Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([CH3:10])=[CH:8][C:6]([NH2:7])=[C:5]([CH3:11])[C:4]=1[CH3:12].[CH:13]([C:15]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCl.O>[CH3:1][O:2][C:3]1[C:9]([CH3:10])=[CH:8][C:6]([NH:7][CH2:13][C:15]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]2)=[C:5]([CH3:11])[C:4]=1[CH3:12]
Reactant: COc1c(C)cc(N)c(C)c1C
Reactant: CCOC(=O)C1(C=O)CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1(CNc2cc(C)c(OC)c(C)c2C)CCC1
Reaction time: 3.5 h

Procedure:
To a solution of 4-methoxy-2,3,5-trimethylaniline (400 mg) in dichloromethane (24 mL) was added ethyl 1-formylcyclobutanecarboxylate, prepared as described in Step 1 (377.8 μL). Then NaBH(OAc)3 (771.4 mg) and acetic acid (152.2 μL) were added sequentially. After 3.5 h, water was added. The two layers were separated and the aqueous layer was extracted with more dichloromethane. The combined organic phases were washed with brine, dried and evaporated. Elution of the residue on a silica column (EtOAc/DCM, 0-5%) gave ethyl 1-((4-methoxy-2,3,5-trimethylphenylamino)methyl)-cyclobutanecarboxylate (400 mg) as an oil. 1H-NMR, (300 MHz, CDCl3) δ=6.37 (s,1H), 4.262-3.974 (q, 2H), 3.63 (s, 3H), 3.745-3.474 (br s, 1H), 3.41 (s, 2H), 2.693-2.339 (m, 2H), 2.27 (s, 3H), 2.21, (s, 3H), 2.14-1.818, (m, 4H), 2.02, (s, 3H), 1.333-1.174 (t, 3H) ppm., 13C-NMR, (75 MHz, CDCl3) δ=176.51, 142.52, 129.68, 128.09, 119.78, 110.29, 60.85, 60.37, 50.67, 47.2, 28.43, 16.38, 15.9, 14.3, 12.94, 12.85 ppm.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:10])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[N+:1]([C:4]1[C:5](=[O:10])[N:6]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccnc1O
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1cccc([N+](=O)[O-])c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.6 %

Procedure:
Sodium hydride (4.08 g of a 60% dispersion in mineral oil, 0.10 mole) was washed with hexanes three times (10 mL each) and suspended in dimethylformamide (50 mL). The stirred suspension was cooled in an ice bath, then 3-nitro-2-hydroxypyridine (13.0 g, 0.093 mole) was added in small portions over a 45-minute period. After the addition was complete, the reaction was stirred at 0° C. for 10 minutes, then room temperature for 30 minutes. The reaction mixture was recooled in an ice bath. Ethyl bromoacetate (0.75 mL, 0.097 mole) was added. The reaction was stirred at 0° C. for 1 hour, then 1.5 hours at room temperature. The reaction mixture was partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with water (4×100 mL), brine, and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to afford 15.7 g (75% yield) of the title compound as yellow solid. Rf=0.30 (silica gel, 20% ethyl acetate in dichloromethane).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C:13]([O:24][CH2:25][CH3:26])(=[O:23])[C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1>>[CH3:18][O:17][C:16]1[CH:15]=[C:14]([CH:22]=[CH:21][C:19]=1[O:20][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)[C:13]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Product: CCOC(=O)c1ccc(OCc2ccc3ccccc3c2)c(OC)c1
Yield: 54 %

