Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH:2]1[CH2:5][CH2:4][C:3]1([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[C:21](=O)([O-])[O-].[Na+].[Na+]>CO>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:3]2([C:6]([O:8][CH3:21])=[O:7])[CH2:4][CH2:5][CH2:2]2)=[CH:10][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CC1CCC1(C(=O)O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(c2ccc(Cl)cc2)CCC1

Procedure:
To a solution of methyl 1-(4-chlorophenyl)cyclobutanecarboxylic acid (5.0 g, 23.73 mmol) in anhydrous methanol was added 1 mL of the concentration of sulfuric acid. The mixture was refluxed for overnight. The mixture was neutralized to pH 4-5 with sodium carbonate. The solvent was evaporated. The residue was dissolved in ethyl acetate (50 mL), washed with brine (3×10 mL), dried over MgSO4. The crude product was used for the next reaction without further purification.
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)=O.[NH2:18][C:19]1[C:24]([O:25][CH2:26][CH3:27])=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH2:26]([O:25][C:24]1[C:19]2[N:20]([C:2]([CH3:17])=[C:3]([C:5]3[CH:6]=[CH:7][C:8]4[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=4[CH:16]=3)[N:18]=2)[CH:21]=[CH:22][CH:23]=1)[CH3:27]
Reactant: CCOc1cccnc1N
Reactant: CC(Br)C(=O)c1ccc2c(c1)NC(=O)C(C)O2
Product: CCOc1cccn2c(C)c(-c3ccc4c(c3)NC(=O)C(C)O4)nc12
Yield: 46 %

Procedure:
6-(8-Ethoxy-3-methylimidazo[1,2-a]pyridin-2-yl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.25 g) was prepared in substantially the same manner as that of Example 16 from 6-(2-bromopropionyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.4 g) and 2-amino-3-ethoxypyridine (2.8 g). mp. 180°-181° C. (dec.).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>C(C(C)=O)C>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCCCCBr
Reactant: Oc1ccccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: OCCCCCCOc1ccccc1-c1ccccc1
Yield: 84.5 %

Procedure:
Seventy-eight point five (78.5) g (461 mmol) of 2-phenylphenol from Tokyo Chemical Industry Co., Ltd. were dissolved in 600 mL of methyl ethyl ketone from Kanto Chemical Co., Inc. to prepare a solution. One hundred ninety one (191) g (1.38 mol) of sodium carbonate from Kanto Chemical Co., Inc. and 100 g (553 mmol) of 6-bromo-1-hexanol from Tokyo Chemical Industry Co., Ltd. were added to the solution, and refluxed for 8 hrs. After the solution was cooled to have room temperature, it was filtered and a solvent was removed therefrom. The residue was dissolved in methylene chloride from Junsei Chemical Co., Ltd. and washed with water. The isolated organic layer was dried with magnesium sulfide from Kanto Chemical Co., Inc., and a solvent was removed therefrom. The residue was refined by silica gel column chromatography using a mixed solvent in which a volume ratio of methylene chloride from Junsei Chemical Co., Ltd. to methanol from Kanto Chemical Co., Inc. is 99/1 as an eluent to obtain 105.3 g of 6-(2-phenyl-phenoxy)hexane-1-ol.
Reaction SMILES: [P:1]([O:9][CH2:10][CH3:11])([O:6][CH2:7][CH3:8])([O:3]CC)=O.[CH2:12]([O:19][C:20]1[C:29]([CH2:30]Br)=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([O:32][CH3:33])=[N:27]2)=[N:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:10]([O:9][P:1]([CH2:30][C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:32][CH3:33])[N:27]=2)[N:22]=[CH:21][C:20]=1[O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[O:6][CH2:7][CH3:8])[CH3:11]
Reactant: CCOP(=O)(OCC)OCC
Reactant: COc1ccc2ncc(OCc3ccccc3)c(CBr)c2n1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1c(OCc2ccccc2)cnc2ccc(OC)nc12)OCC
Yield: 77.2 %

