Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[N:7]([CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([NH2:38])[CH:36]=2)[NH:31][C:30]=1[C:39]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([CH3:46])[CH:40]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([S:19]([CH3:22])(=[O:21])=[O:20])[C:13]=1[S:23]([CH3:26])(=[O:25])=[O:24])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:55](Cl)([O:57]C(=O)OC(Cl)(Cl)Cl)Cl>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:47])[N:7]([CH2:27][CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([N:38]=[C:55]=[O:57])[CH:36]=2)[NH:31][C:30]=1[C:39]1[CH:40]=[C:41]([CH3:46])[CH:42]=[C:43]([CH3:45])[CH:44]=1)[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([S:19]([CH3:22])(=[O:20])=[O:21])[C:13]=1[S:23]([CH3:26])(=[O:25])=[O:24])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCN(CCCCc2ccc(N)c(S(C)(=O)=O)c2S(C)(=O)=O)C(=O)OC(C)(C)C)c1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2[nH]c3ccc(N=C=O)cc3c2CCN(CCCCc2ccc(N)c(S(C)(=O)=O)c2S(C)(=O)=O)C(=O)OC(C)(C)C)c1
Reaction time: 0.33 h
Yield: 243.8 %

Procedure:
To a solution of {2-[5-amino-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl}-[4-(4-amino(dimethanesulfonyl)phenyl)butyl]carbamic acid tert-butyl ester (120 mg in 8 mL dry methylene chloride) at 0° C. was added 0.040 mL pyridine followed by 18.2 mg triphosgene and the mixture stirred at low temperature. After 20 minutes, 0.025 mL triethylamine was added and after another 10 minutes the mixture was applied to a silica gel column for purification by flash chromatography (hexane:ethyl acetate, 2:3) to give the title compound (106 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[C:7](/[CH:13]=[N:14]/[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH3:25])[C:3]=1[C:4]([OH:6])=O.[CH3:26][Li].Cl>C1COCC1>[Cl:1][C:2]1[C:3]2[C:4](=[O:6])[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH3:25])[CH:13]([CH3:26])[C:7]=2[C:8]([F:12])=[C:9]([Cl:11])[N:10]=1
Reactant: [Li]C
Reactant: COc1ccc(C/N=C/c2c(F)c(Cl)nc(Cl)c2C(=O)O)c(OC)c1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)c3c(Cl)nc(Cl)c(F)c3C2C)c(OC)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 19.5 %

Procedure:
To a mixture of (E)-2,6-dichloro-4-(((2,4-dimethoxybenzyl)imino)methyl)-5-fluoronicotinic acid (72.0 g, 186.5 mmol) in THF (700 mL) was added methyllithium (933.0 mL, 933.0 mmol) dropwise at −78° C. After the addition was complete, the solution was stirred for an additional 2 h. The reaction mixture was then acidified with 1N HCl to pH 6, heated to 50° C. for 7 h, and subsequently extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous Na2SO4. The concentrated crude was purified by silica gel chromatography to give the title compound as a white solid (14 g, 15%). 1H NMR (CDCl3, 400 MHz) δ ppm 1.58 (d, J=6.8 Hz, 3H), 3.79 (s, 3H), 3.84 (s, 3H), 4.35 (d, J=14.4 Hz, 1H), 4.52 (q, J=6.8 Hz, 1H), 5.07 (d, J=14.4 Hz, 1H), 6.43-6.45 (m, 2H), 7.28 (d, J=9.2 Hz, 1H). [M+H] calc'd for C17H15Cl2FN2O3, 385. found, 385.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[CH:26](OC)(OC)OC.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O.[BH4-].[Na+]>CO>[CH2:18]([N:17]([CH2:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][CH2:38][C:34]3[N:35]([CH3:26])[CH:36]=[CH:37][N:33]=3)=[CH:25][CH:24]=2)=[CH:11][CH:12]=1)[CH2:21][CH2:22][CH3:23])[CH2:19][CH3:20]
Reactant: O=Cc1ncc[nH]1
Reactant: COC(OC)OC
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CNCc3nccn3C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (389 mg) obtained in Example 15-4 was dissolved in anhydrous methanol (10 ml) and then added with trimethyl orthoformate (188 μl) and 2-imidazole carboxaldehyde (139 mg). The whole was stirred overnight at room temperature under a nitrogen atmosphere. Then, sodium borohydride (43.4 mg) was added thereto in an ice bath and the whole was stirred at room temperature for 2.5 hours. After completion of the reaction, distilled water was added thereto and the whole was stirred for a while. The solution was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (346 mg) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[Br:23][C:24]1[N:28]2[N:29]=[C:30]([Cl:34])[CH:31]=[C:32](Br)[C:27]2=[N:26][CH:25]=1>CN(C=O)C.C(OCC)(=O)C>[Br:23][C:24]1[N:28]2[N:29]=[C:30]([Cl:34])[CH:31]=[C:32]([N:8]([CH2:7][C:6]3[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:27]2=[N:26][CH:25]=1
