-yl)-2-methylpyrrolidine-1,2-dicarboxylate (255 mg, 98% yield) as a clear oil. MS (apci) m/z=353.1 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:21]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([F:20])[CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:37]1([NH2:44])[CH2:42][CH2:41][C@H:40]([NH2:43])[CH2:39][CH2:38]1>CN1C(=O)CCC1>[NH2:43][C@H:40]1[CH2:41][CH2:42][C@H:37]([NH:44][C:2]2[CH:3]=[C:4]([N:21]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[C:16]([F:20])[CH:15]=4)=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:38][CH2:39]1
Reactant: COc1ccc(CN(c2ccccn2)c2cc(Cl)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CN1CCCC1=O
Product: COc1ccc(CN(c2ccccn2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(F)c4)cnc23)cc1
Temperature: 25 °C

Procedure:
A solution of 6-chloro-N-(2-fluoropyridin-4-yl)-8-((4-methoxybenzyl)(pyridin-2-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (60 mg, 0.119 mmol) and (trans)-cyclohexane-1,4-diamine (136 mg, 1.191 mmol) in NMP (1 mL) was heated at 90° C. for 8 h and then cooled to room temperature. The crude reaction mixture was purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) to obtain the pure product as a white solid, which was used without further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:18](=[N:19][C:20]([NH:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[N:21][CH:22]=3)[N:17](COCC[Si](C)(C)C)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1(CCNC2N=C3N(COCC[Si](C)(C)C)N=C(C4C=CC=CC=4)C3=CN=2)CCOCC1.C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:18](=[N:19][C:20]([NH:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)=[N:21][CH:22]=3)[NH:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3ccccc3)c2)c2cnc(NCCN3CCOCC3)nc21
Agent: C[Si](C)(C)CCOCn1nc(-c2ccccc2)c2cnc(NCCN3CCOCC3)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CNc2cccc(-c3n[nH]c4nc(NCCN5CCOCC5)ncc34)c2)cc1
Reaction time: 3 h

Procedure:
To a stirred solution of a mixture of [3-(3-benzylamino-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine and (2-morpholin-4-yl-ethyl)-[3-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-amine (210 mg, crude) in dichloromethane (5 mL) was added TFA (5 mL) at room temperature. The resulting mixture was stirred for another three hours at this temperature. The solvent was evaporated under reduced pressure and the residue was treated with saturated aqueous NaHCO3 (3 mL) and extracted with EtOAc (10 mL). The organic phase was washed with brine (5 mL) and dried to give crude product. It was purified by prep-HPLC to give [3-(3-benzylamino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine as yellow solid. (Yield 24 mg, 14.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:18])=[C:6]([N:8]2[N:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[O:10][C:9]2=[O:17])[CH:7]=1.[S-:19][C:20]#[N:21].[NH4+].BrBr.O>C(O)(=O)C>[NH2:21][C:20]1[S:19][C:3]2[CH:4]=[C:5]([Cl:18])[C:6]([N:8]3[N:12]=[C:11]([C:13]([CH3:15])([CH3:14])[CH3:16])[O:10][C:9]3=[O:17])=[CH:7][C:2]=2[N:1]=1
Reactant: CC(C)(C)c1nn(-c2cc(N)ccc2Cl)c(=O)o1
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1nn(-c2cc3nc(N)sc3cc2Cl)c(=O)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
3-(5-Amino-2-chlorophenyl)-5-(1,1-dimethyl-ethyl) -1,3,4-oxadiazol-2(3H)-one (38.28 g) was dissolved in 95% acetic acid (138.20 g), and ammonium thiocyanate (27.64 g) was added thereto, followed by stirring at room temperature for 3 hours. To the resultant mixture, a solution of bromine (27.64 g) in acetic acid (41.46 g) was added, followed by stirring at room temperature for 12 hours. The reaction mixture was combined with hot water (274.7 ml), heated to 100° C. and filtered while hot. The filtrate was neutralized with sodium carbonate and extracted with ethyl acetate. The extract was washed with water, dried and distilled under reduced pressure to give 3-(2-amino-6-chloro-benzothiazol -5-yl)-5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2(3H)-one (39.06 g) as a resinous substance.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:37]=[CH:36][C:17]2[NH:18][C:19]([S:21][CH2:22][C:23]3[C:28]([CH3:29])=[C:27]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[N:26]=[CH:25][N:24]=3)=[N:20][C:16]=2[CH:15]=1.N>ClCCl>[CH3:12][O:13][C:14]1[CH:37]=[CH:36][C:17]2[NH:18][C:19]([S:21]([CH2:22][C:23]3[C:28]([CH3:29])=[C:27]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[N:26]=[CH:25][N:24]=3)=[O:9])=[N:20][C:16]=2[CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2[nH]c(SCc3ncnc(N4CCCCC4)c3C)nc2c1
Agent: N
Solvent: ClCCl
Product: COc1ccc2[nH]c(S(=O)Cc3ncnc(N4CCCCC4)c3C)nc2c1
Yield: 63.7 %