Procedure:
Triethyl phosphate (960 μL, 5.60 mmol, 10.0 eq) is added at room temperature to a stirred solution of 7-benzyloxy-8-bromomethyl-2-methoxy-[1,5]naphthyridine (200 mg, 0.56 mmol, 1.0 eq) in toluene (1 mL) and the resulting mixture is heated under reflux for 6 hours. Solvent is then removed and the residue is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 1:1, v/v) to afford (3-benzyloxy-6-methoxy-[1,5]naphthyridin-4-ylmethyl)-phosphonic acid diethyl ester as a yellow oil (180 mg, 79% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([CH:9]=[O:10])[C:7]([OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17][O:12][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: ClC/C=C/CCl
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc([N+](=O)[O-])ccc1OC/C=C/CCl
Reaction time: 2 h
Yield: 43.3 %

Procedure:
A solution of 8 g of 5-nitrosalicylaldehyde, 30.8 g of trans-1,4-dichloro-2-butene and 13.2 g of potassium carbonate in 35 ml of dimethylformamide was stirred at room temperature for 19 hours, and further stirred at 80°-87° C. (outside temperature) for 2 hours. The mixture was allowed to cool, poured into 80 ml of water, and extracted with chloroform. The extract (organic layer separated) was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The product was eluted with benzene to give 5.3 g of 2-[(E)-4-chloro-2-butenyloxy]-5-nitrobenzaldehyde. (mp. 65°-66° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH2:27][CH2:28]CS([O-])(=O)=O)[CH2:12][CH2:11][N:10]([C:13](=[O:26])[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[CH2:9]1.Cl.[C:35]1([C:41]2([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH2:27][CH2:28][N:44]2[CH2:43][CH2:42][C:41]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45]2)[CH2:12][CH2:11][N:10]([C:13](=[O:26])[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[CH2:9]1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccccc3F)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccccc3F)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(2-fluoro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (12 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][N:3]=1.[NH3:17].[OH-].[NH4+]>>[NH2:17][C:2]1[CH:7]=[N:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=S(=O)(c1ccccc1)c1cnc(Cl)cn1
Reactant: N
Agent: [NH4+]
Agent: [OH-]
Product: Nc1cnc(S(=O)(=O)c2ccccc2)cn1

Procedure:
The 2-chloro-5-phenylsulfonylpyrazine can then be allowed to react with ammonia or ammonium hydroxide in a high pressure reaction vessel, at a temperature of about 100° to about 200° C. to yield the 2-amino-5-phenylsulfonylpyrazine intermediate. Reaction conditions may vary depending on the chemical structure of the phenylsulfonyl grouping.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:25](Cl)(=[O:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:23][CH:24]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Reaction time: 0.75 h

Procedure:
1-[1-(4-Aminophenethyl)piperidin-4-yl]indoline (310 mg) was dissolved in methylene chloride (3 ml). Under ice cooling, acetyl chloride (0.103 ml) was added to the resultant solution followed by stirring the obtained mixture for 45 min. After adding a 10% aqueous solution of potassium carbonate, the reaction solution was extracted with ethyl acetate. Then the organic layer was washed with brine and dried over magnesium sulfate. After evaporating the solvent, the resulting residue was purified by NH-silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (200 mg) as an oil.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C:9](=[O:10])[C:5](=[C:6]([CH3:8])[CH3:7])[CH2:4][CH2:3]1.[CH3:12][SH:13]>C(N(CC)CC)C>[CH3:12][S:13][C:6]([CH3:7])([CH3:8])[CH:5]1[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:11][C:9]1=[O:10]
Reactant: CS
Reactant: CC(C)=C1CC[C@@H](C)CC1=O
Solvent: CCN(CC)CC
Product: CSC(C)(C)C1CCC(C)CC1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
15.2 g of pulegone are treated with 0.5 ml of triethylamine and cooled to ca 0° by means of an ice-common salt mixture. With stirring, methyl mercaptan in excess is condensed into the mixture and, after condensation of 200% of the calculated amount, the mixture is transferred into an autoclave. After standing overnight at room temperature, the reaction mixture is heated to 50° and, after cooling of the autoclave, the reaction product immediately distilled in vacuum. 9.8 g of 8-methylthio-p-menthan-3-one are obtained as a clear liquid with pleasant odour reminiscent of peppermint, geranium and caraway, boiling point 72°-73°/0.15 mm Hg, nD20 1.4982. The yield amounts to 73% of the theory based on reacted pulegone. The two stereoisomeric compounds 8-methylthio-cis-p-menthan-3-one and 8-methylio-trans-p-menthan-3-one obtained can be separated gas-chromatographically.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.Cl.[CH3:25][O:26][C:27]([C@H:29]1[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31][CH2:30]1)=[O:28]>>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([NH:11][C:9]2[N:10]=[C:6]3[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=[C:2]([NH:35][C@H:32]4[CH2:31][CH2:30][C@H:29]([C:27]([O:26][CH3:25])=[O:28])[CH2:34][CH2:33]4)[N:7]3[N:8]=2)=[O:19])[CH:14]=1
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Agent: Cl
Product: COC(=O)[C@H]1CC[C@H](Nc2cc(C(F)(F)F)cc3nc(NC(=O)c4cccnc4)nn23)CC1

