Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([C:20]1[N:21]([C:30]2[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[C:33]([OH:39])=[CH:32][C:31]=2[OH:40])[N:22]=[N:23][C:24]=1[C:25](=[O:29])[NH:26][CH2:27][CH3:28])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:27]([NH:26][C:25]([C:24]1[N:23]=[N:22][N:21]([C:30]2[CH:35]=[C:34]([CH:36]([CH3:37])[CH3:38])[C:33]([OH:39])=[CH:32][C:31]=2[OH:40])[C:20]=1[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][CH:9]=1)=[O:29])[CH3:28]
Reactant: CCNC(=O)c1nnn(-c2cc(C(C)C)c(O)cc2O)c1N(C(=O)OC(C)(C)C)c1ccc(N2CCOCC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)c1nnn(-c2cc(C(C)C)c(O)cc2O)c1Nc1ccc(N2CCOCC2)cc1
Yield: 45 %

Procedure:
A solution of the intermediate from Step D in DCM/TFA (1/1, 2 ml) was stirred for 12 hours at RT. The reaction mixture was concentrated under reduced pressure and the crude reaction mixture was purified by column chromatography (DCM/MeOH: 95/5). The title compound was obtained as a slightly brown solid.
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:17]=1>>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)[CH2:24][CH2:25]1)#[N:2]
Reactant: CC(C)C(C#N)(CCCI)c1cccs1
Reactant: c1cncc(NC2CCNCC2)c1
Product: CC(C)C(C#N)(CCCN1CCC(Nc2cccnc2)CC1)c1cccs1

Procedure:
The title compound was synthesized in accordance with Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and 4-(3-pyridylamino)piperidine. The physico-chemical data of the compound was as below.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH2:13][CH3:14]>>[CH2:12]([C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:17][CH:16]=1)[CH2:13][CH3:14]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CCCc1ccc(N)cc1
Product: CCCc1ccc(Nc2ccccc2CC(=O)O)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-propylaniline to yield 2-[(4-propylphenyl)amino]phenylacetic acid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6](=[O:16])[CH2:5]1.[CH3:17][C:18]1([CH3:42])[N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:21]([CH2:30]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:20][O:19]1>CN(C=O)C>[CH3:3][N:4]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[N:7]([CH2:30][C@@H:21]2[CH2:20][O:19][C:18]([CH3:17])([CH3:42])[N:22]2[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C:6](=[O:16])[CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Reactant: CN1CC(=O)Nc2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC(=O)N(C[C@@H]2COC(C)(C)N2C(=O)OC(C)(C)C)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.3 %

Procedure:
1.1 g of sodium hydride dispersion (60%) are suspended in 50 ml of DMF. 5.23 g of 4-methyl-3H-1,4-benzodiazepine-2,5(1H, 4H)-dione are added thereto so that the temperature does not exceed 35° C. and the mixture is stirred at room temperature for 90 minutes. Subsequently, a solution of 5.3 g of t-butyl (S)-2,2-dimethyl-4-(p-tolylsulfonyloxymethyl)-3-oxazolidinecaboxylate (Example 6a) in 50 ml of DMF is added thereto and the mixture is stirred at 50° C. overnight. The reaction mixture is evaporated and the residue is taken up in ethyl acetate, washed with water and dried. After evaporation of the solvent the residue is purified over silica gel with ethyl acetate/hexane (1:1). There are obtained 1.85 g of t-butyl (R)-(2,3,4,5-tetrahydro-4-methyl-2,5-dioxo-1H-1,4-benzodiazepin-1-ylmethyl)-2,2-dimethyl-3-oxazolidinecarboxylate.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C([O-])(=O)C.[Na+].C(O[CH2:20][O:21][CH2:22][CH3:23])C.[CH3:24][N:25]1[C:33]2[N:32]=[CH:31][NH:30][C:29]=2[C:28](=[O:34])[NH:27][C:26]1=[O:35]>CN(C)C=O>[CH2:22]([O:21][CH2:20][N:30]1[C:29]2[C:28](=[O:34])[NH:27][C:26](=[O:35])[N:25]([CH3:24])[C:33]=2[N:32]=[CH:31]1)[CH3:23]
Reactant: CCOCOCC
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCn1cnc2c1c(=O)[nH]c(=O)n2C
Temperature: 90 °C

