Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COS(O)(=O)=O.[CH2:7]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[NH:14])[CH2:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].C([O:28][CH:29]=[C:30]([C:36](OCC)=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32])C.C(O)(=O)C>C(O)C>[O:28]=[C:29]1[NH:15][C:13]([C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[O:10][CH2:7][CH2:8][CH3:9])=[N:14][CH:36]=[C:30]1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCCOc1ccccc1C(=N)N
Agent: COS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCOc1ccccc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 17 h
Yield: 85 %

Procedure:
A mixture of 2-n-propoxybenzamidine methyl sulfate 7.4 g., 0.0255 mole), potassium carbonate (3.53 g., 0.025 mole), and diethyl ethoxymethylenemalonate (5.99 g., 0.0277 mole) in ethanol (80 ml.) was heated under reflux with stirring for 17 hours. The cooled mixture was added to ice-water (160 ml.) which was then acidified with glacial acetic acid. The precipitate was collected by filtration, washed with water, and dried to give the title compound (6.55 g., 89%), m.p. 106°-107°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][CH:5]=1)[CH3:2].C(N(CC)CC)C.CS([Cl:23])(=O)=O>C(Cl)Cl>[Cl:23][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[N:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOc1ccc(CO)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(CCl)cn1
Reaction time: 2 h

Procedure:
(6-Ethoxypyridin-3-yl)methanol (1.0 g, 6.5 mmol) was dissolved in methylene chloride (20 mL), and triethylamine (1.8 mL, 13 mmol) was added. The reaction mixture was cooled in an ice bath and methanesulfonyl chloride (0.67 mL, 8.6 mmol, Aldrich, Cat. 471259) was slowly added. The reaction mixture was stirred for 2 hours and then the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with MgSO4, and concentrated. The residue was purified by flash chromatograph on a silica gel column using 20% Ethyl acetate in hexane as eluent to afford the desired compound. LCMS (M+H)+: m/z=172.2.
Reaction SMILES: C(Cl)Cl.[CH:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:12]1([C:18]([O:21][Si](C)(C)C)=[CH:19][CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.O.CC(O)C>[C:12]1([C:18](=[O:21])[CH:19]([CH3:20])[CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[OH:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC=C(O[Si](C)(C)C)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C(=O)c1ccccc1)C(O)c1ccccc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
From the methylene chloride solution of the chiral lead catalyst thus prepared, the solvent was evaporated, then dissolved in H2O-i-PrOH (1:4.5, 0.50 ml). After cooling at 0° C., H2O:i-PrOH (1:4.5, 1.0 ml) solutions of benzaldehyde (0.5 mmols) and 1-phenyl-1-trimethylsiloxy-1-propene (0.75 mmols) were added consecutively. After stirring for 20 hours, ethyl acetate (15 ml) and aqueous saturated NaHCO3 solution (10 ml) were added thereto to separate the organic layer, followed by the extraction of the product with ethyl acetate (10 ml×2). The resulting organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure, and the residue was purified through thin-layer silica gel chromatography to obtain 1,3-diphenyl-3-hydroxy-2-methyl-1-propanone (89%, syn:anti=91:9, 69% ee (syn)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:17])OC(C)(C)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[NH:10][C:11](=[O:17])[NH:1][C:2]=2[CH:7]=1
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c(=O)[nH]c2c1
Temperature: 130 °C
Yield: 71.7 %

Procedure:
Intermediate 36 (7.3 g, 30.6 mmol) was dissolved in DMF (70 mL). To this solution was added anhydrous K2CO3 (4.7 g, 33.7 mmol) and the mixture was heated to reflux (130° C.) for 5 h. The solvent was removed under pressure, the residue was poured into ice water, and the aq phase was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, concentrated under vacuum, and the resulting yellow solid was recrystallized from EtOH to give 5-methoxy-1H-benzo[d]imidazol-2(3H)-one (intermediate 37) (3.6 g, 72%) as a yellow solid. mp: 249-251° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)#[N:2].[H-].[Na+].[CH3:16][N:17]([CH2:19][CH2:20]Cl)[CH3:18]>CN(C)C=O>[CH3:16][N:17]([CH2:19][CH2:20][CH:3]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[C:1]#[N:2])[CH3:18]
Reactant: COC(=O)c1ccc(CC#N)cc1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(C#N)CCN(C)C)cc1
Reaction time: 1 h

