Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12](O)(=[O:15])[C:13]#[CH:14].C1C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:12]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:15])[C:13]#[CH:14]
Reactant: C#CC(=O)O
Reactant: OCCOCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C#CC(=O)OCCOCc1ccccc1
Yield: 89.1 %

Procedure:
A mixture of 2 g of 2-benzyloxyethanol, 2.8 g of propiolic acid, 0.005 g of p-toluenesulfonic acid and 25 ml of benzene was refluxed with stirring for six hours while water formed was removed by a Dean-Stark water separator. After the reaction was completed, the reaction solution was washed successively with a 5% aqueous sodium bicarbonate solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the obtained residue was subjected to silicagel column chromatography to yield 2.39 g of 2-benzyloxyethyl propiolate (compound 16).
Reaction SMILES: [C:1]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=O.[CH3:18][C:19]1([CH3:27])[CH2:24][C:23](=[O:25])[CH2:22][C:21](=[O:26])[CH2:20]1.C1(N=C=NC2CCCCC2)CCCCC1.CCOC(C)=O.CCCCCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[OH:8][C:6](=[C:22]1[C:23](=[O:25])[CH2:24][C:19]([CH3:27])([CH3:18])[CH2:20][C:21]1=[O:26])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: O=C([O-])CCCCC(=O)OCc1ccccc1
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CC1(C)CC(=O)C(=C(O)CCCCC(=O)OCc2ccccc2)C(=O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.7 %

Procedure:
To a stirred solution of mono-benzyl adipate (2.36g, 10 mmol) in dry CH2Cl2 (50 ml) was added 5,5-dimethyl-1,3-cyclohexanedione (1.4 g, 10 mmol), N,N′-dicyclohexylcarbodiimide (2.1 g, 10.1 mmol) and 4-dimethylaminopyridine (1.22 g, 10 mmol). The resulting solution was allowed to stir at room temperature for 18 h. The solution was cooled and filtered to remove the precipitated N,N′-dicyclohexylurea. The filtrate was evaporated and the residue redissolved in EtOAc (50 ml) and washed with 1 M KHSO4. The organic extract was washed with brine (92×10 ml), dried (MgSO4) and evaporated to yield a white/yellow amorphous powder. Flash silica chromatography (EtOAc/hexane 1:2 v/v) afforded benzyl 6-hydroxy-6-(4,4-dimethyl-2,6-dioxocyclohexylidene)-hexanoate (3.00 g, 84%) as a white crystalline solid. 1H NMR (CDCl3) δ 18.10 (s, 1H, OH), 7.30 (s, 5H, 5Ar—H), 5.06 (s, 2H, CH2Ar), 3.00 (t, 2H, CH2), 2.47 (s, 2H, Dde CH2), 2.35 (t, 2H, CH2CO2), 2.29 (s, 2H, Dde CH2), 1.65 (m, 4H, 2 CH2), 1.01 (s, 6H, 2 CH3); FAB MS C21H26O5 (358.18) m/z (%) 359 [M+H]+ (100), 267 (40); HRMS (FAB) Found: m/z 359.1858 Calcd for C21H27O5: (M+H), 359.1850.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:19]([O:30][CH2:31][CH2:32][OH:33])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:36][C:37]1[CH:38]=[N:39][C:40](Cl)=[N:41][CH:42]=1.[Cl-].[NH4+]>CC(N(C)C)=O>[Br:36][C:37]1[CH:38]=[N:39][C:40]([O:33][CH2:32][CH2:31][O:30][C:19]2[N:18]=[CH:17][N:16]=[C:15]([NH:14][S:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=3)(=[O:12])=[O:13])[C:20]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[N:41][CH:42]=1
Reactant: Clc1ncc(Br)cn1
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCO)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(Br)cn2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 84.1 %