Procedure:
52.5 g (0.28 mol) of p-toluenesulfonyl chloride were initially introduced into 50 ml of dimethylformamide and 22.6 g (0.29 mol) of sodium acetate were introduced with stirring and ice-cooling. The mixture was subsequently stirred for one hour, treated with 39.1 g of formaldehyde diethyl acetal and again subsequently stirred for one hour. 41.5 g of 3-methylxanthine were then introduced and the reaction mixture was heated at 90° C. for 2 hours. After cooling to 10° C., the precipitated product was filtered off with suction, washed with a little dimethylformamide and washed with demineralized water until chloride-free. The crude product obtained was recrystallized from dimethylformamide.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C[O-].[Na+].Cl[CH2:16][C:17]([O:19][CH3:20])=[O:18]>CN(C=O)C>[CH:7]1[C:8]2[C:3](=[C:2]([O:1][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: COC(=O)CCl
Reactant: Oc1cccc2cnccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2cnccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of 29.0 g of 5-hydroxyisoquinoline in 300 ml of DMF, 11.0 g of sodium methylate was added portionwise. After stirring for 30 min, 17.9 ml of methyl chloroacetate was added dropwise, and the resultant mixture was stirred at room temperature overnight and concentrated under reduced pressure. To the residue, 300 ml of toluene and 300 ml of water were added, and the whole mixture was filtered. The aqueous layer was extracted with 50 ml of toluene, and the combined toluene solution was treated with 2 g of charcoal and evaporated to give methyl 5-isoquinolyloxyacetate. The ester was dissolved in 100 ml of methanol, reacted with 80 ml of 3 N sodium hydroxide aqueous solution for 30 min. The reaction mixture was concentrated under reduced pressure, diluted with 80 ml of water and 160 ml of acetone, and neutralized with 20 ml of concentrated hydrochloric acid. The precipitates formed were filtered, washed with 80 ml of 50% aqueous acetone, and dried to give 34.5 g (85% yield) of the title compound.
Reaction SMILES: COC([CH:5]1[CH2:10][CH2:9][C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:11][NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]#C)=[O:14])[CH2:7][CH2:6]1)=O.C[CH2:31][O:32][C:33]([CH3:35])=[O:34].CO>[Pd]>[CH3:31][O:32][C:33]([CH2:35][CH:5]1[CH2:10][CH2:9][C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:11][NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[O:14])[CH2:7][CH2:6]1)=[O:34]
Reactant: C#COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(C(=O)OC)CC1
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1CCC(CNC(=O)c2ccccc2OC)(c2ccccc2)CC1
Reaction time: 16 h

