Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(F)cc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)cc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 101.4 %

Procedure:
Trans-methyl 2-(2,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.18 g, 3.08 mmol) (from example 134, step 1) was dissolved in MeOH (15 mL) and cooled to −40° C. Sodium hydroxide (0.123 g, 3.08 mmol) dissolved in water (1.7 mL) was added over 1 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.2 mL, 3.26 mmol) was added over 1 min and stirring continued at −40° C. for 2 h. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. Crude trans-methyl 2-(2,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.1 g, 101%) was isolated as a pale orange foam. 1H NMR (500 MHz, cdcl3) δ 1.43-2.15 (m, 4H), 2.66-3.23 (m, 4H), 3.39-3.79 (m, 3H), 4.04-4.41 (m, 1H), 4.45-4.78 (m, 1H), 5.67 (s, 1H), 6.73-6.90 (m, 2H), 7.03-7.37 (m, 1H). MS m/z 353 (M+H)+
Reaction SMILES: [C:1]1([OH:7])C=CC=CC=1.[CH2:8]=[O:9].C(S)C.C(SC[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])C>C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:1]=[O:7].[OH:9][CH2:8][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]
Reactant: Oc1ccccc1
Reactant: CCSCc1ccccc1O
Agent: C=O
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: CCS
Product: OCc1ccccc1O
Reaction time: 12 h

Procedure:
A mixture of 450 g of phenol, 0.8 g of zinc acetate and 24 g of paraformaldehyde was warmed for 6 hours to 70° C. in a flask equipped with a stirrer and a reflux condenser. 49.6 g of ethylmercaptan were then added to the reaction mixture and the reaction temperature in the flask was raised progressively so that there was always a slight reflux. After about 12 hours, when a final temperature of 120° C. had been reached, the reaction was stopped by cooling and the reaction mixture was worked up by distillation. The phenol could be re-used in a subsequent reaction. The yield of isolated 2-ethylthiomethyl-phenol was 70% of theory, relative to paraformaldehyde, and about 95%, relative to the 2-hydroxymethyl-phenol formed as an intermediate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.II.[Mg].Cl[P:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([P:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Brc1ccccc1-c1ccccc1
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A solution of 2-bromobiphenyl (5.38 g, 23.1 mmol) and a few iodine crystals in 40 mL of THF with magnesium turnings (617 mg, 25.4 mmol) was heated to a reflux for 2 h. Heat was temporarily removed for the addition of cuprous chloride (2.40 g, 24.2 mmol) followed by chlorodi-tert-butylphosphine. Heating was resumed for 8 h. The reaction mixture was then removed from heat and allowed to cool to rt. The reaction mixture was poured onto 200 mL of 1:1 hexane/ether. The suspension was filtered and the filtercake was washed with 60 mL of hexane. The solid was partitioned between 150 mL of 1:1 hexane/ethyl acetate and 60 mL of concentrated ammonium hydroxide with 100 mL of water. The organic layer was washed with 100 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The white solid was recrystallized from 30 mL of MeOH to give white crystals of 2-(di-tert-butylphosphino)biphenyl (4.01 g, 58%). A second crop (464 mg, 67%) was obtained by recrystallization from 50 mL of MeOH and 25 mL of water.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.Cl[CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]>C1COCC1>[CH3:28][O:29][CH2:30][CH2:31][O:32][CH2:33][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: COCCOCCl
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(COCCOC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (2.0 g, 7.8 mmol) in THF (70 mL) at −78° C. was added dropwise LDA over 8 minutes, maintaining the temperature below −75° C. The mixture was stirred at −78° C. for 1 hour. 1-Chloromethoxy-2-methoxy-ethane (0.97 g. 7.8 mmol) was added dropwise while maintaining the temperature below −75° C. The mixture was stirred at −78° C. for 3 hours, and then allowed to warm slowly to room temperature overnight. The mixture was quenched with sat. aq. NH4Cl and extracted 3 times with EtOAc. The organics were combined, washed with brine, dried over MgSO4, and concentrated. Silica gel chromatography (10-20% ethyl acetate:hexanes) gave the title compound in 67% yield. MS (ES+) [M+H]+=346.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([NH:9][CH2:10][CH2:11][N:12]1[C:16]3[C:17]([C:21]([O-])=[O:22])=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[CH:13]1)[CH2:2]2.[Li+].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C)C=O>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([N:9]1[C:21](=[O:22])[C:17]3[CH:18]=[CH:19][CH:20]=[C:15]4[N:14]=[CH:13][N:12]([C:16]=34)[CH2:11][CH2:10]1)[CH2:2]2
Reactant: O=C([O-])c1cccc2ncn(CCN[C@@H]3CN4CCC3CC4)c12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2cccc3ncn(c23)CCN1[C@@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of lithium (S)-1-(2-(quinuclidin-3-ylamino)ethyl)-1H-benzo[d]imidazole-7-carboxylate (0.2 g, 0.7 mmol) from Step G above, N,N-diisopropylethylamine (0.7 mL, 4.1 mmol), and 1-propanephosphonic acid cyclic anhydride (T3P) (2.1 mL, 3.4 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 7 h. The crude reaction was concentrated under reduced pressure and then purified by SCX column and preparative thin layer chromatography (90:9:1 methylene chloride/methanol/ammonium hydroxide) to afford 6-((S)-quinuclidin-3-yl)-5,6-dihydroimidazo[4,5,1-jk][1,4]benzodiazepin-7(4H)-one: 1H NMR (500 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.86 (dd, J=8.0, 1.0 Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 4.85-4.50 (m, 2H), 4.48-4.39 (m, 2H), 3.91-3.33 (m, 1H), 3.31-3.11 (m, 1H), 3.08-3.02 (m, 1H), 2.99-2.89 (m, 1H), 2.81-2.71 (m, 3H), 1.97-1.95 (m, 1H), 1.71-1.56 (m, 3H), 1.49-1.39 (m, 1H).
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][CH2:7][OH:8])([O-:3])=[O:2].C(N(CC)CC)C.[C:16](Cl)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(OCC)C>[C:16]([O:8][CH2:7][CH2:6][CH2:5][O:4][N+:1]([O-:3])=[O:2])(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=[N+]([O-])OCCCO
Reactant: CCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCC(=O)OCCCO[N+](=O)[O-]
Reaction time: 19 h