Procedure:
A solution of m-chloroperbenzoic acid (2.16 g) in dichloromethane (40 ml) was added to a stirred solution of 5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylthio)-(1H)-benzimidazole (4.0 g) in dichloromethane (110 ml) cooled to between -40° and -50°. After a further hour at -40°, ammonia was passed through the reaction mixture and the precipitated solid filtered off. The filtrate was stripped, and the residual glass triturated with acetonitrile to give 5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylsulphinyl)-(1H)-benzimidazole 2.66 g, m.p. 87°-89°.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([O:22][P:23]([O:29][Si](C)(C)C)[O:24][Si](C)(C)C)(C)C>>[C:1]1([S:7]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14][P:23](=[O:22])([OH:29])[OH:24])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)OP(O[Si](C)(C)C)O[Si](C)(C)C
Reactant: O=S(=O)(c1ccccc1)c1ccc(CBr)cc1
Product: O=P(O)(O)Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Reaction time: 18 h
Yield: 32 %

Procedure:
A solution of 4.3 g (14 mmol) of 4-(phenylsulfonyl)benzyl bromide and 30 g (0.1 mole) of tris-trimethylsilylphosphite was heated at 120° C. for 18 hours. The excess tris-trimethylsilylphosphite was distilled off under reduced pressure. The residue was dissolved in 200 ml of 9:1 tetrahydrofuran/water and was allowed to stand at room temperature for 18 hours. The tetrahydrofuran was evaporated and the resulting solids were filtered and washed with water to give 1.4 g of product; m.p. 217-219° C.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C@@H:5]1[CH2:9][NH:8][C@H:7]([C:10]2[NH:11][C:12]([C:15]3[CH:28]=[C:27]4[O:29][CH2:30][C:24]5[C:25]6[C:26]4=[C:17]([CH2:18][O:19][C:20]=6[CH:21]=[C:22]([C:31]4[NH:35][C:34]([C@@H:36]6[CH2:40][CH2:39][C@H:38]([CH3:41])[N:37]6[C:42](=[O:52])[C@@H:43]([NH:47][C:48](=[O:51])[O:49][CH3:50])[CH:44]([CH3:46])[CH3:45])=[N:33][CH:32]=4)[CH:23]=5)[CH:16]=3)=[CH:13][N:14]=2)[CH2:6]1.[CH3:53][O:54][C:55]([NH:57][C@@H:58]([CH:62]([CH3:64])[CH3:63])[C:59](O)=[O:60])=[O:56].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:50][O:49][C:48]([NH:47][C@@H:43]([CH:44]([CH3:46])[CH3:45])[C:42]([N:37]1[C@@H:38]([CH3:41])[CH2:39][CH2:40][C@H:36]1[C:34]1[NH:35][C:31]([C:22]2[CH:21]=[C:20]3[O:19][CH2:18][C:17]4[C:26]5[C:25]3=[C:24]([CH2:30][O:29][C:27]=5[CH:28]=[C:15]([C:12]3[NH:11][C:10]([C@@H:7]5[CH2:6][C@H:5]([CH2:4][O:3][CH3:2])[CH2:9][N:8]5[C:59](=[O:60])[C@@H:58]([NH:57][C:55](=[O:56])[O:54][CH3:53])[CH:62]([CH3:64])[CH3:63])=[N:14][CH:13]=3)[CH:16]=4)[CH:23]=2)=[CH:32][N:33]=1)=[O:52])=[O:51]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC[C@@H]1CN[C@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]6)cc(c3-5)OC4)[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC[C@H]1C[C@@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]6)cc(c3-5)OC4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Reaction time: 3 h
Yield: 87.7 %