Procedure:
To a solution of 1-methoxycarbonylmethylidenyl-4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)-cyclohexane (29.2 mg, 0.074 mmol) in a mixture of EtOAc/methanol (5 mL/5 mL) was added Pd/C (10%) (32 mg) and the reaction mixture was shaken under 50 psi of H2 for 16 h. The mixture was filtered through a plug of celite, concentrated and the residue was purified by HPLC (Waters RCM, μ Porosil, 25 mm×10 cm) using a mixture of (5:4:1 hexane-methyl tert-butyl ether-acetonitrile:hexane, 2.25/8.0 to 3.6/7.0 mL/min) to give the separated isomers of the title compound.
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:32])[C@H:10]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[NH3:33]>C1COCC1>[CH2:15]([O:14][C:12]([NH:11][C@H:10]([C:9]([NH2:33])=[O:32])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To THF (150 mL) solution of Nα-benzyloxycarbonyl-L-tryptophan-2,5-dioxopyrrolidin-1-yl ester (5.0 g) was added dropwise a 30% aqueous ammonia (3.3 mL) at 0° C., and thereafter the mixture was stirred for 2 hours at room temperature. The crystals were distilled off, and thereafter to the residue obtained by distilling off the solvent of the filtrate under a reduced pressure was added petroleum ether and a small amount of diethyl ether, and the crystals precipitated were filtered, to give the captioned compound (3.6 g, 91%).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH3:7][C@@H:8]1[O:13][S:12](=[O:14])[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]1.Cl.CC[O:25]C(C)=O>C(#N)C.O>[CH3:7][C@@H:8]1[O:13][S:12](=[O:25])(=[O:14])[N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:10][CH2:9]1
Reactant: CCOC(C)=O
Reactant: C[C@H]1CCN(C(=O)OC(C)(C)C)S(=O)O1
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C[C@H]1CCN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Sodium periodate (341 g, 1.6 mol) is added to a solution of tert-butyl (6S)-6-methyl-1,2,3-oxathiazinane-3-carboxylate 2-oxide (250 g, 1062 mmol) in acetonitrile (2.5 L) and water (1.5 L) at 0° C. The pH of the mixture is adjusted to 7 by the addition of saturated Na2HPO4 solution. A solution of RuCl33H2O (2.20 g, 10.62 mmol) is added at 5° C. and the pH of mixture is kept at 7 by addition of saturated Na2HPO4 solution. The reaction is stirred at room temperature for 2 h. Water is added and pH is adjusted to 6 by addition of 2.0 M HCl solution. EtOAc (1.0 L) is added and the aqueous layer is separated and extracted with EtOAc (2×500 mL). The organic layers are combined, washed with saturated NaHCO3 solution and brine, dried (Na2SO4) and concentrated to afford the crude compound which is purified by flash column chromatography using EtOAc in hexane to afford the title compound (140 g, 52%) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[N:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccncc1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Product: c1cc(-c2ccncc2)c2[nH]c3c(c2c1)CN1CCC3CC1

Procedure:
The product of Example 1B (100 mg, 0.34 mmol) and pyridine-4-boronic acid (52 mg, 0.38 mmol; Aldrich) were processed as described in Example 4 to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.06-2.17 (m, 4 H), 3.06-3.18 (m, 3 H), 3.23-3.29 (m, 2 H), 4.30 (s, 2 H), 7.13 (t, J=7.6 Hz, 1 H), 7.17-7.20 (m, 1 H), 7.41 (dd, J=7.6, 1.2 Hz, 1 H), 7.70-7.74 (m, 2 H), 8.58-8.64 (m, 2 H); MS (APCI) m/z 290 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[S:11][CH:12]=[CH:13][C:3]=12.[NH:14]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:8]([C:7]1[C:2]([N:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:15]2)=[C:3]2[CH:13]=[CH:12][S:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2sccc2c1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3sccc23)C1
Temperature: 110 °C
Reaction time: 12 h
Yield: 93.7 %

Procedure:
To a vial containing 4-chloro-5-nitrothieno[2,3-b]pyridine (138.2 mg, 0.6439 mmol) and tert-butyl (3S)-piperidin-3-ylcarbamate (Combi-Blocks, 325.5 mg, 1.625 mmol), 1-butanol (3.00 mL) was added, followed by DIPEA (201.4 mg, 1.558 mmol), then the mixture was stirred at 110° C. for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the title compound as a yellow solid (228.4 mg, 94%). LCMS calc. for C17H23N4O4S (M+H)+: m/z=379.1. found 379.2.
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][N:4]([CH3:33])[C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:15]([NH:17][O:18][CH2:19][CH3:20])=[O:16])[CH:8]=[C:7]([N:25]2[CH2:31][CH2:30][CH2:29][N:28]([CH3:32])[CH2:27][CH2:26]2)[N:6]=1.[C-:36]#[N:37].[Na+].BrBr>C(=O)(O)[O-].[Na+].C(Cl)Cl.O>[C:36]([C:8]1[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:15]([NH:17][O:18][CH2:19][CH3:20])=[O:16])=[N:10][C:5]([N:4]([CH2:3][C:2]([CH3:34])([CH3:1])[CH3:35])[CH3:33])=[N:6][C:7]=1[N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH3:32])[CH2:27][CH2:26]1)#[N:37]
Reactant: [C-]#N
Reactant: CCONC(=O)c1ccc(C)c(Nc2cc(N3CCCN(C)CC3)nc(N(C)CC(C)(C)C)n2)c1
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCONC(=O)c1ccc(C)c(Nc2nc(N(C)CC(C)(C)C)nc(N3CCCN(C)CC3)c2C#N)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 3-[2-[(2,2-dimethyl-propyl)-methyl-amino]-6-(4-methyl-[1,4]diazepan-1-yl)-pyrimidin-4-ylamino]-N-ethoxy-4-methyl-benzamide (50 mg, 0.1 mmol) and sodium cyanide (0.044 g, 0.89 mmol) in sat. aq. sodium bicarbonate (1 mL) and methylene chloride (3 mL) was added at room temp bromine (0.045 mL, 0.87 mmol). The resulting mixture was continued stirring for 16 h at room temp. The reaction mixture was diluted with water and extracted with methylene chloride (2×15 mL). The combined organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure, and the product was purified by HPLC. C27H40N8O2 MS m/e=509 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[OH:31]>>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[O:31][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1
Reactant: CSc1ccc(-c2nnc(Cl)cc2-c2ccc(F)cc2)cc1
Reactant: Oc1ccc(F)cc1F
Product: CSc1ccc(-c2nnc(Oc3ccc(F)cc3F)cc2-c2ccc(F)cc2)cc1