Procedure:
2-Bromomethylnaphthalene was reacted with ethyl vanillate using the conditions described in Example 1 to give ethyl 3-methoxy-4-(naphth-2-ylmethoxy)benzoate in 54% yield, m.p. 86°-87° C. Following the procedures described in the portion of Example 6 which is concerned with the preparation of starting materials the product so obtained was reacted with thiazol-2-yl-lithium and the resultant product was reacted with ethylmagnesium iodide to give the required starting material as an oil in 20% yield, m.p. 124°-126° C. (recrystallised from a mixture of hexane and ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([CH:21](O)[C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[C:19]([CH:33]([CH3:35])[CH3:34])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:36])[CH2:11][C:12]2([O:16]3)[CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:43])CC)C.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:20]([CH:21]([F:43])[C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:27]=3)=[C:19]([CH:33]([CH3:34])[CH3:35])[CH:18]=[C:17]3[C:9]=2[C:10](=[O:36])[CH2:11][C:12]2([O:16]3)[CH2:13][CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(C(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under argon, 180 mg (0.32 mmol) of 5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethyl)phenyl]-methyl}-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 52A) are dissolved in 3.2 ml of toluene, 52 μl (0.39 mmol) of diethylaminosulfur trifluoride are slowly added at −78° C. and the mixture is stirred at −78° C. for 1 h. The temperature is then slowly increased to −60° C. After 2 h, water is added and the mixture is extracted twice with ethyl acetate. The combined organic phases are washed once with saturated sodium bicarbonate solution and once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate 12:1). This gives 107 mg (66% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:21][NH2:22].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[NH:22][N:21]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)C(=O)CC(=O)c1cc(Cl)cc(Cl)c1
Reactant: NN
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1cc(-c2cc(Cl)cc(Cl)c2)n[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product from step C (6.8 g, 21.7 mmol) in 125 mL of ethanol was added hydrazine (0.75 mL, 23.9 mmol) and 10 mL of glacial acetic acid. The reaction mixture was stirred at ambient temperature for 16 h then was concentrated in vacuo and the residue suspended in ethyl acetate. The organic layer was washed successively with two portions of saturated aqueous sodium bicarbonate solution and one portion of brine. The organic layer was dried over magnesium sulfate, and concentrated in vacuo to provide the title compound as a pale yellow solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11](Cl)[N:10]=[C:9]([N:18]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]2)[N:8]=1.[N:30]1[CH:31]=[CH:32][N:33]2[CH2:38][CH2:37][NH:36][CH2:35][C:34]=12.C(=O)([O-])O.[Na+]>CN(C)C(=O)C.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([N:36]2[CH2:37][CH2:38][N:33]3[CH:32]=[CH:31][N:30]=[C:34]3[CH2:35]2)[N:10]=[C:9]([N:18]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]2)[N:8]=1
Reactant: c1cn2c(n1)CNCC2
Reactant: COC(=O)c1c(Cl)nc(N2CCC(O)CC2)nc1NCc1ccc(OC)c(Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(N2CCC(O)CC2)nc1N1CCn2ccnc2C1
Temperature: 85 °C
Reaction time: 5 h

Procedure:
To a solution of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-chloro-2-(4-hydroxypiperidin-1-yl)pyrimidine (prepared in the above (3)) 56 mg in N,N-dimethylacetamide 0.5 ml are added a solution of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 31 mg in N,N-dimethylacetamide 0.5 ml and triethylamine 27 μl at room temperature, and the mixture is stirred at 80-90° C. for 5 hours. The reaction mixture is diluted with an aqueous citric acid solution, made basic with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-2-(4-hydroxypiperidin-1-yl)pyrimidine as a pale yellow powder, 66 mg.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[C:23]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]#N)[CH2:26][CH2:25]3)=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:13][CH2:12]1.CC(C[AlH]CC(C)C)C.C1C[O:44]CC1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[C:23]([N:24]3[CH2:29][CH2:28][CH:27]([CH:30]=[O:44])[CH2:26][CH2:25]3)=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:13][CH2:12]1
Reactant: C1CCOC1
Reactant: N#CC1CCN(c2cccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Agent: CC(C)C[AlH]CC(C)C
Product: O=CC1CCN(c2cccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 1-(2-((1-(quinolin-2-yl)piperidin-4-yl)oxy)pyridin-3-yl)piperidine-4-carbonitrile (290 mg, 0.70 mol) in 20 mL of THF was added DIBAL-H (1.4 mol, 1 M in toluene) dropwise at −65° C. The mixture was stirred for 1 hour at RT and then quenched with saturated aqueous NH4Cl. The resulting mixture was extracted with EtOAc (2×20 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the product (0.232 g, 0.56 mmol, 80% yield). ESI-MS (M+1): 417 calc. for C25H28N4O2 416.
Reaction SMILES: [OH:1][C@@H:2]([CH3:12])[CH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[OH:11].C(OC1C=CC(C)=CC=1C[C@H](O)C)C1C=CC=CC=1>>[OH:1][C@H:2]([CH3:12])[CH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[OH:11]
Reactant: Cc1ccc(O)c(C[C@H](C)O)c1
Agent: Cc1ccc(OCc2ccccc2)c(C[C@@H](C)O)c1
Product: Cc1ccc(O)c(C[C@@H](C)O)c1