Procedure:
To a solution of 4-tert-butyl-N-{6-(2-hydroxyethoxy)-5-(3-methoxyphenoxy)pyrimidin-4-yl}benzenesulfonamide (250 mg) in dimethylacetamide (5 ml) is added sodium hydride (60% dispersion-type, 64 mg) at room temperature, and the mixture is stirred for 20 minutes. To the reaction solution is added 5-bromo-2-chloropyrimidine (133 mg), and the mixture is stirred at room temperature for 18 hours. The reaction solution is poured into ice-water, and the mixture is neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol=40:1) to give crude crystals, which are recrystallized from ethyl acetate/diisopropyl ether to give N-[-6-{2-(5-bromopyrimidin-2-yloxy)ethoxy}-5-(3-methoxyphenoxy)pyrimidin-4-yl]-4-tert-butylbenzenesulfonamide (280 mg) as crystals.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3]1.C(N(CC)CC)C.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[S:2]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:3]1
Reactant: NCCc1ccsc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCc1ccsc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
2-(Thiophen-3-yl)ethanamine hydrochloride (3 g, 18 mmol) was taken in THF (40 mL) and treated with triethylamine (9.92 mL, 71.2 mmol). The reaction was cooled down to 0° C. and benzoyl chloride (2.55 mL, 21.9 mmol), diluted with THF was added dropwise to the reaction. The reaction was stirred for 3 h and the volatiles removed in vacuo. The residue was dissolved in ethyl acetate and washed with an aqueous saturated solution of sodium bicarbonate, water and brine. The organic solution was dried with sodium sulfate and purified by flash chromatography using a gradient of 25 to 70% ethyl acetate in hexanes to afford an off-white solid (4 g). MS (M+H)+ 232.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.C[CH:15]1[C:24]2[C:19](=[C:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:15]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c(-c3ccccn3)cccc21
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2c(cccc2-c2ccccn2)C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-5-pyridin-2-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [N+](=CC([O-])=O)=[N-].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:16][C@H:15]2[C:17]([O:19]CC)=[O:18])=[CH:10][CH:9]=1.BrC1C=CC(C=C)=CC=1.[Li+].[OH-]>>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C@@H:14]2[CH2:16][C@H:15]2[C:17]([OH:19])=[O:18])=[CH:12][CH:13]=1
Reactant: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(Br)cc1
Agent: C=Cc1ccc(Br)cc1
Agent: [Li+]
Agent: [N-]=[N+]=CC(=O)[O-]
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(Br)cc1

Procedure:
Another alternative is an enantioselective cyclopropanation using for example a bis-oxazoline chiral ligand/copper complex and diazoacetate (Evans et al. J. Am. Chem. Soc. 1991, 113, 726) to prepare optically active ethyl 2-(cis)-(4-bromophenyl)cyclopropanecarboxylate from 4-bromostyrene. Selective hydrolysis of the mixture of cis and trans isomer with LiOH (1 eq based on trans isomer) gave 2-(trans)-(4-bromophenyl)cyclopropanecarboxylic acid (used in EXAMPLE 1) and the desired ethyl 2-(cis)-(4-bromophenyl)cyclopropanecarboxylate.
Reaction SMILES: [CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=O)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O.NN>[CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:11][C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccccc21
Agent: NN
Solvent: O
Product: O=C1Cc2ccccc2N1Cc1ccccc1
Temperature: 125 °C
Yield: 78.2 %

Procedure:
N-benzylisatin (13.0 g, 55 mmol) was mixed with hydrazine hydrate (60 mL) and placed in an oil bath. The mixture was heated in stages to 125° C., becoming first a green sludge, then yellow with clumps of a sticky solid. After a total of 5 h at 125° C., the mixture was cooled and extracted with EtOAc (2×100 mL). The combined organic portions were washed twice with 1.0 M aq. H2SO4, and once each with half-saturated brine then brine, dried over MgSO4, filtered and concentrated to afford a pale yellow solid. Re— precipitation from ether/pentane gave the title compound as an off-white solid (9.6 g, 75%). Spectral data matches literature values (C. Martin and E. M. Carreira, J. Am. Chem. Soc., 2005, 127, 11505-11515).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:5](=O)[C:4]([CH3:8])([CH3:7])[S:3]1.Cl.[NH2:11]O.C([O-])(=O)C.[Na+].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1([CH3:9])[CH:5]([NH2:11])[C:4]([CH3:8])([CH3:7])[S:3]1
Reactant: CC1(C)SC(C)(C)C1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Al+3]
Solvent: C1CCOC1
Product: CC1(C)SC(C)(C)C1N
Temperature: 25 °C