Procedure:
In a similar manner as in Example 2, 6-chloro-4-(4-fluorophenyl)-3-[4-(methylthio)phenyl]pyridazine (198 mg, 0.599 mmol) and 2,4-difluorophenol were reacted as starting materials at 150° C. for 20 hours and post-treatment was then conducted, whereby the title compound was obtained as pale yellow crystals (197 mg, 77.4%). Melting point: 140.6-143.4° C. (acetone-water).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Cl>CN(C)C=O.C(OCC)(=O)C>[F:18][C:19]([F:28])([F:29])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][S:15][C:13]1[O:14][C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)=[N:11][N:12]=1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: Sc1nnc(-c2ccc3[nH]ncc3c2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccc(CSc2nnc(-c3ccc4[nH]ncc4c3)o2)c1
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of 5-(1H-indazol-5-yl)-1,3,4-oxadiazole-2-thiol (218 mg, 1.00 mmol) and 1 M aqueous sodium hydroxide solution (1.00 mL, 1.00 mmol) in N,N-dimethylformamide (5 mL) was added 3-(trifluoromethyl)benzyl chloride (0.155 mL, 1.00 mmol) at room temperature, and the resulting mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (tetrahydrofuran) and recrystallized from methanol to give the title compound (279 mg, yield 74%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:14])[F:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]([CH3:24])[CH3:23]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH:12]([F:13])[F:14])=[C:6]([O:9][CH3:10])[C:7]=1[O:8][CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)CBr
Reactant: COc1c(OC(F)F)ccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(Br)c1OCC(C)C
Temperature: 80 °C
Yield: 248.7 %

