Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:16]=[CH:17][C:10]=2[N:9]([CH3:30])[C:8]1=[O:31])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[N:16]=[CH:17][C:10]3[N:9]([CH3:30])[C:8](=[O:31])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:12](=[O:13])[C:11]=3[C:14]=2[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:19][CH:20]=1
Reactant: CC(C)CCc1c(-c2ccc(Cl)cc2)ncc2c1c(=O)n(CCCOC=O)c(=O)n2C
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCc1c(-c2ccc(Cl)cc2)ncc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
To a solution of 3-(6-(4-chlorophenyl)-5-isopentyl-1-methyl-2,4-dioxo-1,2-dihydropyrido[3,4-d]pyrimidin-3(4H)-yl)propyl formate (13 mg, 0.029 mmol) in THF (0.5 mL) and H2O (0.5 mL) was added LiOH.H2O (2.46 mg, 0.058 mmol). The reaction was stirred at RT for 30 min then diluted with EA (5 mL). The organic layer was washed with brine (1 mL), dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 6-(4-chlorophenyl)-3-(3-hydroxypropyl)-5-isopentyl-1-methylpyrido[3,4-d]pyrimidine-2,4(1H,3H)-dione (6.9 mg, 57% yield) as a white solid. 1H NMR (CDCl3) δ: 8.65 (s, 1H), 7.49-7.41 (m, 2H), 7.38-7.31 (m, 2H), 4.28 (t, J=6.1 Hz, 2H), 3.71 (s, 3H), 3.64-3.53 (m, 2H), 3.27-3.13 (m, 2H), 3.07 (t, J=6.9 Hz, 1H), 2.02-1.90 (m, 2H), 1.53 (dd, J=13.2, 6.6 Hz, 1H), 1.31 (dd, J=16.3, 6.7 Hz, 2H), 0.78 (d, J=6.6 Hz, 6H). LCMS: MH+ 416 and TR=3.048 min.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([O:16][N:17]=[C:18]([C:24](=[O:26])[CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OC(C)C)(C)C>[Si:27]([O:26][C:24](=[CH2:25])[C:18](=[N:17][O:16][CH:13]1[CH2:15][CH2:14]1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CCOC(=O)C(=NOC1CC1)C(C)=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: C=C(O[Si](C)(C)C(C)(C)C)C(=NOC1CC1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (1.32 ml) in tetrahydrofuran (10 ml) was added dropwise 1.55N n-butyl lithium in n-hexane (4.57 ml) at 0° C. The mixture was stirred at 0° C. for 30 minutes. To the mixture was added dropwise a solution of ethyl 2-cyclopropyloxyimino-3-oxobutyrate (syn isomer)(940 mg) in tetrahydrofuran (1 ml) at -60° C. The mixture was stirred at the same temperature for 30 minutes. To the mixture was added tert-butyldimethylsilyl chloride (1.42 g) at -60° C. and the mixture was gently warmed to ambient temperature. After stirred at ambient temperature for an hour, the mixture was poured into saturated aqueous solution of ammonium chloride and extracted with diethyl ether. The extract was washed successively with cold 1N hydrochloric acid, saturated aqueous solution of sodium bicarbonate, saturated aqueous solution of sodium chloride quickly, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. The residue was subjected to column chromatography on silica gel (15 g) using a mixture of n-hexane and diisopropyl ether (3:1 V/V) as an eluent to give ethyl 3-tert-butyldimethylsilyloxy- 2-cyclopropyloxyimino-3-butenoate (syn isomer)(l.09 g) as an oil.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]2[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]2)=[CH:38][CH:37]=1.Cl>C1COCC1.CCOC(C)=O.O>[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([C@H:42]2[CH2:47][CH2:46][C@H:45]([CH:2]=[O:3])[CH2:44][CH2:43]2)=[CH:38][CH:37]=1
Reactant: COc1ccc(C2CCC(=O)CC2)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of (methoxymethyl)triphenylphosphonium chloride (4632 mg, 13.51 mmol) in THF (60 mL) was cooled to 0° C. Potassium hexamethyldisilazide (22.52 ml, 11.26 mmol) was added dropwise via syringe and the solution turned dark red. After the reaction was stirred at 0° C. for 15 minutes, 4-(4-methoxyphenyl)cyclohexanone (920 mg, 4.50 mmol) was added as a solution in THF (15 mL). The reaction was warmed to r.t. and stirred at r.t. for 2 hours. Next, 5 mL of concentrated HCl was added to 10 mL of water and this solution was added to the reaction dropwise via addition funnel. The reaction was allowed to stir for 16 hours at room temperature. The reaction was then diluted with EtOAc (150 mL). The organic layer was washed with H2O (3×50 mL), saturated NaHCO3 (50 mL), and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 0 to 50% EtOAc/hexanes and isolation of the major product afforded trans-4-(4-methoxyphenyl)cyclohexanecarbaldehyde. 1H NMR (CDCl3, 500 MHz) δ 9.67 (s, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 3.79 (s, 3H), 2.45 (m, 1H), 2.27 (m, 1H), 1.98-2.14 (m, 4H), 1.36-1.53 (m, 4H).