Procedure:
A solution of 4-cyanomethylbenzoic acid, methyl ester (28.8 g) in dry dimethylformamide (DMF) (100 ml) was added dropwise to a stirred suspension of sodium hydride (80%, dispersion in oil, 5.4 g) in DMF (50 ml) under nitrogen. The mixture was stirred at 50° for 1 h., then a solution of dimethylaminoethyl chloride (21.3 g) in DMF (50 ml) was added and stirring was continued at 50° for 18 h.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][CH:9]2[CH2:12][N:11]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[CH2:10]2)=[C:4]([N:23]2[CH2:28][CH2:27][CH:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]2)[CH:3]=1>CO.[Pd]>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[N:11]1[CH2:10][CH:9]([O:8][C:5]2[N:6]=[N:7][CH:2]=[CH:3][C:4]=2[N:23]2[CH2:24][CH2:25][CH:26]([C:29](=[O:31])[CH3:30])[CH2:27][CH2:28]2)[CH2:12]1
Reactant: CC(=O)C1CCN(c2cc(Cl)nnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(=O)C1CCN(c2ccnnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
A mixture of 1-(1-(6-chloro-3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyridazin-4-yl)piperidin-4-yl)ethanone (1.1 g, 2.6 mmol) and wet Pd—C (50%, 1.0 g) in MeOH (30 mL) was stirred under H2 (40 psi) at room temperature for 1.5 hours then the reaction mixture was filtered through CELITE® and washed with MeOH. The filtrate was concentrated in vacuo to give 1-(1-(3-((1-(quinolin-2-yl)azetidin-3-yl)oxy)pyridazin-4-yl)piperidin-4-yl)ethanone (0.98 g, 2.5 mmol, yield 96%). ESI-MS (M+1): 404 calc. for C24H26N4O2 403.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH2:12][NH:13][N:14](COCC[Si](C)(C)C)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:5][C:4]=2[N:3]1[CH2:34][C:35]([F:38])([F:37])[F:36].O=C1C2=CN(COCC[Si](C)(C)C)N=C2C2C=CC(C3C=CC=CC=3NS(C)(=O)=O)=CC=2N1CC(F)(F)F>>[O:1]=[C:2]1[C:11]2=[CH:12][NH:13][N:14]=[C:10]2[C:9]2[CH:8]=[CH:7][C:6]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:5][C:4]=2[N:3]1[CH2:34][C:35]([F:36])([F:37])[F:38]
Reactant: C[Si](C)(C)CCOCN1NCc2c1c1ccc(-c3ccccc3NS(C)(=O)=O)cc1n(CC(F)(F)F)c2=O
Agent: C[Si](C)(C)CCOCn1cc2c(=O)n(CC(F)(F)F)c3cc(-c4ccccc4NS(C)(=O)=O)ccc3c2n1
Product: CS(=O)(=O)Nc1ccccc1-c1ccc2c3n[nH]cc3c(=O)n(CC(F)(F)F)c2c1
Yield: 74 %

Procedure:
The product is obtained according to the procedure described in Step 4.3. starting with N-{2-[4-oxo-5-(2,2,2-trifluoroethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-7-yl]phenyl}methanesulfonamide and N-{2-[4-oxo-5-(2,2,2-trifluoroethyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-7-yl]phenyl}methanesulfonamide, in the form of a white powder (yield 74%).
Reaction SMILES: [CH3:1][C:2]([CH3:52])([CH3:51])[C:3]([O:5][CH2:6][O:7][C:8]([C:10]1([C:41]([O:43]CC2C=CC=CC=2)=[O:42])[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[C:30]([F:40])[CH:29]=4)[O:25][N:24]=3)=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)=[O:9])=[O:4]>C(O)C.C(OCC)(=O)C.[Pd]>[CH3:1][C:2]([CH3:52])([CH3:51])[C:3]([O:5][CH2:6][O:7][C:8]([C:10]1([C:41]([OH:43])=[O:42])[CH2:11][CH2:12][N:13]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)=[C:30]([F:40])[CH:29]=4)[O:25][N:24]=3)=[CH:21][CH:22]=2)[CH2:14][CH2:15]1)=[O:9])=[O:4]
Reactant: CC(C)(C)C(=O)OCOC(=O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCOC(=O)C1(C(=O)O)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 1-{4-[5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazol-3-yl]benzyl}-piperidine-4,4-dicarboxylic acid benzyl ester (2,2-dimethyl-propanoyl-oxymethyl) ester (0.37 g, 0.00052 mol) in a mixture of ethanol and ethyl acetate (20 mL, 1:1) is added 5% Pd/C (0.133 g). The reaction mixture is stirred at room temperature and hydrogen gas is bubbled through it. This process is continued for 2.5 hours. The reaction mixture is filtered through a celite bed, washed with tetrahydrofuran (2×30 mL) and the filtrate is concentrated under reduced pressure to give a solid mass which is purified by column chromatography (silica gel 230-400 mesh, methanol:dichloromethane 15:85) to give 1-{4-[5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazol-3-yl]benzyl}-piperidine-4,4-dicarboxylic acid (2,2-dimethyl-propanoyloxymethyl)ester (e.g. 39).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[CH:17][CH:16]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(OC2CCNCC2)cc1
Temperature: 22 °C
Reaction time: 0.25 h