Procedure:
The title compound was prepared following procedure described for example 85, but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.15 mmol; 1.0 eq.) and trans-4-amino-cyclohexylcarboxylic acid methyl ester hydrochloride (IRIS), 52 μl; 0.73 mmol; 5.0 eq.) as a white powder (23 mg, 34%). HPLC, Rt: 3.33 min. (purity 96.4%). LC/MS, M+(ESI): 463.1, M−(ESI): 461.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O-:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1.[C:26]1([CH:32]2[CH2:34][CH:33]2[CH2:35]O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH2:35][CH:33]3[CH2:34][CH:32]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C(=O)[O-])C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Reactant: OCC1CC1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)OCC2CC2c2ccccc2)=C(C)N1

Procedure:
306 mg (0.85 mmol) of mono(2-cyanoethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, 188 mg (1.27 mmol) of 2-phenylcyclopropylmethanol, 243 mg (1.27 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 23 mg (0.18 mmol) of 4-dimethylaminopyridine were stirred together in 10 ml of dichloromethane at room temperature for one hour. Water was added to the reaction liquid. After the extraction with dichloromethane, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=2/1) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][O:13][C:14]([C@H:16]1[CH2:19][C@H:18](O)[CH2:17]1)=[O:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:12][O:13][C:14]([C@H:16]1[CH2:19][C@@H:18]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=3[C:10]([I:11])=[CH:9]2)[CH2:17]1)=[O:15]
Reactant: COC(=O)[C@H]1C[C@H](O)C1
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@@H](n2cc(I)c3c(Cl)ncnc32)C1
Temperature: 85 °C