Procedure:
To the HCl salt of methyl (S)-1-((2S,5S)-2-(5-(7-(2-((2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (40 mg) in DMF (1 mL) was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (13 mg, 0.075 mmol), HATU (21 mg, 0.055 mmol) and N-methylmorpholine (0.016 mL, 0.15 mmol). After 3 h, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl {(2S)-1-[(2S,4S)-2-[5-(7-{2-[(2S,5S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-5-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (43 mg). LCMS-ESI+: calculated for C45H56N8O9: 852.4; observed [M+1]+: 853.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[N:7][CH:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl.FC(F)(F)S(O[C:27]1[C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1)(=O)=O>O1CCOCC1.O.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]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:27]2[C:39]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[NH:32][C:31]=3[CH:30]=[CH:29][CH:28]=2)[CH:6]=[N:7][CH:8]=1
Reactant: COc1cncc(B(O)O)c1
Reactant: O=S(=O)(Oc1cccc2[nH]c3ccccc3c12)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: COc1cncc(-c2cccc3[nH]c4ccccc4c23)c1
Yield: 100.6 %

Procedure:
0.54 g of (5-methoxypyridin-3-yl)boronic acid, 3.3 g of caesium carbonate and 93 mg of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride as a complex with dichloromethane (1/1) [PdCl2(dppf)CH2Cl2] are successively added, under argon, to a solution of 0.8 g of 4-trifluoromethanesulphonyloxycarbazole, obtained in stage 1 of Example 1, in a mixture of 37 ml of dioxane and 12 ml of water. The reaction mixture is refluxed for 3 and a half hours, filtered through celite and concentrated under reduced pressure. The residue is subsequently purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (75/25 by volume), so as to give 0.7 g of 4-(5-methoxypyridin-3-yl)-9H-carbazole in the form of a colourless oil, the characteristics of which are the following:
Reaction SMILES: CC(C)(C)C([O:5][CH:6]1[CH:13]2[CH:9]([CH2:10][CH:11]([CH:14]=O)[CH2:12]2)[C:8](=[O:16])[CH:7]1[C:17]1[C:22]([CH2:23][CH3:24])=[CH:21][C:20]([CH3:25])=[CH:19][C:18]=1[CH2:26][CH3:27])=O.C([O-])=O.[Na+].Cl.[NH2:35]O.O>C(O)=O.C(OCC)(=O)C>[CH2:26]([C:18]1[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH2:23][CH3:24])[C:17]=1[CH:7]1[C:6](=[O:5])[CH:13]2[CH:9]([CH2:10][CH:11]([C:14]#[N:35])[CH2:12]2)[C:8]1=[O:16])[CH3:27]
Reactant: NO
Reactant: CCc1cc(C)cc(CC)c1C1C(=O)C2CC(C=O)CC2C1OC(=O)C(C)(C)C
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=CO
Product: CCc1cc(C)cc(CC)c1C1C(=O)C2CC(C#N)CC2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.91 g (2.30 mmol) of 2-(2,6-diethyl-4-methylphenyl)-5-formyl-3-oxooctahydropentalen-1-yl 2,2-dimethylpropanoate (Example I-b-2), 0.78 g (11.48 mmol) of sodium formate and 0.80 g (11.48 mmol) of hydroxylamine hydrochloride in 30 ml of formic acid are heated at reflux for 72 h. 50 ml of water are then added, and the mixture is stirred at room temperature for 1 h, taken up in ethyl acetate, washed twice with water, dried (magnesium sulphate) and concentrated using a rotary evaporator. The residue is chromatographed on silica gel (mobile phase ethyl acetate/hexane 1:6). This gives 0.31 g (44%) of the desired compound as a colourless oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C@:7]1([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[CH2:9][C@@H:8]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])#[N:6].C(=O)([O-])O.[Na+]>CSC.ClCCl>[C:5]([C@:7]1([C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)[CH2:9][C@@H:8]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])#[N:6]
Reactant: CCCCCC[C@H]1C[C@]1(C#N)c1ccc(OC)cc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CSC
Product: CCCCCC[C@H]1C[C@]1(C#N)c1ccc(O)cc1
Yield: 81 %