Procedure:
1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-{4-[1-(tert-butoxy)carbonyl-piperidin-4-yloxy]phenyl}urea (Example 1. below, 2.25 g, 4.77 mmol) is suspended in a solution of trifluoroacetic acid in dichloromethane (25% v/v, 100 mL). The reaction mixture is stirred at 22° C. for 15 min. After removal of the solvent, the oily residue is neutralized with sodium hydroxide solution to pH 12 and extracted with dichloromethane (6×50 mL). The combined-organic phases are dried over anhydrous sodium sulfate and concentrated to yield a yellow solid (2.28 g, ES+(m/z) 372.1 [M+H]).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.[NH2:36][C:37]1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.C(C1C=CC(N=C=S)=CC=1)#N>>[C:37]([C:6]1[CH:5]=[CH:4][C:3]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:15][CH:16]=2)=[CH:2][CH:7]=1)#[N:36]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Agent: N#Cc1ccc(N=C=S)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccc(C#N)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 268 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 4-cyanophenyl isothiocyanate. The compound of example 268 was used directly without isolation for the preparation of compound of example 269.
Reaction SMILES: [F:1][C:2]([F:12])([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1)[CH2:3][OH:4].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C1COCC1>[F:12][C:2]([F:1])([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1)[CH2:3][O:4][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: Cc1cccc(C(F)(F)CO)n1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(C(F)(F)COS(C)(=O)=O)n1
Reaction time: 2.5 h
Yield: 90.3 %

Procedure:
To a solution of 2,2-difluoro-2-(6-methyl-pyridin-2-yl)-ethanol (2.82 g, 16.3 mmol) (prepared essentially as described in Example 1f) in anhydrous THF (60 mL) at 0° C. was added methanesulfonyl chloride (1.52 mL, 19.6 mmol), followed by triethylamine (4.54 mL, 32.6 mmol). After 2.5 hours, the reaction mixture was quenched with ice/water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and evaporated to afford the desired product as a clear oil (3.7 g, 97%). 1H NMR (CDCl3) δ 7.73 (t, J=7.77 Hz, 1H), 7.51 (d, J=7.75 Hz, 1H), 7.28 (d, J=8.04 Hz, 1H), 4.89 (t, J=12.88 Hz, 2H), 3.07 (s, 3H), 2.58 (s, 3H); LC/MS (m/z) [M+1] 252.2 (calculated for C9H12F2NO3S, 252.0).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([C:13](=[O:16])[CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4]([CH2:18][CH2:19][CH3:20])=[CH:5][C:6](=[O:17])[O:7]2.CO[CH:23](OC)[CH2:24][C:25]([CH3:28])(O)[CH3:26]>N1C=CC=CC=1>[CH3:26][C:25]1([CH3:28])[O:1][C:2]2[C:3]3[C:4]([CH2:18][CH2:19][CH3:20])=[CH:5][C:6](=[O:17])[O:7][C:8]=3[C:9]([C:13](=[O:16])[CH2:14][CH3:15])=[C:10]([OH:12])[C:11]=2[CH:23]=[CH:24]1
Reactant: CCCc1cc(=O)oc2c(C(=O)CC)c(O)cc(O)c12
Reactant: COC(CC(C)(C)O)OC
Solvent: c1ccncc1
Product: CCCc1cc(=O)oc2c(C(=O)CC)c(O)c3c(c12)OC(C)(C)C=C3
Yield: 79.1 %