Procedure:
The 2,2,4,4-tetramethylthietan-3-one of Example 9, Step 1a, was converted to the corresponding oxime using hydroxylamine hydrochloride and sodium acetate by the procedure described in Example 12B of U.S. Pat. No. 4,411,925. The oxime (12.0 g., 0.045 moles) in 50 ml. of THF was added dropwise to a stirred suspension of LiAlH4 (6 g., 0.15 moles) in 50 ml. of THF at 0° C. After addition of the oxime was completed, the reaction mixture was allowed to warm to room temperature and was then refluxed for 1.5 hours. The reaction was carefully quenched by dropwise addition of 6 ml. of H2O, 6 ml. of 15% NaOH and 18 ml. of H2O. The quenched solution was filtered and the filtrate evaporated to give 8 g. of crude amine. The crude amine was purified by silica gel chromatography with 5% methanol/chloroform as the eluting solvent. Yield: 3.8 l g.
Reaction SMILES: C(Br)(Br)(Br)[Br:2].[C:6]1([C:12]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21]O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:6]1([C:12]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH:20]([Br:2])[CH3:21])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCOCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(Br)OCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of carbon tetrabromide (8.3 g, 25 mmol) and 10 g of 2-[2-(2-triphenylmethoxyethoxy)ethoxy]ethanol are stirred together in 75 mL dichloromethane at 0° C. To this solution is added a solution of 6.7 g triphenylphosphine (25 mmol) in 75 mL dichloromethane dropwise over 1½ hours at 0° C. After stirring for an additional 2 hours, the solution is evaporated to dryness and the residual solids are resuspended in 150 mL diethyl ether. The triphenylphosphine by-product is removed via vacuum filtration and the product is then purified via column chromatography over silica gel, eluting with dichloromethane.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O>CC(OC(C)=O)=O>[O:12]1[C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1=[O:10]
Reactant: O=C(O)CCCCCCC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CCCCCCC(=O)O1

Procedure:
Under N2 atmosphere 50 g suberic acid and 100 ml acetanhydride were refluxed for 2 hours. The solvent was evaporated and 200 ml acetonitrile were added to the residue and the mixture was kept in a freezer over night. Then the mixture was fritted and the resulting residue was washed with 50 ml acetonitrile and dried.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:38][O:39][C:40](=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45](Cl)=[CH:44][C:43]=1[F:49].[CH2:51]([C:53]([C:75]1[CH:80]=[CH:79][C:78](B2OC(C)(C)C(C)(C)O2)=[C:77]([CH3:90])[CH:76]=1)([C:56]1[CH:61]=[CH:60][C:59]([C:62]#[C:63][C:64]2([O:69][Si:70]([CH3:73])([CH3:72])[CH3:71])[CH2:68][CH2:67][CH2:66][CH2:65]2)=[C:58]([CH3:74])[CH:57]=1)[CH2:54][CH3:55])[CH3:52]>O.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:38][O:39][C:40](=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:78]2[CH:79]=[CH:80][C:75]([C:53]([CH2:54][CH3:55])([C:56]3[CH:61]=[CH:60][C:59]([C:62]#[C:63][C:64]4([O:69][Si:70]([CH3:72])([CH3:73])[CH3:71])[CH2:68][CH2:67][CH2:66][CH2:65]4)=[C:58]([CH3:74])[CH:57]=3)[CH2:51][CH3:52])=[CH:76][C:77]=2[CH3:90])=[CH:44][C:43]=1[F:49]
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1ccc(Cl)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
A solution of palladium acetate (3.4 mg, 0.015 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (12.3 mg, 0.03 mmol) and potassium phosphate (63.7 mg, 0.3 mmol) in water (0.045 mL) and toluene (0.200 mL) was stirred for three minutes. A solution of (4-chloro-2-fluoro-phenyl)acetic acid methyl ester (Example 40; 32.6 mg, 0.16 mmol) and 2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclopentylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 32-(4); 60.0 mg, 0.10 mmol) in toluene (0.25 mL) was added, and the mixture was stirred in a nitrogen atmosphere at 100° C. for one hour. After filtration through cotton plug, the filtrate was concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (3% ethyl acetate/hexane) to give the title compound (52.6 mg, 81%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].CC(O)=O.C1C(=O)N([Br:20])C(=O)C1.O>C(Cl)(Cl)Cl>[Br:20][C:5]1[S:1][C:2]([CH2:6][CH2:7][OH:8])=[CH:3][CH:4]=1
Reactant: OCCc1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: OCCc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(thiophen-2-yl)ethanol (3 g, 23.4 mmol, 1 eq) and HOAc (5 mL) in CHCl3 was added NBS in portions at room temperature. After stirring at room temperature overnight, the reaction mixture was poured into water and extracted with CHCl3 twice. The combined organic layer was dried over Na2SO4, concentrated and purified by column chromatography to give the desired product.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22](C(F)(F)F)[CH:21]=3)[N:17]=[C:16]([C:30]#[N:31])[N:15]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH:32](N(C(C)C)CC)([CH3:34])[CH3:33].BrC(C)C.[I-].[Na+]>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:32]([N:11]1[CH2:10][CH2:9][N:8]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:2]([F:7])([F:6])[F:1])[N:17]=[C:16]([C:30]#[N:31])[N:15]=2)[CH2:13][CH2:12]1)([CH3:34])[CH3:33]
Reactant: CCN(C(C)C)C(C)C
Reactant: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc(N2CCNCC2)n1
Agent: [I-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CC(C)Br
Product: CC(C)N1CCN(c2cc(-c3ccccc3C(F)(F)F)nc(C#N)n2)CC1
Temperature: 150 °C