Reactant: COc1ccc(CNc2ccccc2)cc1
Reactant: Clc1cc(Br)c2ncc(Br)n2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(Br)cnc23)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
N-(4-Methoxybenzyl)aniline (215 mg, 1 mmol) was dissolved in dry DMF (4 mL), placed under a nitrogen atmosphere, and cooled to 0° C. in an ice bath. Potassium t-butoxide (1 mL, 1 mmol, 1M THF solution) was added and the mixture was allowed to stir for 10 min at 0° C. and room temperature for 30 min. The resulting mixture was cool to 0° C. Solid 3,8-dibromo-6-chloroimidazo[1,2-b]pyridazine (310 mg, 1 mmol) from Example XXIV, step 1a was added. The mixture was allowed to stir for 30 min at 0° C. and overnight at room temperature. The mixture was diluted with ethyl acetate (100 mL), washed sequentially with 10% LiCl, water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the resulting material was purified by silica gel chromatography (ethyl acetate/heptane, 25 min gradient: 5-50% ethyl acetate) to provide 0.27 g of 3-bromo-6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][N:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[CH:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([NH2:1])[CH:13]=2)[CH:8]=[CH:9][N:10]=1
Reactant: O=[N+]([O-])c1ccc2ccncc2c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2ccncc2c1
Yield: 73.5 %

Procedure:
7-Nitroisoquinoline (1.62 g, 9.25 mmol) in ethanol (150 ml) was hydrogenated on a Paar Hydrogenator Apparatus over 5% palladium on carbon (0.2 g) as catalyst for 3 h at 50 psi. The reaction mixture was filtered and the solvent removed at reduced pressure. Recrystallization of the solid from ethanol (3 ml) gave isoquinolin-7-amine (0.98 g) as a tan solid. MS 145 (M+H), NMR (CDCl3) 9.02 (s, 1H), 8.29 (d, 1H), 7.63 (d, 1H), 7.47 (d, 1H),7.13 (dd, H), 7.03 (d, 1H), 4.00 (broad, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[NH:23]1[C:27]([S:28](Cl)(=[O:30])=[O:29])=[N:26][CH:25]=[N:24]1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:10](=[O:13])[N:11]([S:28]([C:27]3[NH:23][N:24]=[CH:25][N:26]=3)(=[O:30])=[O:29])[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1
Reactant: O=S(=O)(Cl)c1ncn[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1n(S(=O)(=O)c2ncn[nH]2)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
300 mg (1.27 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one [preparation according to WO 2007/134862 Example 36A] were dissolved in 10 ml of THF, and 143 mg (1.27 mmol) of potassium tert-butoxide were added at −78° C. Over a period of 30 min, the reaction mixture was warmed to RT, and the mixture was stirred at this temperature for a further 20 min. The mixture was then once more cooled to −78° C., and 213 mg (1.27 mmol) of 1H-1,2,4-triazole-5-sulfonyl chloride, dissolved in 5 ml of THF, were added. Over a period of 30 min, the reaction mixture was warmed to RT, and the mixture was stirred at this temperature for a further 20 h. For work-up, 10 ml of water were added. The mixture was extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 136 mg (29% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[CH2:22]([N:9]1[C:10]2[C@@:11]3([CH3:21])[C:18]([CH3:20])([CH3:19])[C@H:14]([CH2:13][CH2:12]3)[C:15]=2[C:16](=[O:17])[N:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3F)c(=O)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccccc2F)n1Cc1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 30.1 %

Procedure:
A mixture of a (4S,7R)-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 12; 150 mg, 0.52 mmol) and benzyl bromide (130 μL, 1.09 mmol) in N,N-dimethylformamide (2 mL) in a microwave reaction tube was heated to 100° C. and stirred for 18 h. The reaction mixture was allowed to cool, diluted with saturated sodium bicarbonate, and extracted twice with ethyl acetate. The organic extracts were combined, washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO CombiFlash® Sg100c chromatography system with an Isco 12 g column, eluting with 25-100% ethyl acetate/hexanes to give (4S,7R)-1-benzyl-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (59 mg, 30%) as an light brown solid. ES(+)-MS (M+H) 377.