Procedure:
20 mmol 3-Nitrooxypropanol dissolved in 10 ml Diethylether and 20 mmol Triethylamine were cooled to 0° C. 18.2 mmol hexoylchlorid were dropped over a period of 5 minutes at 0 to 5° C. After 19 hours stirring without cooling, the reaction mixture was extracted with 1N HCl, twice with water, washed with brine, dried over Na2SO4 and the solvent was removed in vacuo leaving 3.1 g.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Si]([O:20][CH2:21][C@H:22]([OH:31])[CH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)(C(C)(C)C)(C)C.[C:32](O)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:32]([O:31][C@H:22]([CH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[CH2:21][OH:20])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](O)CCc1cccnc1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(O[C@@H](CO)CCc1cccnc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.8 %

Procedure:
Solid 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.01 g) was added to a stirring solution of (2R)-1-(tert-butyldimethylsilyloxy)-4-(3-pyridyl)-2-butanol (1.97 g), benzoic acid (1.28 g) and 4-dimethylaminopyridine (0.85 g) in dichloromethane (50 ml) and the resulting solution stirred at room temperature for 20 hours. The solution was then concentrated under reduced pressure and the residue dissolved in acetonitrile (30 ml). Aqueous hydrofluoric acid (40%, 3 ml) was added and the mixture stirred for 30 minutes before being poured into saturated aqueous sodium bicarbonate solution (200 ml). The mixture was extracted with ethyl acetate, the combined extracts dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate to give the sub-title compound as a solid (1.8 g).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17]C)[C:10]=3[CH:9]=2)=[CH:5][CH:4]=1)[CH3:2].B(Br)(Br)Br>>[CH2:1]([C:3]1[S:7][C:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:10]=3[CH:9]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2cc3c(OC)cccc3o2)s1
Agent: BrB(Br)Br
Product: CCc1ccc(-c2cc3c(O)cccc3o2)s1
Yield: 81.8 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 5 using 2-(5-ethylthiophen-2-yl)-4-methoxybenzo(b)furan (1.00 g) and boron tribromide (1.0 ml), the title compound (774 mg) was obtained as colorless crystals, melting point 87-90° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:22][CH3:23])[CH2:4][NH:5][C:6](=[O:21])[C@H:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][C:9]#[CH:10].[Cl:24]C1C=CC(S(N[C@H](CC#C)C(O)=O)(=O)=O)=CC=1>>[CH3:23][O:22][CH:3]([O:2][CH3:1])[CH2:4][NH:5][C:6](=[O:21])[C@H:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([Cl:24])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH2:8][C:9]#[CH:10]
Reactant: C#CC[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Reactant: C#CC[C@@H](NS(=O)(=O)c1ccccc1)C(=O)NCC(OC)OC
Product: C#CC[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)NCC(OC)OC