Procedure:
To a solution of 1.38 g (10.4 mmol) of aluminum chloride in 10 ml of dimethyl sulfide (Me2S) was added, with cooling with ice, a solution of 267 mg (1 mmol) of (1R,2S)-1-cyano-2-hexyl-1-(4-methoxyphenyl)cyclopropane in 10 ml of dichloromethane. This mixture was stirred with heating for 30 minutes. Saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the mixture was then subjected to extraction with 250 ml of ethyl acetate. The resulting ethyl acetate solution was washed with saturated sodium chloride aqueous solution, dried with anhydrous magnesium sulfate, and then concentrated. The residue was separated and purified by column chromatography (Kieselgel 60, hexane/ethyl acetate=5/1), thereby obtaining 197 mg (yield 81%) of (1R,2S)-1-cyano-2-hexyl-1-(4-hydroxyphenyl)cyclopropane.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:24])[CH2:8][CH:9]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[C:15]([CH:21]=O)[C:14]=2[CH3:23])[CH2:10][C:11]=1[OH:12])(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.[NH2:26]O>C(O)=O>[C:1]([C:6]1[C:7](=[O:24])[CH2:8][CH:9]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[C:15]([C:21]#[N:26])[C:14]=2[CH3:23])[CH2:10][C:11]=1[OH:12])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)c(C=O)c2C)CC1=O
Agent: Cl
Solvent: O=CO
Product: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)c(C#N)c2C)CC1=O
Temperature: 0 °C
Yield: 45.1 %

Procedure:
A solution of 2-butyryl-3-hydroxy-5-(3-formyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (1.50 g) and hydroxylamine hydrochloride (0.35 g) in 98% formic acid (7 ml) was refluxed for an hour and then allowed to cool. The mixture was diluted with ice water and the precipitate collected. Purification by column chromatography over silica gel (eluant dichloromethane) gave 2-butyryl-3-hydroxy-5-(3-cyano-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (0.67 g; 44%) as a pale yellow oil. Proton nuclear magnetic resonance spectrum (CDCl3 ; δ in ppm): 100 (3H, t); 1.68 (2H, m); 2.45 (6H, s); 2.60 (3H, s); 2.65-4.20 (7H, m); 7.42 (1H, s); 18.35 (1H, s).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([Cl:12])[CH:6]=1)(=[O:3])[CH3:2].[Br:13]Br.O>C(O)(=O)C>[C:1]([NH:4][C:5]1[C:10]([Br:13])=[CH:9][C:8]([CH3:11])=[C:7]([Cl:12])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)Nc1ccc(C)c(Cl)c1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1cc(Cl)c(C)cc1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 48 %

Procedure:
To a solution of 4-acetamido-2-chlorotoluene (89.2 g, 0.486 mol) in glacial acetic acid (480 ml) that was stirred with an overhead mechanical stirrer and under argon was dropwise added bromine (28.5 ml) during a period of 2 h while the temperature of the reaction mixture was kept below 15° C. by using an ice-bath. Stirring was continued for a further 1.5 h after the addition of bromine, under an argon atmosphere. Then the brownish reaction mixture was poured into ice-water (1.8 lt), with the aid of water (1 lt), washed with water (6 lt), and dried in vacuo over P2O5. Purification by recrystallisation from acetonitrile afforded the desired product as a white crystals (61.5 g, 48%), mp 154-155° C.; 1H-NMR (CDCl3) 2.24, 2.32 (2×s, 6H, 2×CH3), 7.40, 7.73 (2×s, 2H, 3-H, 6-H), 7.49 (br s, 1H, CONH); MS (FAB, m/z): 262, 264, 266 [(M+H)+, 80%, 100%, 25% respectively; BrCl isotopic pattern];
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:20]([O-:22])=[O:21])[CH:6]=[CH:7][C:8]=2B2OC(C)(C)C(C)(C)O2)[C:3]1=[O:23].FC(F)(F)S(O[C:30]1[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH:31]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].ClCCl.O1CCOCC1.O>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]>[CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:20]([O-:22])=[O:21])[CH:6]=[CH:7][C:8]=2[C:30]2[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH:31]=2)[C:3]1=[O:23]
Reactant: CN1Cc2c(B3OC(C)(C)C(C)(C)O3)ccc([N+](=O)[O-])c2C1=O
Reactant: CCOC(=O)C1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1CC=C(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Yield: 63.4 %

