Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[C:21]1[N:26]2[CH:27]=[CH:28][N:29]=[C:25]2[C:24]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)=[N:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:50][N:51](C)[CH:52]=O>O1CCOCC1.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>[CH3:50][N:51]([CH3:52])[C:2]1[CH:10]=[C:9]([C:21]2[N:26]3[CH:27]=[CH:28][N:29]=[C:25]3[C:24]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)=[CH:33][CH:32]=3)=[N:23][CH:22]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CN(C)C=O
Reactant: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Reactant: CC1(C)OB(c2ccc(C(N)=O)c(F)c2)OC1(C)C
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: C1COCCO1
Product: CN1CCN(c2ccc(Nc3ncc(-c4ccc(C(N)=O)c(N(C)C)c4)n4ccnc34)cc2)CC1

Procedure:
In the same way as described for Compound 127, step 4, using 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (148 mg, 0.414 mmol), (5-bromoimidazo[1,2-a]pyrazin-8-yl)-(4-(4-methylpiperazin-1-yl)phenyl)amine (80 mg, 0.279 mol) and Pd(PPh3)4 (81 mg, 0.069 mmol) and 1.5M Na2CO3 (1.49 mL), in dioxane (0.93 mL) and N,N-dimethylformamide (2.06 mL). The residue is chromatographed on silica gel, eluting with DCM followed by 96:4 DCM:NH3 (7M in MeOH). The compound, isolated after additional purification by reverse phase prep HPLC is 2-dimethylamino-4-{8-[4-(4-methyl-piperazin-1-yl)-phenylamino]-imidazo[1,2-a]pyrazin-5-yl}-benzamide (3.2 mg). LCMS: Rt 1.67 min (97%) m/z (APCI) 471 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.26 (3H, s), 2.48-2.53 (4H, m), 2.85 (6H, s), 3.12-3.14 (4H, m), 6.96 (2H, d), 7.32 (1H, d), 7.36 (1H, d), 7.52 (1H, s), 7.54 (1H, br s), 7.71 (1H, s), 7.74 (1H, d), 7.91 (2H, d), 8.02 (1H, s), 8.28 (1H, br s), 9.48 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].C(OCC)(=O)C>CN(C=O)C.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1cnc2[nH]cc(I)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
5-Bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (7 g, 21.6 mmol) dissolved in dry DMF (50 ml) was added drop wise to a stirred slurry of sodium hydride (1.73 g, 43.2 mmol) in dry DMF (20 ml) at 0° C. and stirred for 30 min. Tosyl chloride (6.15 g, 32.4 mmol) dissolved in dry DMF (14 ml) and added slowly to the above reaction mixture and the reaction temperature was brought to RT and stirred for 30 min. The reaction was monitored by TLC (15% Ethyl acetate in hexane). The reaction mixture was quenched with ice water (500 ml) at 0° C. and filtered the solid precipitated and dried under vacuum to afford 9.92 g (96.3% yield) of 5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine MS: m/z=476.8 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:9])([CH2:7]O)[CH2:5][OH:6].[CH3:10][O:11][CH2:12][CH:13]=[O:14].C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O>[CH3:10][O:11][CH2:12][CH:13]1[O:6][CH2:5][C:4]([CH2:3][O:2][CH3:1])([CH3:9])[CH2:7][O:14]1
Reactant: COCC=O
Reactant: COCC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: COCC1OCC(C)(COC)CO1
Yield: 91 %

Procedure:
A mixture of 670 g (5 moles) of 2-methoxymethyl2-methyl-1,3-propanediol, 479 g (5.5 moles) of 85% strength methoxyacetaldehyde and 250 ml of chloroform was heated with 10 g of pyridinium p-toluenesulfonate under a water separator until water no longer separated off. The solution was deionized using a mixed-bed ion exchanger, the solvent was stripped off under reduced pressure and the residue was subjected to fractional distillation under reduced pressure. 864 g (91% yield) of 2,5-dimethoxymethyl-5-methyl-1,3-dioxane of boiling point 95° C./10 mbar were obtained.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8])[CH3:2].C(O)(=O)C.[N:13]#[C:14][NH2:15].C([O-])(=O)C>>[CH3:8][O:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:14]([NH2:15])=[NH:13]
Reactant: CCNCCCOC
Reactant: N#CN
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCN(CCCOC)C(=N)N
Temperature: 90 °C
Yield: 50 %