Procedure:
Using the same procedure describe for the synthesis of 39, (R)-2-(4-chlorobenzenesulfonamido)pent-4-ynoic acid afforded the title compound. 1H NMR (400 MHz, CDCl3): δ 2.43 (m, 2H), 2.71 (s, 3H), 2.85 (s, 1H), 2.89 (s, 3H), 2.96 (m, 2H), 3.98 (t, 7.1 Hz, 3H), 4.15 (t, 5.5 Hz, 1H), 7.65(d, 8.0 Hz, 2H), 7.80 (d, 8.0 Hz, 2H), 7.97 (s, 1H), 8.11 (t, 5.5 Hz, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].C[NH:30][CH2:31][CH2:32][OH:33].[I-].[Na+]>COCCOC>[OH:33][CH2:32][CH2:31][NH:30][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28]
Reactant: CNCCO
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCNCCO
Temperature: 135 °C

Procedure:
Using an analogous procedure to that described in Example 157, 196.5 mg (0.5 mmol) of the 7-(2-chloro-ethoxy)-4-(1H-indazol-6-ylamino)-6-methoxy-quinoline-3-carbonitrile, 375.6 mg (5.0 mmol) of 2-(methylamino)-ethanol and 75.0 mg (0.5 mmol) of sodium iodide in 5 mL of DME was heated at 135° C. for 15 hr. The work up gave 116.4 mg (54.0%) of the product as a yellow solid, m.p. 179° C. (dec.), mass (electrospray, m/e): M+H 433.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17](I)[CH:18]=[C:13]3[N:12]=2)[CH:4]=1.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17]([C:32]4[CH:33]=[CH:34][C:29]([O:28][CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:30][CH:31]=4)[CH:18]=[C:13]3[N:12]=2)[CH:4]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(OCc5ccccc5)cc4)cnc3[nH]2)c1
Yield: 64.2 %

Procedure:
0.38 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (example 7) and 0.342 g of 4-benzyloxyphenylboronic acid are dissolved in 16 ml degassed dioxane. Then a solution of 0.276 g of potassium carbonate and 0.85 g of lithium chloride in 13 ml of degassed water and 0.115 g of tetrakis(triphenylphosphine)palladium(0) are added. The mixture is heated to reflux under N2 for 20 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 30–26:1). Concentration of the chromatographically pure fractions and crystallisation from ethyl acetate gives 0.28 g of the title compound as a colourless solid of m.p. 161–162° C. The mass spectrum shows the molecular peaks MH+ and 2MNa+ at 437.3 and 894.2 Da.
Reaction SMILES: CON=[C:4]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH:8]([O:13][CH3:14])[CH:7]([N:15]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)C(=O)C)[CH:6]=[C:5]1[CH3:26].C(O)(=O)C(C)=[O:29].Cl>C(O)C>[CH2:19]([NH:15][CH:7]1[CH:8]([O:13][CH3:14])[C:9]([CH3:12])([CH3:11])[CH2:10][C:4](=[O:29])[C:5]([CH3:26])=[CH:6]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)C(=O)O
Reactant: CON=C1CC(C)(C)C(OC)C(N(Cc2ccccc2)C(C)=O)C=C1C
Agent: Cl
Solvent: CCO
Product: COC1C(NCc2ccccc2)C=C(C)C(=O)CC1(C)C
Temperature: 75 °C
Yield: 69.3 %