Procedure:
A mixture of 3 (2.60 g, 9.42 mmol) and 4,4-dimethoxy-2-methylbutan-2-ol (5.54 g, 37.7 mmol) were dissolved in anhydrous pyridine (6.5 mL). The mixture was refluxed under nitrogen for three days. After removal of the solvent in vacuo, the residue was dissolved in ethyl acetate. The ethyl acetate was washed several times with 1 N HCl and brine. It was then dried over Na2SO4. The crude product obtained by evaporation in vacuo was purified by silica gel column chromatography, eluting with 25% ethyl acetate/hexane to afford 2.55 g of 4 in 78.6% yield, mp 96-98° C. 1H-NMR (CDCl3) δ1.05 (3H, t, J=7.3 Hz, CH3); 1.22 (3H, t, J=7.5 Hz, CH3); 1.53 (6H, s, 2 CH3); 1.75 (2H, m, CH2); 2.92 (2H, t, J=7.1 Hz, CH2); 3.35 (2H, q, J=7.1 Hz, CH2); 5.56 (1H, d, J=10.0 Hz, H3); 5.98 (1H, s, H9); 6.72 (1H, d, J=10.0 Hz, H4); MS EI): 343 (5.7, M+1); 342 (22.5, M+); 327 (100, M-CH3); IR (KBr): 1728 (vs, C═O) cm−1; Anal. calcd. for C20H22O5: C, 70.16; H, 6.48; Found: C, 70.45; H, 6.92.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(C)(C)Oc1cccc(Br)c1
Yield: 89 %

Procedure:
25 g (144.5 mmol) of 3-bromophenol are placed in the presence of K2CO3 (21 g, 152 mmol) in 75 ml of ethyl 2-bromoisobutyrate and heated to reflux for 7 h. After elimination of K2CO3 by filtration, the reaction medium is dry concentrated. After purification by flash chromatography on silica (petroleum ether:AcOEt 90:10), 37 g of intermediate 10d are collected in the form of clear oil (yield=89%). TLC silica gel 60 F 254 Merck, petroleum ether:AcOEt 90:10, Rf=0.40.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[NH:29]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(O[Na])(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[N:29]1([C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][C:11]4[CH:10]=[C:9]([C:15]5[N:16]([C:20]6[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=6[F:27])[N:17]=[CH:18][N:19]=5)[S:8][C:7]=4[C:6]=3[N:28]=2)[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: C1CNCCNC1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(N4CCCNCC4)ccc2OCC3)c(F)c1
Temperature: 112 °C
Yield: 25 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (416 mg, 1.0 mmol), 1,4-diazepane (120 mg, 1.2 mmol), Pd2(dba)3 (210 mg, 0.3 mmol), Xphos (142 mg, 0.3 mmol), t-BuONa (576 mg, 6 mmol) and dioxane (6 mL) were added into a 10 mL of sealed tube, and the mixture was heated by microwave at 112° C. for 7 min under N2. The reaction mixture was filtered to gather the solution. The water was added and extracted by DCM (50 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and separated by column (DCM/EtOAc=4:1) to get 350 (120 mg, yield: 25%). 1HNMR (DMSO-d6, 400 MHz): δ8.04 (s, 1H), 7.97 (s, 1H), 7.67-7.65 (m, 1H), 7.50-7.46 (m, 1H), 7.20 (t, J=8 Hz, 1H), 7.02 (s, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.36 (d, J=8.8 Hz, 1H), 3.92 (d, J=4.4 Hz, 2H), 3.37-3.31 (m, 4H), 2.87 (d, J=4.4 Hz, 4H), 2.72 (s, 2H), 2.57 (s, 2H), 1.59 (s, 2H). ESI-MS: m/z=481 [M+H+]
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][N:14]=1>>[CH3:11][O:12][C:13]1[N:14]=[CH:15][C:16]([CH2:19][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])=[CH:17][CH:18]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: COc1ccc(C=O)cn1
Product: COc1ccc(CNc2ccccc2C(=O)O)cn1

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from anthranilic acid and 2-methoxypyridine-5-carboxaldehyde (Aldrich). 13C-NMR (DMSO-d6) δ 169.9, 162.9, 150.4, 145.7, 138.6, 134.4, 131.7, 127.7, 114.7, 111.7, 110.5, 110.5, 53.1, 42.8.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].Cl.[CH:18](OCC)=[O:19]>>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[CH:18][OH:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC=O
Reactant: CCOC(=O)Cc1cc(F)cc(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(=CO)c1cc(F)cc(F)c1