Procedure:
The title compound 5b was prepared according to the method for preparation of compound 3c of Example 3 by replacing 3b with 5a.
Reaction SMILES: O[CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[Br:16][C:17]1[CH:18]=[N:19][NH:20][CH:21]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCCC1>[Br:16][C:17]1[CH:18]=[N:19][N:20]([CH2:2][C@H:3]2[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4]2)[CH:21]=1
Reactant: Brc1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CO)C1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Br)cn2)C1
Reaction time: 192 h

Procedure:
Tetrahydrofuran was added to a mixture of (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (250 mg, 1.15 mmol), 4-bromo-1H-pyrazole (186 mg, 1.27 mmol), di-tert-butyl azodicarboxylate (530 mg, 2.30 mmol), and triphenylphosphine resin (3 mmol/g loading, 601 mg, 2.30 mmol) under argon. The resulting suspension was stirred for 8 days and then filtered through CELITE. The supernatant was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (5-100% ethyl acetate/hexanes) to afford tert-butyl (2S)-2-[(4-bromo-1H-pyrazol-1-yl)methyl]morpholine-4-carboxylate. ESI calc'd. for C9H13BrN3O3 [M+H t-Bu]+ 289 and 291. found 289 and 291. 1H NMR (500 MHz, CDCl3) δ 7.49 (s, 1H), 7.46 (s, 1H), 4.22-4.08 (m, 2H), 4.04-3.78 (m, 3H), 3.76-3.69 (br s, 1H), 3.52-3.46 (m, 1H), 2.99-2.82 (br s, 1H), 2.63-2.51 (br s, 1H), 1.45 (s, 9H).
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[OH-].[Li+].O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([OH:3])=[O:12])=[CH:16][CH:15]=1
Reactant: Oc1ccc(F)cc1
Reactant: CCOC(=O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccnc1Oc1ccc(F)cc1
Temperature: 25 °C

Procedure:
2-Chloro-nicotinic acid ethyl ester, 4-fluoro-phenol, and cesium carbonate were mixed in anhydrous dioxane and the resulting slurry heated to reflux for about 16 h. In a separate flask, lithium hydroxide was dissolved in water with warming and then added to the refluxing mixture, which was heated for an additional 4 h. The mixture was cooled to ambient temperature and concentrated in vacuo to remove the dioxane. Concentrated hydrochloric acid was added dropwise until the pH=3. The acidified solution was then extracted with ethyl acetate to yield crude product, which was recrystallized from ethyl acetate to yield the purified title compound (10.8 g).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH2:7]([O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:7]([O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:2])=[O:23])=[CH:20][CH:19]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1
Product: CCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Temperature: 80 °C

Procedure:
Phosphorus pentachloride (0.80g, 0.0038 mol) was added to 4-n-decyloxybenzoic acid (1.0g, 0.0036 mol) and the mixture was allowed to react by heating at about 80° C. POCl3 and excess phosphorus pentachloride were completely removed by evaporation in vacuo to obtain 4-n-decyloxybenzoyl chloride. This chloride was dissolved in toluene (10 ml) and to the mixture were added R-(+)-α-(4-n-octylphenyl)ethyl alcohol (0.84g, 0.0036 mol) and pyridine (1 ml, a dehydrochlorination agent). The mixture was allowed to stand for 10 hours at room temperature, warmed at 60° C. and maintained as such for 3 hours, and then cooled. The resulting mixture was added to diluted hydrochloric acid and the resultant was extracted with ether. The ether layer was washed with an aqueous solution of NaHCO3 and then with water, and dried over Na2SO4. The ether was distilled off and the residue was purified by means of a column chromatography (solvent : chloroform) to obtain the objective compound of α-(4-n-octylphenyl)ethyl 4-n-decyloxybenzoate. The infrared spectrum of said compound is shown in FIG. 2. This compound did not show any liquid crystalline phase and it was a liquid at room temperature. The angle of rotation [α]25D of the compound was -26.0° C. (solvent : chloroform).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1.N([O-])=[O:13].[Na+].S(=O)(=O)(O)O>Cl.O>[OH:13][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: CC(C#N)c1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C#N)c1ccc(O)cc1
Reaction time: 0.33 h
Yield: 81 %