Procedure:
To a solution of ethanol (40 ml) containing the 4-(N-acetylbenzylamino)-5-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one methyloxime obtained in step 3 (8.5 g, 23.7 millimoles) there were added pyruvic acid (4.18 g, 47.4 millimoles) and 6N hydrochloric acid (40 ml), and the mixture was heated at 75° C. for 4 hours. The reaction solution was concentrated and the resulting residue was dissolved in methanol (50 ml) and then neutralized with a 10% aqueous sodium hydroxide solution while stirring on ice. Water (100 ml) was added, extraction was performed with benzene, and after washing the benzene solution with water it was dried over anhydrous magnesium sulfate. The benzene was distilled off and the resulting residue was subjected to silica gel column chromatography with benzene-ethyl acetate (19:1) as the eluent, to obtain 4.72 g (69%) of 4-benzylamino-5-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[N:13][CH:12]=1.[Li+].[OH-]>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[N:13][CH:12]=1
Reactant: COC(=O)c1cc(-c2cnnn2C)c(Cl)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nncc1-c1cc(C(=O)O)sc1Cl
Yield: 98 %

Procedure:
A solution of methyl 5-chloro-4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxylate (400 mg, 1.55 mmol) and 1N LiOH (2.0 ml, 2.0 mmol) in THF (6 ml) was stirred at rt overnight. After removal of THF, the residue was diluted with 10 ml of H2O and washed with DCM (10 ml×2). The aqueous layer was acidified to pH 3 with 1N HCl and then extracted with EtOAc (30 ml×4). The organic layers were combined and concentrated to give 370 mg of the title compound as a white solid. LCMS (ES) m/z 244.0 (M+H)+
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)=[O:23])=[CH:17][CH:16]=4)=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Cl:33][C:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[CH:36][N:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[C:38]([N:14]2[C:15]3[C:20](=[CH:19][C:18]([C:22]([N:24]4[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:29]4)=[O:23])=[CH:17][CH:16]=3)[CH:21]=[C:13]2[C:11]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[O:12])[CH:37]=[CH:36][N:35]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC5(CC4)OCCO5)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC4(CC2)OCCO4)n3-c2ccnc(Cl)c2)CC1
Yield: 42 %

Procedure:
The title compound was synthesized in analogy to example 66, from (1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 196), 2-chloropyridine-4-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (42%).
Reaction SMILES: [S:1]1[C:5]([C:6]2[N:7]=[N:8][C:9](Cl)=[CH:10][CH:11]=2)=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2.[CH3:17][N:18]1[C:23]([CH3:25])([CH3:24])[CH2:22][CH:21]([NH2:26])[CH2:20][C:19]1([CH3:28])[CH3:27].CCN(C(C)C)C(C)C>C(O)CCC.CCOC(C)=O>[S:1]1[C:5]([C:6]2[N:7]=[N:8][C:9]([NH:26][CH:21]3[CH2:20][C:19]([CH3:27])([CH3:28])[N:18]([CH3:17])[C:23]([CH3:25])([CH3:24])[CH2:22]3)=[CH:10][CH:11]=2)=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2
Reactant: Clc1ccc(-c2cc3ccccc3s2)nn1
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN1C(C)(C)CC(Nc2ccc(-c3cc4ccccc4s3)nn2)CC1(C)C
Temperature: 180 °C
Yield: 16 %