Procedure:
5.0 g of ethyl 3,5-difluorophenylacetate are dissolved in 50 ml of ethyl formate. 2.0 g of 60% NaH are added portionwise. The mixture is poured onto a 1N HCl solution and then extraction is carried out with AcOEt. The residue is triturated in petroleum ether, the remaining white precipitate is filtered off and then the filtrate is evaporated to produce 3.3 g of the expected compound in the form of a liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([NH:20][C:21]([NH:23][C:24]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[N:27]=[C:26]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:25]=2)=[O:22])=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C.[CH3:49][O:50][CH2:51][C:52](Cl)=[O:53]>C(Cl)Cl.CN(C=O)C>[C:36]([C:26]1[CH:25]=[C:24]([NH:23][C:21](=[O:22])[NH:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([O:9][CH2:8][C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[NH:1][C:52](=[O:53])[CH2:51][O:50][CH3:49])=[CH:11][CH:12]=2)[N:28]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)[N:27]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccncc3N)c3ccccc23)cc1
Reactant: COCC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)Nc1cnccc1COc1ccc(NC(=O)Nc2cc(C(C)(C)C)nn2-c2ccc(C)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(4-((3-aminopyridin-4-yl)methoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate C) (50 mg, 0.10 mmol) and DIPEA (33.5 μl, 0.19 mmol) in anhydrous DCM (1.0 mL) and anhydrous DMF (0.1 mL) was added methoxyacetyl chloride (10 μl, 0.11 mmol). The reaction mixture was stirred for 12 hr at RT. LC-MS indicated 50% conversion to the desired product. Methoxyacetyl chloride (10 μl, 0.11 mmol) was added and the reaction mixture was stirred at RT for a further 5 hr; LC-MS indicated the reaction was nearing completion. A further portion of methoxyacetyl chloride (8 μl, 0.09 mmol) was added, and after 2 hr, LC-MS indicated the reaction had reached completion. 1% NH3 In MeOH (10 mL) was added and the reaction mixture was stirred for 20 min at RT. The solvents were removed in vacuo to afford a purple oily solid. This was dissolved in MeOH (2.0 mL) and 3 drops of AcOH were added. The solution was subjected to SCX capture and release, eluting the product with 1% NH3 in MeOH. The solvent was removed in vacuo and the residue was triturated with diethyl ether (10 mL) to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-3-yl)-2-methoxyacetamide (Example 16) as a light purple solid (24 mg, 41%) m/z 593 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 3.31 (3 H, s (obscured by DHO peak)), 4.06 (2H, s), 5.34 (2H, s), 6.35 (1H, s), 6.96 (1H, d), 7.35 (2H, d), 7.43 (2H, d), 7.64-7.54 (4H, m), 7.93 (1H, d), 8.29 (1H, dd), 8.45 (1H, d), 8.58 (1H, s), 8.70 (1H, s), 8.79 (1H, s), 9.76 (1H, s).
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[OH-].[Na+].[C:11](=O)([O:17]C(C)(C)C)[O:12][C:13]([CH3:16])([CH3:15])[CH3:14]>O1CCOCC1.O.C(OCC)(=O)C>[C:13]([O:12][C:11]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([OH:2])[CH2:4]1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: OC1CCCNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a solution of 3-hydroxypiperidine hydrochloride (827 mg, 6 mmol) in dioxane (12 ml) and water (6 ml) cooled to 0° C. is added 1 N NaOH (12 ml, 12 mmol) and dit-butyl carbonate (827 mg, 6 mmol) in dioxane (35 ml) and the reaction mixture is stirred at 25° C. for 1 hr. The reaction mixture is diluted with ethyl acetate, washed with aqueous sodium bicarbonate, 1 N KHSO4, water and brine, dried over sodium sulfate and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, 50% ethyl acetate in hexane) to give N-t-butoxycarbonyl-3-hydroxypiperidine (1.07 g).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:24])[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[Si]([O:32][CH2:33][CH:34]=O)(C(C)(C)C)(C)C.C[N+](C)(C)C.C1COCC1>>[CH3:2][C:3]1([CH3:24])[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][CH:20]([NH:23][CH2:34][CH2:33][OH:32])[CH2:19][CH2:18]4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CC1(C)CCc2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Agent: C[N+](C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)CCc2cc(-c3csc(N4CCC(NCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out starting from 1-[4-(1,1-dimethylindan-5-yl)thiazol-2-yl]piperidin-4-ylamine hydrochloride and (tert-butyldimethylsilanyloxy)acetaldehyde. The protecting group is cleaved off as already described by means of a 1M tetramethylammonium/THF solution. The product was purified by means of preparative HPLC and converted into the hydrochloride.