Procedure:
To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (100 mg, 0.371 mmol) in acetonitrile (10 mL), was added potassium carbonate (153.8 mg, 1.114 mmol) and isobutyl bromide (152.6 mg, 1.114 mmol) and the resultant reaction mixture was heated to 80° C. for 3 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 300 mg of 1-Bromo-4-(difluoromethoxy)-2-isobutoxy-3-methoxybenzene as a solid. To a stirring solution of 1-bromo-4-(difluoromethoxy)-2-isobutoxy-3-methoxybenzene (200 mg, 0.615 mmol) in dimethylformamide (5 mL) was purged with argon for 1 h. To this cesium carbonate (599 mg, 1.84 mmol), tetrakis(triphenylphosphine) palladium(0) (35 mg, 0.030 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (191 mg, 0.738 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 3 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded the title compound as a (30 mg, 13%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH3:10].Br[C:22]1[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:22]2[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCOc1ccc(B(O)O)cc1
Reactant: Nc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCCCOc1ccc(-c2cccnc2N)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
A mixture of sodium carbonate (0.978 g), tetrakis(triphenylphosphine)palladium(0) (0.267 g), 4-butoxyphenylboronic acid (1.16 g) and 3-bromopyridin-2-amine (0.799 g,) in DME (23 mL) and water (4.6 mL) was stirred at 80° C. overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (0.690 g) as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([Sn](C)(C)C)[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26].O>C1C=CC=CC=1>[CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:25](=[O:26])[CH2:24][O:23][CH3:22])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: COCC(=O)Cl
Reactant: CCCN(CCC)C1CCc2cccc([Sn](C)(C)C)c2C1
Solvent: c1ccccc1
Solvent: O
Product: CCCN(CCC)C1CCc2cccc(C(=O)COC)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
Bis-triphenylphosphine palladium dichloride (120 mg) was added to a solution of 2-dipropylamino-8-trimethylstannyl-1,2,3,4-tetrahydronaphthalene (500 mg, 1.27 mmol) in benzene (20 ml). Methoxyacetyl chloride (1.5 ml; 1.77 g; 16.5 mmol) was added. The reaction mixture was stirred at room temperature overnight and then heated to reflux for 5 hr. The reaction mixture was poured into water and extracted with methylene chloride. The extract was dried (MgSO4) and concentrated to give 800 mg of crude product. Purification by chromatography using 1:10 methanol: methylene chloride as solvent gave 380 mg of 2-di-n-propylamino-8-methoxyacetyl-1,2,3,4-tetrahydronaphthalene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[O:8][CH2:9][C:10]1([CH3:14])[CH2:13][O:12][CH2:11]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CCN(C(C)C)C(C)C.[CH3:45][C:46]([CH3:53])([C:48]1[S:49][CH:50]=[CH:51][N:52]=1)[NH2:47]>CN(C=O)C>[CH3:45][C:46]([NH:47][C:15]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][C:10]2([CH3:14])[CH2:11][O:12][CH2:13]2)[N:6]=1)=[O:17])([C:48]1[S:49][CH:50]=[CH:51][N:52]=1)[CH3:53]
Reactant: CC1(COc2nc(C(=O)O)ccc2Br)COC1
Reactant: CC(C)(N)c1nccs1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(COc2nc(C(=O)NC(C)(C)c3nccs3)ccc2Br)COC1
Reaction time: 0.5 h
Yield: 23 %

Procedure:
To a solution of 5-bromo-6-(3-methyl-oxetan-3-ylmethoxy)-pyridine-2-carboxylic acid (Example 280b) (30 mg, 100 μmol) in dry DMF (1 ml) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (29.1 mg, 105 μmol) and Hunig's base (52.4 uL, 300 umol). The reaction was stirred at r.t for 30 min, followed by addition of α,α-Dimethyl-2-thiazolemethanamine (Example 12c) (14.2 mg, 100 μmol). The reactions was stirred at room temperature overnight and monitored by LC-MS. When the reaction was complete, purification was directly done by preparative HPLC without any work-up procedure to give the title compound (9.8 mg, 23%). MS (EI): m/e=425.9 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[N:4]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[N:38]=2)[N:3]=1.[ClH:44].[H][H]>CO.C(O)(C)C.[Pd]>[ClH:44].[ClH:44].[ClH:44].[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[N:4]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[N:38]=2)[N:3]=1
Reactant: [H][H]
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(C6=CCN(C(=O)OC(C)(C)C)CC6)ccn45)cccc32)n1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(C6CCNCC6)ccn45)cccc32)n1
Yield: 17 %

Procedure:
tert-Butyl 4-(3-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Example 51; 0.037 g, 0.064 mmol) was dissolved in 6 mL of methanol and 1.3 mL of 6N HCl in isopropyl alcohol. 10% Pd/C (0.075 g) was added and the mixture hydrogenated under a balloon of hydrogen for 2 hours. Celite was added and the mixture was then filtered through GF/F filter paper and the filtrate concentrated under reduced pressure. The crude material was purified by reverse phase chromatography, followed by treatment of the isolated material with 4M HCl/dioxane to provide the title compound (17% yield). MS (APCI), positive scan, m/z=480.3 (M+H).