Procedure:
To a suspension of 3-(benzo[b]thiophen-2-yl)-6-chloropyridazine (100 mg, 0.41 mmol) in n-butanol (2 mL) in a 2 mL microwave vial was added 1,2,2,6,6-pentamethylpiperidin-4-amine (276 mg, 1.62 mmol) and DIPEA (0.14 mL, 0.81 mmol). The reaction vessel was sealed and heated via microwave radiation for 180 min at 180° C. The crude reaction mixture was diluted in EtOAc. The organic layer was washed with water (5×), brine, dried over MgSO4, filtered and concentrated. The crude product was purified via HPLC to give 25 mg of 6-(benzo[b]thiophen-2-yl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine. LCMS Rt=0.54 min (LCMS method Q); (M+1)=381.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.73-7.82 (m, 1H), 7.64-7.73 (m, 1H), 7.54 (d, J=9.1 Hz, 1H), 7.53 (s, 1H), 7.21-7.34 (m, 2H), 6.56 (d, J=9.3 Hz, 1H), 4.55 (d, J=7.8 Hz, 1H), 4.14-4.32 (m, 1H), 2.20 (s, 3H), 1.93 (dd, J=12.4, 3.8 Hz, 2H), 1.30 (apparent t, J=12.1 Hz, 2H), 1.07 (s, 6H), 1.10 (s, 6H).
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[C:7]([O:15][CH:16]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[CH:17]([CH3:19])[CH3:18])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(#N)C.O>[CH3:2][N:1]([C:21]([O:20][CH:16]([O:15][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:14])[CH:17]([CH3:19])[CH3:18])=[O:22])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CNCC(=O)O
Reactant: CC(C)C(OC(=O)ON1C(=O)CCC1=O)OC(=O)c1ccccc1
Solvent: O
Solvent: CC#N
Product: CC(C)C(OC(=O)c1ccccc1)OC(=O)N(C)CC(=O)O
Yield: 39.5 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkylcarbamates, sarcosine (0.345 g, 3.8 mmols) and 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl benzoate (1 g, 2.98 mmol) were reacted in an acetonitrile/water mixture (20 mL) to provide 0.364 g (39.5% yield) of the title compound (48) as a colorless, waxy material after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=8.05 (t, 2H), 7.59 (t, 1H), 7.43 (t, 2H), 6.84 (m, 1H), 4.21-3.88 (br m, 2H), 3.0 (d, 3H), 2.25 (m, 1H), 1.15 (dd, 6H). MS (ESI) m/z 332.20 (M+Na)+; 308.21 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7]C=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].CC1C=CC2C(=CC=CC=2)C=1[N+:28]([O-])=O.C1(/C=C/B(O)O)C=CC=CC=1.C([B-](F)(F)F)=C.[K+]>>[NH2:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:5]([Br:12])=[C:6]2[C:11]=1[CH:10]=[CH:9][N:28]=[CH:7]2
Reactant: Cc1ccc2ccccc2c1[N+](=O)[O-]
Reactant: COC(=O)c1cc(Br)c2ccccc2c1N
Agent: C=C[B-](F)(F)F
Agent: OB(O)/C=C/c1ccccc1
Agent: [K+]
Product: COC(=O)c1cc(Br)c2cnccc2c1N

Procedure:
Methyl 5-amino-8-bromoisoquinoline-6-carboxylate was prepared by the procedure described for the synthesis of methyl 1-amino-4-bromo-2-naphthoate in Example 1, substituting 6-methyl-5-nitroisoquinoline for 2-methyl-1-nitronaphthalene and substituting [(E-2-phenylethenyl]boronic acid for potassium vinyltrifluoroborate.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:26]2[N:31]=[N:30][C:29]([N:32]([CH3:43])[CH:33]3[CH2:38][C:37]([CH3:40])([CH3:39])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]3)=[CH:28][CH:27]=2)=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:14][CH:13]=2)C1C=CC=CC=1>CO.CCOC(C)=O.[Pd]>[CH3:43][N:32]([CH:33]1[CH2:34][C:35]([CH3:42])([CH3:41])[NH:36][C:37]([CH3:40])([CH3:39])[CH2:38]1)[C:29]1[N:30]=[N:31][C:26]([C:10]2[C:9]([OH:8])=[CH:18][C:17]3[C:12]([CH:11]=2)=[CH:13][CH:14]=[C:15]([CH2:19][N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH:16]=3)=[CH:27][CH:28]=1
Reactant: CN(c1ccc(-c2cc3ccc(CN4CCCCC4)cc3cc2OCc2ccccc2)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(c1ccc(-c2cc3ccc(CN4CCCCC4)cc3cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
A H2 purged mixture of 6-(3-(benzyloxy)-6-(piperidin-1-ylmethyl)naphthalen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (34 mg, 0.059 mmol) and 10% wt Pd/C (0.3 mg, 3 μmol) in MeOH (3 mL) and EtOAc (3 mL) was stirred under a H2 atmosphere at RT overnight. The reaction mixture was filtered through celite, rinsed with MeOH and concentrated. The crude material was purified via HPLC to give the desired product as a yellow solid (15 mg, 52.3% yield). LCMS Rt=0.45 min [Method Q], MS (M−1)=486.4. 1H NMR (METHANOL-d4) δ 8.16 (s, 1H), 8.12 (d, J=10.1 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.46 (s, 1H), 7.15-7.22 (m, 2H), 7.14 (s, 1H), 4.98 (t, J=12.1 Hz, 1H), 3.49 (s, 2H), 2.89 (s, 3H), 2.37 (br. s., 4H), 1.34-1.60 (m, 10H), 1.29 (s, 6H), 1.13 (s, 6H).