Procedure:
Finely ground 2-(4-aminophenyl) propionitrile (73 g., 0.5 mole) was suspended in concentrated hydrochloric acid (125 ml.). The stirred suspension was diazotised at 0°-5°C by the dropwise addition of a solution of sodium nitrite (36.23 g., 0.525 mole) in water (60 ml.) during 1-2 hours. The almost clear solution was stirred for a further 20 minutes at 5°-10°C, then poured into a stirred, boiling solution of concentrated sulphuric acid (250 ml.) in water (2.5 l.). After 6 minutes it was cooled in an ice-bath, then extracted with ether (x4). The combined ether extracts were extracted with 2N-sodium hydroxide solution (x6). The combined alkaline extracts were cooled in ice-bath, acidified with concentrated hydrochloric acid and extracted with ether (x3). The combined ether extracts were washed with saturated sodium chloride solution (x3), dried (Na2SO4) and evaporated to leave a dark brown oil (66.7 g.) which on distillation gave 2-(4-hydroxyphenyl) propionitrile (59.58 g.), b.p. 112°-122°C/0.125 m.m., m.p. 41°-46°C.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH+:14]=[CH:13]1)([OH:10])=O.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[NH2:26]>>[N:12]1([CH2:11][C:8]([NH:26][C:25]2[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:10])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: O=C(O)Cn1c[nH+]c2ccccc21
Reactant: COc1cc(N)cc(OC)c1
Agent: O=C([O-])C(F)(F)F
Product: COc1cc(NC(=O)Cn2cnc3ccccc32)cc(OC)c1

Procedure:
The title compound was synthesized according to a procedure described in Example 98 starting from 3-carboxymethyl-3H-benzoimidazol-1-ium trifluoro-acetate (Example 92 part B) and 3,5-dimethoxy-aniline. Calculated for C17H17N3O3 m/z: 311.34, found 311.88 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.69 (s, 6 H), 5.14 (s, 2H), 6.23 (t, J=2.3 Hz, 1H), 6.82 (d, J=2.0 Hz, 2H), 7.22 (m, 2H), 7.51 (d, J=7.6 Hz, 1H), 7.66 (dd, J=7.3, 1.3 Hz, 1H), 8.21 (s, 1H), 10.41 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[O:2].[CH2:13]([Mg]Br)[CH2:14][CH3:15]>O1CCCC1>[OH:2][CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCC[Mg]Br
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
A solution of methyl 4-formylbenzoate (2.09 g, 12.7 mmol) in tetrahydrofuran (50 mL) was cooled to 0° C. To this solution was added n-propylmagnesium bromide (6.4 mL, 2.0M in THF) dropwise over 20 minutes. The reaction was stirred at 0° C. for 2 h. The reaction was then quenched by addition of saturated aqueous ammonium chloride. This mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography gave methyl 4-(1-hydroxybutyl)benzoate (1.25 g, 47%) as a colorless oil. 1H NMR (400 MHz, CDCl3, δ) 7.97-8.02 (m, 2H), 7.40 (d, J=8.4 Hz, 2H), 4.74 (dd, J=7.8, 5.7 Hz, 1H), 3.90 (s, 3H), 1.61-1.82 (m, 2H), 1.23-1.49 (m, 2H), 0.92 (t, J=7.32 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[N:20]=[CH:19][C:18]2[CH2:17][CH2:16][C:15]3[C:21]([C:33]([NH2:35])=[O:34])=[N:22][N:23]([CH2:24][CH2:25][O:26]C4CCCCO4)[C:14]=3[C:13]=2[N:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[F:37][C:2]([F:1])([F:36])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[N:20]=[CH:19][C:18]2[CH2:17][CH2:16][C:15]3[C:21]([C:33]([NH2:35])=[O:34])=[N:22][N:23]([CH2:24][CH2:25][OH:26])[C:14]=3[C:13]=2[N:12]=1
Reactant: NC(=O)c1nn(CCOC2CCCCO2)c2c1CCc1cnc(Nc3ccccc3OC(F)(F)F)nc1-2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: NC(=O)c1nn(CCO)c2c1CCc1cnc(Nc3ccccc3OC(F)(F)F)nc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
0.085 g (0.15 mmol) of 8-(2-trifluoromethoxy-phenylamino)-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide were dissolved in 10 mL of ethanol and 28 mg of p-toluensulfonic acid (0.15 mmol) were added. The solution was stirred at room temperature overnight and the solvent removed in vacuo. The residue was purified by flash chromatography on silica gel (eluant: ethyl acetate/hexane 80/20) to afford 59 mg (90% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C([OH:12])C.C(OO)(=O)C>C(O)(=O)C>[NH2:1][C:2]1[N+:7]([O-:12])=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: CCO
Agent: CC(=O)OO
Solvent: CC(=O)O
Product: Nc1cc(Cl)nc(N)[n+]1[O-]
Temperature: 35 °C
Reaction time: 0.25 h