Procedure:
3.00 g (25.6 mmol) of N-ethyl-3-methoxypropylamine and 1.54 g (25.6 mmol) of acetic acid were placed in a 50 ml two neck flask. While heating the flask in a 90° C. oil bath, 1.08 g (25.6 mmol) of cyanamide was added. After 12 hours of the reaction, the product was purified by a silica gel column chromatography (eluent, chloroform/ethanol=1/2 containing 0.5% acetic acid) to obtain 2.80 g of the title compound (wax-like, 12.8 mmol, 50.0% in yield) in the form of acetate. Results of the analysis of this compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:12])[C:9]([OH:11])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1.[NH2:36][C:37]1[O:41][N:40]=[C:39]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[C:38]=1[C:49]1[CH:54]=[CH:53][N:52]=[CH:51][N:50]=1>C1COCC1>[F:48][C:45]1[CH:46]=[CH:47][C:42]([C:39]2[C:38]([C:49]3[CH:54]=[CH:53][N:52]=[CH:51][N:50]=3)=[C:37]([NH:36][C:9](=[O:11])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:12])[O:41][N:40]=2)=[CH:43][CH:44]=1
Reactant: Nc1onc(-c2ccc(F)cc2)c1-c1ccncn1
Reactant: CC(C(=O)O)c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C(=O)Nc1onc(-c2ccc(F)cc2)c1-c1ccncn1)c1ccccc1Cl
Temperature: 25 °C
Yield: 71.5 %

Procedure:
In 5 mL of THF, 0.144 g of 2-(2-chlorophenyl)propionic acid and 0.126 g of CDI were dissolved and stirred at room temperature for an hour. Then 5 mL of THF solution containing 0.237 g of DBU and 0.1 g of 5-amino-3 (4-fluorophenyl)-4-4-pyrimidinyl isoxazole was added and stirred at room temperature for 3 hours. The solvent was distilled off from the reaction solution under reduced pressure, and water was added to the residue which was then extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous magnesium sulfate, removed of the solvent by distillation under reduced pressure, and the residue was purified on 20 g silica gel chromatography (eluent, chloroform:methanol=50:1). Washing the residue with ether, 0.118 g (yield: 72%) of the title compound was obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C:23](=[O:29])[CH2:22]2>O1CCCC1.O>[C:17]([O:16][C:13](=[O:15])[CH2:14][C:23]1([OH:29])[CH:24]2[CH2:27][CH2:28][N:21]([CH2:26][CH2:25]2)[CH2:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: O=C1CN2CCC1CC2
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1(O)CN2CCC1CC2
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of diisopropylamine (6.7 mL) in tetrahydrofuran (THF) (20 mL) at 0° C. was added n-butyllithium (2.3M in hexanes; 20 mL). The reaction mixture was stirred for 40 minutes and then cooled to −78° C. To this mixture a solution of t-butyl acetate (6.4 mL) in THF (10 mL) was added dropwise and stirring was continued for an additional 15 minutes. Quinuclidin-3-one (5 g) in THF (15 mL) was added to the mixture dropwise and the mixture was allowed to warm to 0° C. over 1 hour. To this solution water (100 mL) was added, the solution was extracted twice with chloroform and the combined extracts were washed once with brine. The resulting solution was dried over MgSO4, filtered, and evaporated in vacuo to give 9.53 g of the subtitle compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH2:46])[O:45][C:41]=2[C:40]([CH:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:39][CH:38]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:46][C:44]2[O:45][C:41]3[C:40]([CH:47]4[CH2:48][CH2:49][O:50][CH2:51][CH2:52]4)=[CH:39][CH:38]=[C:37]([O:36][CH3:35])[C:42]=3[N:43]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: COc1ccc(C2CCOCC2)c2oc(N)nc12
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(C2CCOCC2)c2oc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
From 4-fluorobenzoic acid, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 371 (M+H+, 100).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]1[CH:13]=[C:12]([CH3:14])[N:11]([CH:15]([C:17]2[C:18]3[CH2:41][NH:40][CH2:39][CH2:38][C:19]=3[N:20]=[C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]4)=[C:26]([O:36][CH3:37])[CH:25]=3)[N:22]=2)[CH3:16])[N:10]=1>C(Cl)Cl>[CH3:8][C:9]1[CH:13]=[C:12]([CH3:14])[N:11]([CH:15]([C:17]2[C:18]3[CH2:41][N:40]([C:1](=[O:3])[CH3:2])[CH2:39][CH2:38][C:19]=3[N:20]=[C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]4)=[C:26]([O:36][CH3:37])[CH:25]=3)[N:22]=2)[CH3:16])[N:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(Nc2nc3c(c(C(C)n4nc(C)cc4C)n2)CNCC3)ccc1-n1cnc(C)c1
Solvent: ClCCl
Product: COc1cc(Nc2nc3c(c(C(C)n4nc(C)cc4C)n2)CN(C(C)=O)CC3)ccc1-n1cnc(C)c1
Reaction time: 1 h
Yield: 16.03 %