Procedure:
A mixture of 2-methyl-7-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one (1.50 g, 4.72 mmol), ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}cyclohex-3-ene-1-carboxylate (1.57 g, 5.19 mmol), potassium carbonate (1.95 g, 14.1 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.385 g, 0.472 mmol) in 1,4-dioxane (12.0 mL, 154 mmol) and H2O (3.00 mL, 166 mmol) was evacuated and refilled with Ar(g)((3×) and irradiated in the microwave at 100° C. for 30 min. The crude mixture was concentrated in vacuo to a solid and purified by CombiFlash® Rf 4× Organic Purification System [120 g RediSep® Normal-phase GOLD Silica Flash Column, dried loaded, elution gradient: 0→40% EtOAc in DCM] to afford 1.03 g (63% yield) of the desired product. 1H NMR (400 MHz, Chloroform-d) δ ppm 7.71 (d, J=8.08 Hz, 1H), 7.45 (d, 1H), 5.93-5.99 (m, 1H), 4.20 (q, J=7.07 Hz, 2H), 2.65-2.75 (m, 1H), 2.49-2.56 (m, 2H), 2.36-2.49 (m, 2H), 2.16-2.24 (m, 1H), 1.87-2.00 (m, 1H), 1.54 (br. s., 3H), 1.31 (t, J=7.20 Hz, 3H). MS (ES+): m/z 346.15/347.15 (100/15) [MH+]. HPLC: tR=1.43 min (UPLC TOF, polar—3 min).
Reaction SMILES: Cl.[CH3:2][C:3]1[N+:4]([O-])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].CS([Cl:21])(=O)=O.COCCOC>ClCCl>[Cl:21][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2oc(C)c(C)[n+]2[O-])cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1ccc(-c2nc(CCl)c(C)o2)cc1
Temperature: 15 °C

Procedure:
32.8 g (137 mmol) of 4,5-dimethyl-2-p-tolyloxazole 3-oxide hydrochloride were suspended in 165 ml of dichloromethane. 17.5 g (151 mmol) of methanesulfonyl chloride were added. The reaction was stirred at reflux up to full conversion (HPLC). Subsequently, 200 ml of ethylene glycol dimethyl ether were added, and the dichloromethane was distilled off under reduced pressure. The reaction mixture was cooled to 15° C. and 250 ml of water were added. The mixture was stirred at 15° C. for 1 hour. The precipitated product was isolated by filtration with suction, washed with water and dried at elevated temperature under reduced pressure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][O:10][C:11]2[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=2[CH3:20])=[C:4]([O:21][CH:22]([CH3:24])[CH3:23])[CH:3]=1.[CH:25]([C:28]1[C:36]2[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][C:31]=2[NH:30][N:29]=1)([CH3:27])[CH3:26].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:22]([O:21][C:4]1[C:5]([CH2:9][O:10][C:11]2[CH:16]=[C:15]([CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=2[CH3:20])=[C:6]([CH3:8])[N:7]=[C:2]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:36]=2[C:28]([CH:25]([CH3:27])[CH3:26])=[N:29][NH:30]3)[CH:3]=1)([CH3:24])[CH3:23]
Reactant: Cc1ccc(C(C)C)cc1OCc1c(OC(C)C)cc(Cl)nc1C
Reactant: CC(C)c1n[nH]c2cccc(B(O)O)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(C)C)cc1OCc1c(OC(C)C)cc(-c2cccc3[nH]nc(C(C)C)c23)nc1C
Temperature: 100 °C

Procedure:
A mixture of 6-chloro-4-isopropoxy-3-(5-isopropyl-2-methyl-phenoxymethyl)-2-methyl-pyridine (185 mg, 0.53 mmol), 3-isopropyl-1H-indazole-4-boronic acid (109 mg, 0.53 mmol), Pd(PPh3)4 (31 mg, 0.027 mmol), and Na2CO3 (169 mg, 1.6 mmol) in dioxane (8 mL) and water (2 mL) is heated for 24 hours at 100° C. The mixture is poured into water and extracted with EtOAc. The combined extract are dried (Na2SO4) and concentrated in vacuo. The residue is purified by flash chromatography (elution with MeOH/CH2Cl2 1:10) to yield 4-[4-isopropoxy-5-(5-isopropyl-2-methyl-phenoxymethyl)-6-methyl-pyridin-2-yl]-3-isopropyl-1H-indazole. 1H NMR (CDCl3) 9.95 (br s, 1H), 7.45 (d, 1H), 7.39 (t, 1H), 7.13 (d, 1H), 7.09 (d, 1H), 6.92 (m, 2H), 6.78 (d, 1H), 5.20 (s, 2H), 4.68 (m, 1H), 3.19 (m, 1H), 2.88 (m, 1H), 2.64 (s, 3H), 2.20 (s, 3H), 1.99 (d, 6H), 1.24 (d, 6H), 1.11 (d, 6H). LCMS (m/z): 472.63 (MH)+