Procedure:
144.5 G. of 2,4-diamino-6-chloropyrimidine are suspended in 2000 ml. of ethanol. The suspension is warmed to 35° C. while stirring (about 15 minutes), the greater part of the material passing into solution. This mixture is then cooled down to 6°-8° C. and at this temperature there are added dropwise within 40 minutes 175 ml. of 40% peracetic acid in glacial acetic acid. After completion of the addition, the mixture is stirred at 6°-8° C. for a further 30 minutes. Thereafter, the mixture is left to warm up to room temperature, and stirred at this temperature for 3 hours. 2000 Ml. of petroleum ether are added, the mixture is stirred for 1 hour and then left to stand overnight. The separated precipitate is filtered off, back-washed with 200 ml. of petroleum ether and dried under reduced pressure, there being obtained 2,4-diamino-6-chloro-pyrimidine-3-oxide. Recrystallization yields analytically pure product having a melting point of 193° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH:27]1[CH2:30][CH2:29][CH2:28]1>>[N:27]1([CH2:21][CH2:20][CH2:19][C:18]#[C:17][C:15]2[CH:14]=[CH:13][C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)=[N:9][S:10][C:11]=3[CH:16]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: C1CNC1
Product: Brc1ccc(-c2nsc3cc(C#CCCCN4CCC4)ccc23)cc1

Procedure:
In analogy to example 16.1, Methanesulfonic acid 5-[3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and azetidine were converted to yield 6-(5-Azetidin-1-yl-pent-1-ynyl)-3-(4-bromo-phenyl)-benzo[d]isothiazole as orange semisolid, MS: 411 (MH+, 1Br).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH:19]=[CH2:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26](COCC[Si](C)(C)C)[C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH:19]=[CH2:20])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:21])=[O:29]
Reactant: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 37.1 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-ethenylbenzonitrile (0.076 g, 0.251 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.069 g, 0.251 mmol) and DIPEA (0.088 mL, 0.502 mmol) were combined in THF (2 mL) and treated with HATU (0.105 g, 0.276 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 3 days. The reaction mixture was concentrated to dryness and partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified on an XTerra™ C-18 column eluted with 5 to 90% CH3CN/H2O (0.2% NH4OH buffer). Appropriate fractions were combined, concentrated to dryness, chased twice with ethanol and twice with toluene to remove residual water to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethenyl phenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.040 g, 0.093 mmol, 36.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.2 (br. s., 1H), 8.31 (br. s., 1H), 7.80 (s, 1H), 7.77 (s, 1H), 7.26-7.53 (m, 4H), 6.75 (dd, 1H), 6.04 (d, 1H), 5.44 (d, 1H), 4.53 (d, 2H). LC-MS (ES−) m/z 429.08, 431.11, 433.00 [M−1]. LC-MS (ES+) m/z 430.97, 432.95, 434.95 [M+H].