Procedure:
Acetic anhydride (0.016 mL, 0.17 mmol) was added to a solution of 4-(1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine in DCM (1 mL) and stirred for one hour. The solvent was evaporated and the crude product was purified on prepHPLC yielding 1-(4-(1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (14.00 mg, 16.03%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C@@H:6]([O:13][C:14]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[C:46]([OH:51])(=[O:50])[C:47]([OH:49])=[O:48]>O1CCCC1.C(O)C>[C:46]([OH:51])(=[O:50])[C:47]([OH:49])=[O:48].[NH2:1][CH2:4][CH2:5][C@@H:6]([O:13][C:14]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1O[C@H](CCN=[N+]=[N-])c1ccccc1
Agent: O=C(O)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(C(F)(F)F)cc1O[C@H](CCN)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
A solution of 2-[[(1R)-3-azido-1-phenylpropyl]oxy]-4-(trifluoromethyl)benzonitrile (7.70 mg, 2.2 mmol) in tetrahydrofuran (50 ml) was treated with triphenylphosphine (1.5 eq.) and water (0.5 ml). The mixture was stirred at ambient temperature for 24 h then concentrated to an oil. The crude amine was purified on silica gel eluting with ethyl acetate, then 10% 7N ammonia in methanol/dichloromethane. The oil obtained was converted into an oxalate salt using 1 equivalent of oxalic acid in ethanol to afford the title compound as a colourless solid (510 mg, 56%).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].Br[C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:31]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:25]4[C:20]3=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:9]=2[CH:8]=1.[S:32](Cl)(Cl)=[O:33].O>C1COCC1>[CH:1]1[C:31]2[C:10]3([C:9]4[CH:8]=[CH:7][CH:19]=[CH:18][C:17]=4[C:16]4[C:11]3=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]=2[CH:4]=[CH:3][C:2]=1[S:32]([C:7]1[CH:8]=[CH:9][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:31]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:25]4[C:20]3=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:18]=2[CH:19]=1)=[O:33]
Reactant: Brc1ccc2c(c1)C1(c3ccccc3-c3ccccc31)c1ccccc1-2
Reactant: O=S(Cl)Cl
Reactant: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=S(c1ccc2c(c1)C1(c3ccccc3-c3ccccc31)c1ccccc1-2)c1ccc2c(c1)C1(c3ccccc3-c3ccccc31)c1ccccc1-2
Temperature: -78 °C
Reaction time: 3 h

Procedure:
110 ml (275 mmol) of an n-butyllithium solution (2.5 M in hexane) were added dropwise to a suspension, cooled to −78° C., of 98.8 g (250 mmol) of 2-bromo-9,9′-spirobifluorene in 1500 ml of THF at such a rate that the temperature did not rise above −65° C. The reaction mixture was stirred at −78° C. for 3 h and then admixed dropwise with a mixture of 7.2 ml (125 mmol) of thionyl chloride and 300 ml of THF, and subsequently stirred at −78° C. for a further 3 h. After the reaction mixture had been warmed to room temperature, the reaction mixture was admixed with 25 ml of water and concentrated to dryness under reduced pressure. The residue was taken up in 1000 ml of dioxane and 500 ml of water, and the organic phase was removed, washed once more with 500 ml of water and subsequently dried over magnesium sulfate. Subsequently, the solid which remained after concentration of the organic phase was recrystallized five times from dioxane (1 g/ml) and then sublimed under high vacuum (T=370° C., p=5×10−5 mbar). The yield at a purity of >99.9% by HPLC was 114.0 g (168 mmol), corresponding to 67.2% of theory.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]2[O:9][C:8](C(O)=O)=[CH:7][C:6]=2[CH:13]=1.[B-](F)(F)(F)[F:16].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(=O)(O)[O-].[Na+]>O.CC(=O)OCC>[Br:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]2[O:9][C:8]([F:16])=[CH:7][C:6]=2[CH:13]=1
Reactant: Cc1cc2oc(C(=O)O)cc2cc1Br
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc2oc(F)cc2cc1Br
Yield: 36.1 %