Reaction SMILES: [N+](=[C:3](P(=O)(OC)OC)C(=O)C)=[N-].C([O-])([O-])=O.[K+].[K+].[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:30])([CH3:29])[CH:27]=O)=[CH:22][CH:21]=1>CO.CCOC(C)=O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([C:27]#[CH:3])[CH3:30])=[CH:22][CH:21]=1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: CC(C)(C=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#CC(C)(C)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
Next, a solution of dimethyl (1-diazo-2-oxopropyl)phosphonate (1.4 eq.) in MeOH (0.6 M) was treated at 0° C. with K2CO3 (2.4 eq.) and 2-(4-fluorophenyl)-2-methylpropanal (1.0 eq.). The reaction mixture was stirred for 1 hour, diluted with EtOAc, washed with water, dried (Na2SO4) and concentrated giving 1-fluoro-4-(2-methylbut-3-yn-2-yl)benzene: 1H NMR (600 MHz, CDCl3) δ 7.48-7.50 (m, 2 H), 6.97-7.00 (m, 2 H), 2.33 (s, 1 H), 1.57 (s, 6 H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[S:7][CH:6]([S:8][C:9](=[O:11])[CH3:10])[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.Cl[CH2:22][O:23][CH2:24][CH3:25].P([O-])(O)(O)=O.[K+].[Cl-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:24]([O:23][CH2:22][O:1][CH2:2][C@@H:3]1[S:7][CH:6]([S:8][C:9](=[O:11])[CH3:10])[CH2:5][CH2:4]1)[CH3:25]
Reactant: CCOCCl
Reactant: CC(=O)SC1CCC(CO)S1
Agent: O=P([O-])(O)O
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOCOC[C@H]1CCC(SC(C)=O)S1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 46.5 %

Procedure:
To a 0° C. mixture of 0.165 g of product from Example 383 in 4 ml of tetrahydrofuran and 0.222 g of diisopropylethyl amine is added 0.122 g of chloromethylethyl ether. The reaction is stirred for 45 minutes at 0° C. and then 23 hours at 20° C. The mixture is given an aqueous workup (ethyl acetate, 0.5M potassium dihydrogen phosphate, saturated sodium chloride) and the purified by chromatography to give 0.100 g of the desired product.