Procedure:
To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (prepared according to: L. B. Townsend et al., J. Med. Chem. 1990, 33 (7), 1984-92) (2.10 g, 7.51 mmol), trans-3-hydroxycyclobutanecarboxylic acid methyl ester (trans/cis=5:1) (1.11 g, 8.53 mmol), and PS—PPh3 (loading 2.21 mmol/g; 6.80 g, 15.0 mmol) in dry THF (80 mL), cooled by ice/water, was added DIAD (2.20 mL, 2.26 g, 11.2 mmol), then the cooling bath was removed, and the mixture was vortexed (150 rpm) overnight. The resin was filtered off and washed thoroughly with THF (≈400 mL), the filtrate and washings were combined, concentrated, and chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with CH2Cl2 (1-16)→5% EtOAc in CH2Cl2 (17-40)]. Fractions 3-32 were combined, concentrated, and suspended in iPrOH (10 mL). The suspension was heated to 85° C. for 20 min and cooled to −20° C. for 2 h, the solid was filtered off, washed with cold (−20° C.) iPrOH, and dried in vacuo. One obtained the title compound as white solid. Analytically pure material with cis/trans=50:1 had a melting point of 168-169° C. 1H NMR (CDCl3, 400 MHz): δ=2.66-2.78 (m, 2H), 2.81-2.93 (m, 2H), 3.06 (quint, J=8.7 Hz, 1H), 3.76 (s, 3H), 5.32 (quint, J=8.7 Hz, 1H), 7.68 (s, 1H), 8.60 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=30.93 (+), 34.09 (2C, −), 44.65 (+), 51.58 (Cquart), 52.19 (+), 117.07 (Cquart), 131.87 (+), 150.48 (Cquart), 150.72 (+), 152.69 (Cquart), 174.31 (Cquart). MS (ES+): m/z 391.9/393.9 (100/38) [MH+]. HPLC: tR=3.5 min (OpenLynx, polar—5 min). C12H11ClIN3O2 (391.60): C: calc. 36.81. found 36.88/36.78. H: calc. 2.83. found 2.81/2.76. N: calc. 10.73. found 10.59/10.50.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].C1C(=O)N([Br:18])C(=O)C1>OS(O)(=O)=O>[Br:18][C:7]1[C:6]([CH3:10])=[C:3]([C:2]([F:1])=[CH:9][CH:8]=1)[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(F)c1C#N
Agent: O=S(=O)(O)O
Product: Cc1c(Br)ccc(F)c1C#N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of 2-fluoro-6-methylbenzonitrile (5.0 g, 37 mmol) in 100 mL of concentrated H2SO4 was added NBS (6.93 g, 38.9 mmol). Then the mixture was stirred at 0° C. for 3 hrs and poured into ice-water (1 L). The solution was extracted three times with EtOAc (200 mL) and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography to give 3-bromo-6-fluoro-2-methylbenzonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[CH:18][C:19](=[O:27])[N:20]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:21]=4)[S:15][C:8]=23)=[C:4]([F:30])[CH:3]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][C:40](=[O:45])[CH2:41][C:42](O)=[O:43].OC1C2N=NNC=2C=CC=1.C(Cl)CCl.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22][N:20]1[C:19](=[O:27])[CH:18]=[CH:17][C:16]([C:14]2[S:15][C:8]3[C:9](=[N:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:42](=[O:43])[CH2:41][C:40]([NH:39][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[O:32][CH3:31])=[O:45])=[CH:3][C:4]=3[F:30])[CH:13]=2)=[CH:21]1
Reactant: COc1ccccc1NC(=O)CC(=O)O
Reactant: CN(C)CCn1cc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)ccc1=O
Agent: O=C([O-])O
Agent: Oc1cccc2[nH]nnc12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(=O)n(CCN(C)C)c4)sc23)c(F)c1
Yield: 52.3 %

Procedure:
To a solution of compound 422 (25 mg, 0.059 mmol) in DMF (0.5 mL) was added the acid 27 (25 mg, 0.12 mmol), hydroxybenzotriazole (11 mg, 0.071 mmol), then EDC (23 mg, 0.12 mmol). The reaction mixture was stirred at room temperature for 6 hours before the addition of saturated NaHCO3 (8 mL). The mixture was then extracted with dichloromethane; the extract was dried over anhydrous Na2SO4, filtered and concentrated. The residue was then purified by flash chromatography (eluent a gradient of 0 to 20% methanol in dichloromethane) to give title compound 417 as a white solid (19 mg, 53% yield). 1H NMR: (DMSO-d6) δ(ppm): 10.58 (s, 1H), 9.62 (s, 1H), 8.45 (d, J=5.6 Hz, 1H), 8.28 (d, J=2.8 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.95 (dd, J=2.8, 9.6 Hz, 1H), 7.88-7.84 (m, 2H), 7.45 (t, J=8.8 Hz, 1H), 7.43-7.40 (m, 1H), 7.07-7.03 (m, 2H), 6.92-6.88 (m, 1H), 6.60 (d, J=5.6 Hz, 1H), 6.51 (d, J=9.6 Hz 1H), 4.05 (t, J=6.0 Hz, 2H), 3.84 (s, 3H), 3.62 (s, 2H), 2.53 (t, J=6.4 Hz, 2H), 2.47 (s, 6H). MS (m/z): 308.5 ([M+2H]/2), 616.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11]#[C:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]=[C:16]2[CH2:23][CH3:24]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]=[C:16]2[CH2:23][CH3:24]
Reactant: CCc1ncnc2ccc(C#Cc3cc(OC)ccc3OC)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1ncnc2ccc(CCc3cc(OC)ccc3OC)cc12
Reaction time: 8 h