Procedure:
A mixture of 5-bromo-6-methyl-benzofuran-2-carboxylic acid (229, 243 mg, 0.95 mmol), Selectfluor (481 mg, 1.36 mmol) and sodium bicarbonate (228 mg, 2.72 mmol) in 3 ml water and 3 ml EA was stirred vigorously at r.t. for 60 h before addition of another 240 mg of Selectfluor. After further 20 h the reaction mixture was diluted with EA, washed twice with 1N NaOH. Org phase was washed with brine, dried over sodium sulfate, concentrated to dryness to give 78.5 mg of title compound as light brown wax (yield: 36.1%, purity>95%).
Reaction SMILES: [H][H].[OH:3][C:4]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)S(=O)=O.O>[CH2:15]([O:12][C:11]1[C:4]([OH:3])=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: O=Cc1cccc(O)c1O
Reactant: BrCc1ccccc1
Agent: CN(C)[SH](=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=Cc1cccc(OCc2ccccc2)c1O
Reaction time: 24 h

Procedure:
Scheme V depicts a method of preparing aldehyde 13. For example, an aldehyde of formula 11 wherein R3, R4 and R5 are hydrogen, i.e., 2,3-dihydroxybenzaldehyde (0.6 g, 4.3 mmol) was added to dimethyl sulfonamide (DMSO) (10 ml) containing sodium hydride (0.25 g, 10.4 mmol). After one hour a solution of benzyl bromide (0.52 ml, 4.3 mmol) in DMSO (5 ml) is added. Stirring the mixture is continued for 24 h, after which time the mixture is poured into water and extracted with chloroform (2×). The aqueous solution then was acidified with 6N hydrochloric acid to adjust the pH from 2 to about 4 and extracted with chloroform (3×). The latter organic layers were washed with 1N hydrochloric acid and filtered over silica gel to give 3-benzyloxy-2-hydroxy benzaldehyde.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][O:12][C:11]3[CH:20]=[CH:21][C:22]([C:24]([O:26]CC)=[O:25])=[CH:23][C:10]2=3)[CH:2]=1.CO.[OH-].[Na+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH2:13][O:12][C:11]3[CH:20]=[CH:21][C:22]([C:24]([OH:26])=[O:25])=[CH:23][C:10]2=3)[CH:2]=1
Reactant: CCOC(=O)c1ccc2c(c1)C(NCc1cccnc1)c1ccccc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)C(NCc1cccnc1)c1ccccc1CO2

Procedure:
Compound 9a, 3.9 g, obtained in Example 1 was heated to reflux for an hour in a solvent mixture of 200 ml of methanol, 50 ml of water and 10 ml of 10 N sodium hydroxide aqueous solution. The solvent was distilled off under reduced pressure and 4 N hydrochloric acid aqueous solution was added to the residue to adjust pH to 7. After concentrating under reduced pressure, the residue was subjected to high porous polymer (HP-10; manufactured by Mitsubishi Chemical Industry Co., Ltd.) column chromatography (eluting solvent; methanol) to give 2.5 g of the crude product. The crude product was recrystallized from water to give 2.0 g of the desired product.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:4]=1.[O:25]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]1>>[CH3:24][O:23][C:13]1[CH:12]=[C:11]([NH:10][C:5]2[N:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:31][CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[N:4]=2)[CH:16]=[CH:15][C:14]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: OC1CCOCC1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Agent: [Na]
Product: COc1cc(Nc2nc(C)cc(OC3CCOCC3)n2)ccc1-n1cnc(C)c1
Temperature: 100 °C
Yield: 11 %

Procedure:
Sodium (10 mg, 0.45 mmol) was dissolved under stirring and heating (100° C. for 3 hours) under an atmosphere of nitrogen in tetrahydro-4H-pyran-4-ol (0.99 mL). (4-Chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (99 mg, 0.3 mmol) was added and the suspension was heated to 100° C. for 2 hours. The solvent was evaporated under reduced pressure and the residue was taken up in water and extracted twice with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to dryness. The residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound as a white solid (13 mg, 11%). MS ISP (m/e): 396.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.65 (s, 1H), 7.62 (s, 1H), 7.17 (d, 1H), 7.15 (s, 1H), 7.13 (d, 1H), 6.87 (s, 1H), 6.12 (s, 1H), 5.30 (m, 1H), 3.98 (m, 2H), 3.86 (s, 3H), 3.62 (m, 2H), 2.36 (s, 3H), 2.31 (s, 3H), 2.04 (m, 2H), 1.84 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[S:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29]>CC(C)=O>[CH3:29][C:28]([CH3:30])=[CH:27][CH2:26][O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[S:10][CH:11]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=CCBr
Reactant: CCOC(=O)c1csc(Nc2cccc(O)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(Nc2cccc(OCC=C(C)C)c2)n1
Yield: 55 %