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl-].[Al+3].[Cl-].[Cl-].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1.Cl>ClCCl.C(OCC)(=O)C>[C:1]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][CH:15]=1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)Cl
Reactant: c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCC(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Heptanoyl chloride was added to a suspension of aluminum chloride in dichloromethane. The mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of indole in dichloromethane. The mixture was stirred at room temperature for 1 hour and poured into a mixture of hydrochloric acid and ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was crystallized from diisopropyl ether to give 3-heptanoylindole as a white powder.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@@H:28]([CH3:32])[C:29]([OH:31])=O)[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH3:32][C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[C:29]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:31]
Reactant: C1COCCN1
Reactant: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)O
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)N1CCOCC1
Yield: 55 %

Procedure:
Using the same procedure as in Example 44, (2S)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoic acid (250 mg, 0.56 mmol) was reacted with morpholine to give the title compound as a white solid (160 mg, 55%); NMR Spectrum 1.58 (d, 3H), 3.70-3.40 (m, 8H), 5.79 (s, 2H), 5.88 (q, 1H), 7.29 (d, 1H), 7.35 (s, 1H), 7.51 (s, 1H), 7.75 (m, 2H), 7.84 (m, 1H), 8.10 (s, 1H), 8.51 (s, 2H), 9.04 (s, 1H), 11.12 (br s, 1H); Mass spectrum MH+ 516.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.OC(C(F)(F)F)=O.[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([CH2:28][C:29]#[N:30])[CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([CH2:28][C:29]#[N:30])[CH2:24][CH2:23]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: N#CC[C@H]1CC[C@H](N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: N#CC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.88 g, 4.1 mmol) in isopropyl alcohol (14 mL), (trans-4-aminocyclohexyl)acetonitrile TFA salt (0.68 g, 4.9 mmol) and N,N-diisopropylethylamine (3.0 mL, 17 mmol) were added. The reaction was stirred at 90° C. for 2 h. The mixture was concentrated and purified on silica gel (eluting with 0 to 60% EtOAc in dichloromethane) to give the desired product (1 g, 77%). LCMS calculated for C15H17N4O2S (M+H)+: m/z=317.1. Found: 317.0.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[CH2:17][C:16]4[C:12]([CH:13]=[CH:14][N:15]=4)=[CH:11][C:10]=3[O:9][CH2:8]2)[CH2:4][CH2:3]1.[CH3:19][C:20]1[CH:25]=[C:24]([C:26]2[O:27][C:28]([CH3:31])=[N:29][N:30]=2)[CH:23]=[CH:22][C:21]=1[C:32]1[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][CH:33]=1.C(N1C2C(=CC(O)=C(Br)C=2)CC1)(=O)C>>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH:13]=[CH:14][N:15]([C:38]([C:35]5[CH:34]=[CH:33][C:32]([C:21]6[CH:22]=[CH:23][C:24]([C:26]7[O:27][C:28]([CH3:31])=[N:29][N:30]=7)=[CH:25][C:20]=6[CH3:19])=[CH:37][CH:36]=5)=[O:39])[C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1
Reactant: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Reactant: CN1CCC2(CC1)COC1=C2CC2=NC=CC2=C1
Agent: CC(=O)N1CCc2cc(O)c(Br)cc21
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)n4ccc5cc6c(cc54)C4(CCN(C)CC4)CO6)cc3)c(C)c2)o1

Procedure:
The title compound was prepared from 2,3-dihydro-1'-methylspiro[furo[2,3-f]indole-3,4'-piperidine] (D7) and 2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carboxylic acid (D11) using a similar procedure to Example 8 (22%). This was converted to its oxalate salt, which crystallised from acetone/methanol as a white solid mp 234-237° C.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.O>C1C=CC=CC=1.N1C=CC=CC=1>[C:1]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)Cl
Reactant: C1CCNC1
Solvent: c1ccncc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCC(=O)N1CCCC1
Yield: 79.9 %

Procedure:
Hexanoyl chloride (13.46 g, 0.1M) was added gradually to a cooled, stirred solution of pyrrolidine (7,25 g, 0.1M) in 200 ml of benzene and dry pyridine (7.91 g, 0.1M). Two hours after the addition water was added. The organic layer was washed successively with 5% aqueous hydrochloric acid, saturated sodium bicarbonate solution, and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. Distillation of the residue gave 13.52 g (80%) of a colorless oil, b.p. 98-100/7 mm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44]O)=[CH:26][CH:25]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N-:58]=[N+:59]=[N-:60].[Na+].C(=O)([O-])O.[Na+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C.O>[C:1]([O:5][C:6](=[O:46])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][N:58]=[N+:59]=[N-:60])=[CH:26][CH:25]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1ccc(OCCOCCOCCOCCOCCO)cc1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1ccc(OCCOCCOCCOCCOCCN=[N+]=[N-])cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of Compound 26 (254 mg, 0.451 mmol) in pyridine (1.5 ml), 4-dimethylaminopyridine (11 mg, 0.09 mmol) was added; after cooling with ice, p-toluenesulfonyl chloride (130 mg, 0.677 mmol) was added, and this was followed by stirring for 2 hours while heating to 30° C.-40° C. Ice was added thereto to stop the reaction, after which ethyl acetate and water were added. Extraction from ethyl acetate was conducted, and the combined organic phases were washed with a saturated aqueous solution of potassium hydrogen sulfate, a saturated aqueous solution of sodium hydrogen carbonate and saturated brine, and dried with sodium sulfate. Filtration and concentration under reduced pressure were conducted to yield a crude product. The crude product obtained was dissolved in DMF (1 ml), and sodium azide (264 mg, 4.1 mmol) was added thereto. The solution was heated to about 60° C., and this was followed by stirring for 90 minutes. The solution was allowed to cool to room temperature, after which it was diluted with ethyl acetate. After a saturated aqueous solution of sodium hydrogen carbonate was further added, extraction from ethyl acetate was conducted. The combined organic phases were washed with saturated brine, thereafter dried with sodium sulfate. Filtration and concentration under reduced pressure were conducted, after which the concentrate was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent; ethyl acetate solution containing 10% methanol) to yield Compound 27 (colorless oil 196 mg, 73%, 2 steps).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)O1.[NH2:32][C:33]1[C:34]([C:40]([O:42][CH3:43])=[O:41])=[N:35][C:36](Br)=[CH:37][N:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC#N>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CCOCC.O>[NH2:32][C:33]1[C:34]([C:40]([O:42][CH3:43])=[O:41])=[N:35][C:36]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:37][N:38]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Reactant: CC(C)(C)OC(=O)N1CCCC(S(=O)(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: COC(=O)c1nc(-c2ccc(S(=O)(=O)C3CCCN(C(=O)OC(C)(C)C)C3)cc2)cnc1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonylpiperidine-1-carboxylate (2 g, 4.431 mmol), methyl 3-amino-6-bromo-pyrazine-2-carboxylate (934.6 mg, 4.028 mmol) and K3PO4 (1.710 g, 8.056 mmol) with MeCN (14.09 mL)/water (3.133 mL). Degassed with vacuum/nitrogen over 5 cycles, treated with Pd[P(tBu)3]2 (114.9 mg, 0.2248 mmol), degassed further 5 cycles and stirred under nitrogen for 2 hours at 60° C. The reaction mixture was cooled to ambient temperature and poured onto icewater/ethylacetate. The organic layer was washed with aq NaHCO3, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with 50-70% EtAc/petrol. The relevant fractions were concentrated in vacuo to a solid. Trituration with ether/petroleumether gave methyl 3-amino-6-[4-[(1-tert-butoxycarbonyl-3-piperidyl)sulfonyl]phenyl]pyrazine-2-carboxylate as a colourless solid (1.728 g, 3.626 mmol, 90.02%). H NMR (400.0 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.3 (d, 2H), 8.0 (d, 2H), 7.7 (br s, 2H), 4.0-4.1 (m, 1H), 3.9 (s, 3H), 3.7-3.8 (m, 1H), 3.3-3.4 (m, 1H), 2.77-2.95 (m, 2H), 1.95-2.05 (m, 1H), 1.7-1.75 (m, 1H), 1.6-1.65 (m, 1H) and 1.20-1.40 (m, 10H) ppm; LC/MS m/z 421.1 [M−56+1]+.