Procedure:
150 mg of 6-[2-(2,5-dimethoxyphenyl)ethynyl]-4-ethyl-quinazoline are dissolved in 10 ml of ethyl acetate. After addition of 20 mg of palladium (10% on charcoal) the mixture is stirred overnight under an atmosphere of hydrogen and subsequently filtered over celite. The filtrate is evaporated in vacuo and the residue crystallised from cylohexane to obtain the title compound as colourless crystals. mp: 74°.
Reaction SMILES: [C:1]([S:4][CH:5]([CH:10]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH2:11]1)[C:6]([O:8][CH3:9])=[O:7])(=O)[CH3:2].C[O-].[Na+].[F:23][C:24]([F:29])([F:28])CCI.O>CO>[O:17]1[C:13]2([CH2:18][CH2:19][CH:10]([CH:5]([S:4][CH2:1][CH2:2][C:24]([F:29])([F:28])[F:23])[C:6]([O:8][CH3:9])=[O:7])[CH2:11][CH2:12]2)[O:14][CH2:15][CH2:16]1
Reactant: FC(F)(F)CCI
Reactant: COC(=O)C(SC(C)=O)C1CCC2(CC1)OCCO2
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(SCCC(F)(F)F)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 4.27 g of methyl 2-(acetylthio)-2-(1,4-dioxaspiro[4.5]dec-8-yl)acetate in 30 ml of methanol was added 3.14 g of a 28% solution of sodium methoxide in methanol at 0° C. under a nitrogen atmosphere. To the mixture was added 4.31 g of 3,3,3-trifluoro-1-iodopropane, and the mixture was stirred at room temperature for 1 hour and then at 70° C. for 1 hours. The reaction mixture was cooled to room temperature, and 100 ml of water was added thereto. The mixture was concentrated to a total amount of about 100 ml under reduced pressure, followed by extraction with 100 ml of ethyl acetate twice. Organic layers were combined, washed with 100 ml of an aqueous saturated sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.60 g of methyl 2-(1,4-dioxaspiro[4.5]dec-8-yl)-2-(3,3,3-trifluoropropylthio)acetate (hereinafter, referred to as the present compound (8)) represented by the formula:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[C:47]1([CH2:53][CH2:54][C:55](Cl)=[O:56])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(CC)CC)C>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:55](=[O:56])[CH2:54][CH2:53][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:43]=[CH:44][CH:45]=2)=[N:8]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol) in 2.5 mL of tetrahydrofuran was added 3-phenyl propanoyl chloride (0.084 g, 0.498 mmol), followed by triethyl amine (0.173 mL, 1.24 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was then partitioned between ethyl acetate and water. (Yield not calculated) ES-MS (m/z) 735 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[CH:5]=[C:4]([OH:11])[CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[CH:5]=[C:4]([O:11][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[CH:3]=1
Reactant: O=Cc1c(O)cc(O)cc1Cl
Reactant: C1=COCCC1
Solvent: ClCCl
Product: O=Cc1c(O)cc(OC2CCCCO2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
To a solution of 6-chloro-2,4-dihydroxybenzaldehyde (9.0 g, 52.2 mmol) in DCM (150 mL) was added 3,4-dihydro-2H-pyran (9 mL, 98.4 mmol), followed by PPTs (1.31 g, 5.2 mmol). The reaction mixture was stirred at room temperature for 1.5 h and quenched by saturated aqueous NaHCO3 (50 mL) at 0° C. The organic layer was separated, washed with brine (40 mL) and dried over anhydrous Na2SO4. Concentration in vacuo followed by purification with column chromatography on silica gel (EtOAc/PE=1:100) gave the title compound as a colorless oil (10.5 g, Yield: 87.3%). 1H NMR (400 MHz, DMSO-d6) δ12.00 (s, 1H), 10.17 (s, 1H), 6.72-6.78 (m, 1H), 6.57-6.64 (m, 1H), 5.50-5.70 (t, 1H), 3.60-3.73 (m, 2H), 1.55-1.87 (m, 6H) MS (ESI) m/z=257 [M+H]+.