Reaction SMILES: [F:1][C:2]([F:9])([CH3:8])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.Cl.[CH3:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)[CH:20]=1.C(N(C(C)C)C(C)C)C>ClCCl.CN(C=O)C>[F:9][C:2]([F:1])([CH3:8])/[CH:3]=[CH:4]/[C:5]([N:28]1[CH2:29][CH2:30][CH2:31][C@@H:26]([NH:25][C:21]2[CH:20]=[C:19]([CH3:18])[CH:24]=[CH:23][N:22]=2)[CH2:27]1)=[O:7]
Reactant: CC(F)(F)/C=C/C(=O)O
Reactant: Cc1ccnc(N[C@@H]2CCCNC2)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccnc(N[C@@H]2CCCN(C(=O)/C=C/C(C)(F)F)C2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.3 %

Procedure:
(E)-4,4-Difluoropent-2-enoic acid (22 mg, 0.16 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (14 μl, 0.16 mol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 4-methyl-N-[(3R)-3-piperidyl]pyridin-2-amine dihydrochloride (23 mg, 0.087 mmol) in DCM (2 ml). Ethyl-N,N-diisopropylamine (DIPEA, 70 μl, 0.4 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters X-bridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 13 mg of a solid (0.042 mmol, 48%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:7])[OH:6].C(=O)(O)[O-].[Na+].[C:20]([O:25][CH:26]([O:28][C:29](OC1CC(=O)NC1=O)=[O:30])[CH3:27])(=[O:24])[CH:21]([CH3:23])[CH3:22]>O.C(#N)C.C(OCC)C>[C:20]([O:25][CH:26]([O:28][C:29]([NH:1][CH2:2][CH2:3][CH2:4][P:5]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:6])[OH:7])=[O:30])[CH3:27])(=[O:24])[CH:21]([CH3:23])[CH3:22]
Reactant: NCCCP(=O)(O)CC1CCCCC1
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: CC(OC(=O)NCCCP(=O)(O)CC1CCCCC1)OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-aminopropyl(cyclohexylmethyl)phosphinic acid (10 mmol) and sodium bicarbonate (20 mmol) in water (40 mL) is added a solution of compound (17) (10 mmol) in acetonitrile (20 mL) over 1 min. The reaction is stirred at ambient temperature for 16 h. The reaction mixture is diluted with diethyl ether (100 mL) and washed with 0.1 M aqueous potassium bisulfate (3×100 mL). The organic phase is separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound (91) as a white solid.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]2[C:26]3[C:21](=[C:22]([C:27]([NH2:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[NH:7]([C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH:16][C:17]2[C:26]3[C:21](=[C:22]([C:27]([NH2:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:30][CH:31]=1)=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC(=O)c1cccc2c(NCc3ccc(N)cc3)ncnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1cccc2c(NCc3ccc(NC(=O)Nc4ccccc4)cc3)ncnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
Phenyl isocyanate (240 μL, 0.5 M in anhydrous DCM, 0.11 mmol, 1.1 equiv.) was added to a solution of 4-[(4-aminobenzyl)amino]quinazoline-8-carboxamide (32 mg, 0.1 mmol, 1.0 equiv.) and triethylamine (40 μL, 0.3 mmol, 3.0 equiv.) in anhydrous DCM (2 mL). The resulting mixture was stirred at rt overnight. The title compound was obtained by pre-HPLC in 27% yield. Mass: M+H+: 413.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][C@H:5]([C:18]([O:20]C)=[O:19])[CH2:4][CH2:3]1.O[Li].O.O.CO>C1COCC1>[CH3:1][C@@H:2]1[N:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][C@H:5]([C:18]([OH:20])=[O:19])[CH2:4][CH2:3]1
Reactant: COC(=O)[C@@H]1CC[C@H](C)N(C(=O)OCc2ccccc2)C1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CC[C@@H](C(=O)O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 101.8 %

Procedure:
To a stirred solution of 3-methyl 1-(phenylmethyl) (3R,6S)-6-methyl-1,3-piperidinedicarboxylate (58.9 g, 202 mmol) in THF (350 mL) at room temperature was added LiOH.H2O (10.18 g, 243 mmol, 1.2 equiv), followed by water (175 mL) and CH3OH (85 mL). The mixture was stirred at ambient temperature for 20 hours. LCMS showed complete hydrolysis. The mixture was concentrated in vacuo. The residue was taken up in EtOAc (500 mL), acidified with 120 mL of cold 2N HCl, and diluted with 200 mL of brine. The phases were separated. The aqueous phase was extracted with EtOAc (2×300 mL). The combined organic was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (57 g) as an oil. LC-MS (ES) m/z=278 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[CH2:7]([O:14][C:15]1[C:16](Br)=[N:17][CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(C)([O-])C.[Na+]>CN(C=O)C>[CH2:7]([O:14][C:15]1[C:16]([O:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])=[N:17][CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Brc1ncccc1OCc1ccccc1
Reactant: CN(C)CCO
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ncccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a mixture of N,N-dimethylaminoethanol (4.16 g, 46.7 mmol) and (3-benzyloxy)-2-bromopyridine (from Step 1; 8.22 g, 31.1 mmol) in dry DMF (50 mL) was sodium tert-butoxide (5.98 g, 62.2 mmol) added in one portion. The reaction mixture was stirred at 80° C. for 1.5 h, the solvent was removed under reduced pressure and the oily residue was taken up between CHCl3/water. The aqueous phase was extracted twice with CHCl3 and the combined organic layers were washed once with brine, dried (MgSO4), and concentrated under reduced pressure. This gave 8.4 g (100%) of the title compound as a light brown oil. Purity 95% (HPLC). HRMS m/z calcd for C16H20N2O2 (M)+ 272.1525. found 272.1537.
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]([CH2:12][C:13]1([N:34]2[CH:38]=[C:37]([C:39]3[C:40]4[CH:47]=[CH:46][N:45](COCC[Si](C)(C)C)[C:41]=4[N:42]=[CH:43][N:44]=3)[CH:36]=[N:35]2)[CH2:16][N:15]([C:17]2[C:31]([F:32])=[CH:30][C:20]([C:21]([NH:23][C@@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])=[O:22])=[C:19]([F:33])[CH:18]=2)[CH2:14]1)#[N:11].O.[OH-].[NH4+]>C(#N)C>[C:10]([CH2:12][C:13]1([N:34]2[CH:38]=[C:37]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH:36]=[N:35]2)[CH2:16][N:15]([C:17]2[C:31]([F:32])=[CH:30][C:20]([C:21]([NH:23][C@@H:24]([CH3:29])[C:25]([F:27])([F:28])[F:26])=[O:22])=[C:19]([F:33])[CH:18]=2)[CH2:14]1)#[N:11]
Reactant: C[C@H](NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1F)C(F)(F)F
Agent: FB(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: C[C@H](NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Boron trifluoride etherate (0.051 mL, 0.40 mmol) was added to a solution of 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide in acetonitrile (1.0 mL) at 0° C. under N2. The reaction mixture was stirred at room temperature for 3 h. (LCMS (M+H)+: m/z=561.3). Then the mixture was cooled to 0° C., water (0.13 mL) was added. After 30 min, 5.0 M ammonium hydroxide in water (0.2 mL, 1 mmol) was added slowly at 0° C. over 5 min. The reaction mixture was stirred at room temperature overnight, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=531.0. 1H NMR (400 MHz, DMSO-d6): δ 12.62 (br, 1H), 9.07 (s, 1H), 8.84 (s, 1H), 8.55 (s, 1H), 8.51 (dd, J=8.8, 1.2 Hz, 1H), 7.78 (br, 1H), 7.35 (dd, J=12.6, 6.5 Hz, 1H), 7.23 (d, J=1.9 Hz, 1H), 6.65 (dd, J=11.9, 7.3 Hz, 1H), 4.76 (m, 1H), 4.70 (d, J=9.3 Hz, 2H), 4.44 (d, J=9.2 Hz, 2H), 3.76 (s, 2H), 1.30 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8](=[O:10])[CH3:9])[C:5]([OH:7])=[O:6].[BrH:11].BrBr>C(Cl)Cl.C(O)(=O)C>[Br:11][CH2:9][C:8](=[O:10])[C:4](=[N:3][O:2][CH3:1])[C:5]([OH:7])=[O:6]
Reactant: Br
Reactant: CON=C(C(C)=O)C(=O)O
Agent: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: CON=C(C(=O)O)C(=O)CBr
Reaction time: 0.5 h

Procedure:
In 3 liters of methylene chloride was dissolved 460 g of the 2-methoxyimino-3-oxobutyric acid obtained by the procedure of Example 1. To the solution was added 46 ml of a 25% hydrogen bromide solution in acetic acid. To the resultant solution was added dropwise over 2 hours at 7° to 15° C. a solution of 372 g of bromine in 372 ml of methylene chloride. Nitrogen was then blown into the mixture violently at 7° to 8° C. for 30 minutes so as to eliminate the byproduct hydrogen bromide. Silica gel (Kieselgel 60, 70 to 230 mesh, manufactured by Merck; 80 g) and activated carbon (Shirasagi of larger grain A grade, manufactured by Takeda Chemical Industries; 30 g) were added to the supernatant obtained. The mixture was stirred at 10° to 15° C. for 30 minutes and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, the oily residue was dissolved in 685 ml of xylene, and the solution was allowed to stand at 5° C. for 15 hours. The resultant crystalline precipitate was collected by filtration, washed with 100 ml of a 1:1 (v/v) mixture of xylene and n-hexane and then with 200 ml of n-hexane, and dried under reduced pressure to give 434 g of 4-bromo-2-methoxyimino-3-oxobutyric acid. The filtrate (mother liquor) was concentrated under reduced pressure and the oily residue was crystallized by addition of 238 ml of a 100:15 (v/v) mixture of xylene and n-hexane to give 82.3 g of 4-bromo-2-methoxyimino-3-oxobutyric acid as a second crop.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[OH:13].Cl[CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][Cl:23].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:13][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:11][CH3:12])[C:3]=1[O:2][CH3:1])[CH:7]=[O:8]
Reactant: COc1cc(C=O)cc(O)c1OC
Reactant: ClCCOCCOCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(OCCOCCOCCCl)c1OC
Temperature: 55 °C
Yield: 80 %

Procedure:
A solution of 500 mg (2.75 mmol) 4,5-dimethoxy-3-hydroxybenzaldehyde 1 and 860 μl (1.03 g, 5.50 mmol) 1,2-bis(2-chloroethoxy)ethane in 20 ml DMF was treated with 2.24 g (6.88 mmol) caesium carbonate and heated to 55° C. for 20 hrs. After cooling the mixture was poured into 100 ml of ice water and extracted with chloroform. The organic extracts were washed twice with 50 ml of water and with brine, dried over sodium sulfate and evaporated. The resulting yellow oil was flash-chromatographed (petroleum ether/ethyl acetate 2/1) to yield 3-{2-[2-(2-chloroethoxy)ethoxy]ethoxy}-4,5-dimethoxybenzaldehyde (730 mg, 2.20 mmol, 80%), which was directly used for the next synthesis step.
Reaction SMILES: [CH2:1]([CH2:11]/[C:12](/[CH3:21])=[CH:13]/[CH2:14][CH2:15]/[C:16](/[CH3:20])=[CH:17]/[CH2:18]Br)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[CH2:22]([NH2:32])[C:23]1[CH:31]=[CH:30][C:29]2[O:28][CH2:27][O:26][C:25]=2[CH:24]=1.O>C1COCC1>[CH2:1]([CH2:11]/[C:12](/[CH3:21])=[CH:13]/[CH2:14][CH2:15]/[C:16](/[CH3:20])=[CH:17]/[CH2:18][NH:32][CH2:22][C:23]1[CH:31]=[CH:30][C:29]2[O:28][CH2:27][O:26][C:25]=2[CH:24]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4]
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CBr
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CNCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 200 ml of THF was dissolved 20.5 g of geranylgeranyl bromide, 14.4 ml of piperonylamine was added and stirred at room temperature for one hour. To the reaction mixture was added water and extracted with ethyl acetate. The extract was washed with water and then brine, dried over magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (using as a developing solvent hexane-ethyl acetate (4:1)→ethyl acetate) to give 17.6 g of N-geranylgeranylpiperonylamine as a yellow liquid.