Reaction SMILES: C([N:4](C(C)C)CC)(C)C.[CH2:10]([O:17][C:18](=[O:31])[CH:19]([C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)[CH2:20][C:21](O)=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH2:4][C:21](=[O:22])[CH2:20][CH:19]([C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)[C:18]([O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:31]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)CC(C(=O)OCc1ccccc1)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Product: NC(=O)CC(C(=O)OCc1ccccc1)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 84.7 %

Procedure:
Di-iso-propylethylamine (2.08 g, 2.80 mL, 16.0 mmol) was added in one portion to a stirred suspension of 4-(benzyloxy)-3-(4-bromophenyl)-4-oxobutanoic acid (1.45 g, 4.01 mmol), ammonium chloride (0.214 g, 4.01 mmol) and N-[(Dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (1.68 g, 4.41 mmol) in dimethylformamide (20 mL) at room temperature under nitrogen. After stirring for 2 h the volatiles were evaporated and the residue partitioned between dichloromethane (50 mL) and aqueous hydrochloric acid solution (1.0 M; 50 mL). The phases were separated and the aqueous layer washed with dichloromethane (2×50 mL). The organic phases were combined, dried (magnesium sulfate) and evaporated to dryness. The residue was chromatographed on silica gel (10% methanol: dichloromethane) to give the title compound as a white solid (1.23 g, 85%). LC/MS: 3.14 min; z/e 362 and 364, calcd (M+1) 362 and 364. 1H NMR (400 MHz: DMSO-d6): 7.55 (2H), 7.30 (8H), 6.85 (1H), 5.05 (2H), 4.05 (1H), 2.90 (1H), 2.50 (1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[N:7]=1.Br[C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([Cl:34])[CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].ClCCl>COCCOC.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:34][C:27]1[CH:26]=[C:25]([C:2]2[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[N:14]=[CH:13][CH:12]=3)[N:7]=2)[CH:33]=[CH:32][C:28]=1[C:29]([OH:31])=[O:30]
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: COc1ccc2c(OCCn3nc(Cl)ccc3=O)ccnc2c1
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ccc2c(OCCn3nc(-c4ccc(C(=O)O)c(Cl)c4)ccc3=O)ccnc2c1

Procedure:
A suspension of 6-chloro-2-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridazin-3(2H)-one (2290 mg, 6903 μmol), 4-bromo-2-chlorobenzoic acid (2766 mg, 13805 μmol), Na2CO3 (2 M, 13805 μl, 27611 μmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium(II) complex with dichloromethane (505 mg, 690 μmol) in DME (20 mL) was sparged with argon for 10 minutes then heated to reflux for 7 hours. The reaction was then partitioned between NaOH (1 M, 75 mL) and EtOAc (25 mL). The organic layer was discarded and the aqueous layer acidified to pH 4 with HCl (2M). The resulting orange precipitate was then collected by filtration and washed with water (50 mL). MS (ESI pos. ion) m/z: 452 (MH+); calc'd for C23H18ClN3O5: 451. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.86 (s, 3 H) 4.68 (s, 4 H) 6.94 (d, J=4.52 Hz, 1 H) 7.02 (d, J=9.03 Hz, 1 H) 7.09 (d, J=9.54 Hz, 1 H) 7.27 (s, 1 H) 7.60 (d, J=7.03 Hz, 1 H) 7.75 (d, J=7.03 Hz, 1 H) 7.81-7.98 (m, 2 H) 8.09 (d, J=9.54 Hz, 1 H) 8.62 (d, J=4.02 Hz, 1 H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([CH3:15])[CH:13]=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:20][CH:21]=[CH2:22])[CH:17]([CH3:19])[CH3:18]>C1(C=CC(O)=CC=1)O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH2:22][CH:21]([O:20][CH2:16][CH:17]([CH3:19])[CH3:18])[O:14][CH2:13][C:12]=2[CH3:15])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=COCC(C)C
Reactant: CC(C=O)=Cc1ccc(C(C)(C)C)cc1
Agent: Oc1ccc(O)cc1
Product: CC1=C(c2ccc(C(C)(C)C)cc2)CC(OCC(C)C)OC1
Temperature: 220 °C
Yield: 30.7 %

Procedure:
3,000 g of 3-(4-tert.-butylphenyl)-2-methylprop-2-enal III and 2,000 g of vinyl isobutyl ether IV are introduced into a 10 l stirred autoclave, and 5 g of hydroquinone are added to the reaction mixture for stabilization. The autoclave is closed and then flushed with nitrogen, after which it is heated to 220° C., maintained under these conditions for 18 hours and then let down and opened. The reaction mixture (4,855 g) consists of about 39.6% of the desired product V. When the reaction mixture is worked up by fractionation in a laboratory column containing 10 sieve trays, a total of 1,379 g of the compound V of boiling point 135°-146° C. under 2 mbar are obtained from the 1,923 g shown to be present in the crude mixture by gas chromatographic analysis. This corresponds to a yield of 23%, based on the starting material III employed. 1,745 g of III, which contains some product V, are recovered. The last-mentioned amounts are reused for the reaction with vinyl isobutyl ether.