Procedure:
To a solution of 4-(piperazin-1-yl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile trifluoroacetic acid salt (Example 1; 50 mg) in acetonitrile (1 ml) was added diisopropylethylamine (39 μl) and 2-bromopropane (15.5 μl). The resulting solution was subjected to microwave heating at 150° C. for 5 mins. Sodium iodide (2 mg) was added and the reaction mixture was subjected to further heating at 180° C. for 30 mins. Reaction mixture was concentrated in vacuo and the residue was dissolved in methanol and purified using the prep-HPLC to give 4-(4-isopropyl-piperazin-1-yl)-6-(trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile trifluoroacetic acid salt (10 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5](OC)=[CH:4][C:3]=1[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:12](=[O:16])[CH:13]([CH3:15])[CH3:14].CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:11]2[C:3]3[C:2](=[CH:7][C:6]([CH3:8])=[CH:5][CH:4]=3)[C:13]([CH3:14])([CH3:15])[C:12]2=[O:16])=[CH:19][CH:20]=1
Reactant: COc1ccc(CN(C(=O)C(C)C)c2cc(OC)c(C)cc2Br)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN2C(=O)C(C)(C)c3cc(C)ccc32)cc1
Temperature: 25 °C
Yield: 77 %

Procedure:
To a solution of N-(2-bromo-5-methoxy-4-methyl-phenyl)-N-(4-methoxy-benzyl)-isobutyramide (8.72 g, 21.4 mmol) in dry 1,4-dioxane (80 mL) was added sodium tert-butoxide (3.09 g, 32.1 mmol). Argon was bubbled through for about 15 minutes before adding palladium(II) acetate (241 mg, 1.07 mmol) and tricyclohexylphosphine (300 mg, 1.07 mmol). The mixture was heated to reflux for 16 hours. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc, washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (hexane: EtOAc/5:1 to 3:1) to give 5.4 g of 6-Methoxy-1-(4-methoxy-benzyl-3,3,5-trimethyl-1,3-dihydro-indol-2-one (77%). 1H NMR (300 MHz, CDCl3, ppm): δ: 1.38 (s, 6 H), 2.16(s, 3 H), 3.71(s, 3 H), 3.77 (s, 3 H), 4.84 (s, 2 H), 6.28 (s, 1 H), 6.82–6.85(m, 2 H), 6.95(s, 1 H), 7.19–7.22 (m, 2 H).
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:8]=[C:9]([C:22]2[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[N:23]=2)[C:10]([NH:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[N:11][CH:12]=1)([CH3:6])[CH3:5])=[N+]=[N-]>[Pd]>[NH2:1][C:4]([C:7]1[CH:8]=[C:9]([C:22]2[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([N:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[N:23]=2)[C:10]([NH:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[N:11][CH:12]=1)([CH3:5])[CH3:6]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C)N=[N+]=[N-])cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: [Pd]
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C)N)cnc3Nc3ccc(OC)nc3)n2)cc1
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
4-(5-(2-Azidopropan-2-yl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.184 g, 0.291 mmol) and 10% palladium on carbon (0.186 g, 0.174 mmol) were combined in a flask and flushed with nitrogen. THF (5 mL) was added and the reaction was stirred under a H2 atmosphere for 1.5 h. The reaction was filtered through Celite® (diatomaceous earth) rinsing with DCM, and the filtrate was concentrated in vacuo to give 4-(5-(2-aminopropan-2-yl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.176 g, 0.290 mmol, 100% yield). m/z (ESI, +ve ion) 607 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.55 (s, 1H); 8.92 (d, J=2.7 Hz, 1H); 8.48 (d, J=2.5 Hz, 1H); 8.23 (d, J=2.5 Hz, 2H); 7.91 (dd, J=8.8, 2.7 Hz, 1H); 7.15-7.25 (m, 4H); 6.78-6.95 (m, 4H); 6.69 (d, J=8.8 Hz, 1H); 4.89 (s, 2H); 4.81 (s, 2H); 3.92 (s, 3H); 3.81 (s, 3H); 3.77 (s, 3H); 2.58 (s, 3H); 1.53 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:4][N:5]([C:7]2[N:28]=[CH:27][CH:26]=[CH:25][C:8]=2[C:9]([NH:11][CH:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]([OH:17])[C:14](O)=[O:15])=[O:10])[CH:6]=1.Cl.