Procedure:
Following the general procedure for O-alkylation, Method A, a mixture of ethyl 2-(3-hydroxyphenylamino)thiazole-4-carboxylate (182 mg, 0.69 mmol) and K2CO3 (105 mg, 0.76 mmol) in acetone (6.9 mL) was treated with 4-bromo-2-methyl-2-butene (0.096 mL, 0.83 mmol). The reaction mixture was heated at reflux for 4 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 55% yield (127 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[N:16]([CH2:19][CH2:20][CH3:21])[N:15]=[N:14]1.[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:22][CH2:8][C:6]1[C:5]([O:9][CH:10]([CH3:11])[CH3:12])=[CH:4][C:3]([N:13]2[C:17](=[O:18])[N:16]([CH2:19][CH2:20][CH3:21])[N:15]=[N:14]2)=[C:2]([Cl:1])[CH:7]=1
Reactant: CCCn1nnn(-c2cc(OC(C)C)c(C)cc2Cl)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCn1nnn(-c2cc(OC(C)C)c(CBr)cc2Cl)c1=O
Temperature: 25 °C
Yield: 49.5 %

Procedure:
Under a dry nitrogen atmosphere, a stirred solution of 4.4 g (0.014 mole) of 1-(2-chloro-4-methyl-5-isopropoxyphenyl)-1,4-dihydro-4-propyl-5H-tetrazol-5-one (compound 91), 2.5 g (0.014 mole) of N-bromosuccinimide, and 0.06 g (0.00025 mole) of benzoyl peroxide in 80 mL of carbon tetrachloride was heated at reflux temperature for two days. The reaction mixture was allowed to cool to room temperature, filtered, and the filtrate washed with a saturated aqueous sodium chloride solution. The washed filtrate was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to leave an oil. The oil was crystallized from petroleum ether to yield 2.7 g of 1-(4-bromomethyl-2-chloro-5-isopropoxyphenyl)-1,4-dihydro-4-propyl-5H-tetrazol-5-one, mp 68°-70° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.[C:20]12([NH:30]CCCN)[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2.[NH2:35][C:36]12CC3CC(C[CH:38](C3)[CH2:37]1)C2.ClC1C=C2C(C(NC34CC5CC(CC(C5)C3)C4)=CC=N2)=CC=1.[OH-].[K+]>CO>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([CH:2]=[C:3]([NH:30][C:20]34[CH2:27][CH:26]5[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]5)[CH2:21]3)[CH2:29]4)[C:4]([CH2:38][CH2:37][CH2:36][NH2:35])=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: NCCCNC12CC3CC(CC(C3)C1)C2
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: Clc1ccc2c(NC34CC5CC(CC(C5)C3)C4)ccnc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Oc1ccccc1
Product: NCCCc1nc2cc(Cl)ccc2cc1NC12CC3CC(CC(C3)C1)C2
Yield: 6 %

Procedure:
4.7-dichloroquinoline (0.29 g), 1 g of phenol and 0.6 g of impure (containing 1-aminoadamantane) 3-adamantylaminopropylamine were heated at 120° C. for 3 hours. By g.c-m.s. analysis it was found that the mixture contained besides the aimed—at product, 1-aminoadamantane, some 4.7-dichloroquinoline and a product which is by its mass spectrum 7-chloro-4-adamantylaminoquinoline (M+=312.5). The mixture was dissolved in several ml of methanol, poured into 50 ml of 10% KOH and extracted with t-butyl methyl ether (2×50 ml). The combined extracts were brought to dryness, the residue dissolved in a mixture of N(C2H5)3, little (CH3)3COCH3 and some methanol, transferred to a column (5 cm. diameter, Kieselgel, wetted with N(C2H5)3: (CH3)3OCH3: CH3OH=125:75:5 (by volume) and eluted with 205 ml of this solvent. The solvent was changed to N(C2H5)3: (CH3)3OCH3:CH3OH=100:100:10 (by volume), and the product together with M+=151 (adamantylamine) was eluted, +another by-product (by g.c.-m.s. perhaps 7-chloroquinolone, which was not in the crude product prior to base-treatment). After re-elution (30 g Kieselgel, N(C2H5)3: CH3OH=200:5, fraction collection and their g.c-m.s. analysis), 33 mg of pure 7-chloro-(3-adamantylamino)-aminopropylquinoline was obtained as a white solid. Yield=6% of theory. G.c.-m.s. (DB5-column, 30 m, injection block temperature=250° C., t0=150° C./2 min, then 11° C./min.→280° C., Rt=24.05 min.): M(35Cl, 37Cl)+=369 (24%), 371 (9%), 135, C10H15+, (100%).