[CH3:36][O:37][NH2:38]>>[OH:17][CH:13]([C:14]([NH:38][O:37][CH3:36])=[O:15])[CH:12]([NH:11][C:9](=[O:10])[C:8]1[CH:25]=[CH:26][CH:27]=[N:28][C:7]=1[N:5]1[CH:6]=[C:2]([CH3:1])[C:3]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[N:4]1)[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cn(-c2ncccc2C(=O)NC(Cc2ccccc2)C(O)C(=O)O)nc1-c1ccccc1
Reactant: CON
Agent: Cl
Product: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc(C)c(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 3-(2-(4-methyl-3-phenyl-1H-pyrazol-1-yl)nicotinamido)-2-hydroxy-4-phenylbutanoic acid with O-methylhydroxylamine hydrochloride. ESI-MS [M+H]+: 486.2
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:18][CH2:19][O:20][CH3:21])[N:14]([CH2:15][CH2:16][CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:22][CH:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[CH:5][C:4]=2[N:3]=1.Cl>C(O)C>[CH3:21][O:20][CH2:19][CH2:18][C:13]1[N:14]([CH2:15][CH2:16][CH3:17])[C:10]2[C:9]3[CH:8]=[CH:7][C:6]([O:22][CH:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1
Reactant: CCCn1c(CCOC)nc2c(N)nc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c21
Agent: Cl
Solvent: CCO
Product: CCCn1c(CCOC)nc2c(N)nc3cc(OC4CCNCC4)ccc3c21
Yield: 101.7 %

Procedure:
tert-Butyl 4-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate (prepared as described in Example 387, 2.11 g, 4.36 mmol) was treated with concentrated hydrochloric acid (3 mL). After vigorous bubbling, a solution formed. The solution was diluted with ethanol (50 mL) and evaporated (3×). The resulting oil was dissolved in brine (15 mL) and water (5 mL) and made basic with 50% aqueous sodium hydroxide (approximately 1.5 mL). The aqueous layer was extracted with dichloromethane (3×). The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 1.7 g of 2-(2-methoxyethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-ylamine as a white solid.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:35])=[C:13]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=4[CH3:31])=[CH:19][C:18]=3[N+:32]([O-:34])=[O:33])=[O:16])[CH:14]=2)[CH2:4][O:3]1.Cl>C1COCC1>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:35])=[C:13]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])=[CH:19][C:18]=2[N+:32]([O-:34])=[O:33])=[O:16])[CH:14]=1
Reactant: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc(OCC3COC(C)(C)O3)ccc2C)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1Nc1ccc(C(=O)c2cc(OCC(O)CO)ccc2C)c([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
Compound 301 (0.025, 0.05 mmol) was dissolved in THF (2 mL) and 1 M HCl (0.2 mL) was added. The solution was kept at room temperature for 3 h after which the solution was concentrated in vacuo. This afforded the title compound. 1H NMR (CDCl3) δ 7.36 (d, 1H), 7.22 (dd, 1H), 7.18 (d, 1H), 7.10 (d, 1H), 7.06-6.88 (m, 3H), 6.87-6.77 (m, 2H), 5.89 (bs, 1H), 4.05 (m, 1H), 3.95 (m, 2H), 3.85-3.65 (m, 2H), 2.46 (s, 3H), 2.25 (s, 3H)