Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:8][CH2:9][CH2:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([CH:19]=[CH:18][C:16]([OH:17])=[CH:15][CH:14]=1)[OH:13]>>[C:7]([NH:11][CH2:10][CH2:9][O:13][C:12]1[CH:19]=[CH:18][C:16]([O:17][CH2:9][CH2:10][NH:11][C:7](=[O:8])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:15][CH:14]=1)(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2=NCCO2)cc1
Reactant: Oc1ccc(O)cc1
Product: O=C(NCCOc1ccc(OCCNC(=O)c2ccccc2)cc1)c1ccccc1

Procedure:
In German Pat. No. 1,062,253, A. Jager describes the preparation of various ether and carboxamide compounds by treating certain substituted oxazolines with certain phenols, with the exclusion of water. A mixture of phenol and 2-phenyloxazoline refluxed for 7 hours yielded PhCONHCH2CH2OPh as a product. Similarly, p-bis(oxazolinyl)benzene and phenol gave N,N'-bis(β-phenoxyethyl)terephthalamide. Finally, Jager found that a mixture of 2-phenyl-2-oxazoline and hydroquinone produced 1,4-bis(β-benzamidoethoxy)benzene.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].[C:5]1([S:11](Cl)(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N1C=CC=CC=1>O>[Cl:1][CH2:2][CH2:3][O:4][S:11]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: OCCCl
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(OCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.9 %

Procedure:
2-Chloroethanol (1168 g, 975 mol) and benzene sulfonyl chloride (2780 g, 2015 mol) were stirred together at −5° C. and pyridine (2158 g, 2200 mol) was added over a 3 hours period, maintaining the temperature below 0° C. The reaction was stirred for a further 3 hours at −5° C. to 0° C. and was then allowed to warm to room temperature over 18 hours. After pouring into a mixture of ice (10 liters) and water (10 liters) the reaction was stirred for 15 minutes, extracted with ether (10 liters) and the organic phase was washed with 5N HCl (2×2 liters) and water (2×4 liters). It was then dried over MgSO4 and concentrated under reduced pressure to give benzene sulfonic acid 2-chloro-ethyl ester (1921 g) as an orange oil. 1H NMR (250 MHz, CDCl3): δ=7.78-8.02 (2H, m), 7.58-7.78 (3H, m), 420-4.45 (2H, t), 3.60-3.81 (2H, t) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[O:44][N:43]=[C:42]([CH3:45])[CH:41]=2)[CH:35]=1)=[O:33])(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:17])[CH3:18])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[O:44][N:43]=[C:42]([CH3:45])[CH:41]=2)[CH:35]=1)=[O:33])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from [2-amino-5-(isopropyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J37) (350 mg, 1.01 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (304 mg, 1.01 mmol) according to the general procedure M. Obtained as a light brown foam (380 mg, 66%).
Reaction SMILES: Cl.[NH2:2][C:3](=[N:15][OH:16])[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1.[O-]CC.[Na+].[NH2:21][C:22]1[C:27]2[CH2:28][CH2:29][O:30][C:26]=2[C:25]([C:31](OC)=O)=[CH:24][C:23]=1[Cl:35]>C(O)C>[NH2:21][C:22]1[C:27]2[CH2:28][CH2:29][O:30][C:26]=2[C:25]([C:31]2[O:16][N:15]=[C:3]([CH:4]3[CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9]3)[N:2]=2)=[CH:24][C:23]=1[Cl:35]
Reactant: COC(=O)c1cc(Cl)c(N)c2c1OCC2
Reactant: CCOC(=O)N1CCC(C(N)=NO)CC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N1CCC(c2noc(-c3cc(Cl)c(N)c4c3OCC4)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
A mixture of intermediate 2 (10.07 g), sodium ethoxide (5.42 g) and molecular sieves (45 g) in ethanol (150 ml) was stirred for 30 minutes at RT. Intermediate 1 (9.1 g) was added and the reaction mixture was stirred and refluxed for 10 hours. The reaction mixture was cooled, filtered and the filtrate evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent evaporated, yielding 11.6 g (74%) of ethyl 4- [5-(4-amino-5-chloro-2,3-dihydro-7-benzofuranyl)- 1,2,4-oxadiazol-3-yl]-1-piperidinecarboxylate (intermediate 3; mp. 162.4° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:14][C:15]([F:28])([F:27])[C:16]1[N:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](O)=[O:25])=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:24](=[O:25])[CH2:23][CH2:22][C:19]2[CH:20]=[N:21][C:16]([C:15]([F:14])([F:27])[F:28])=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(O)CCc1ccc(C(F)(F)F)nc1
Product: COc1ccc(CCNC(=O)CCc2ccc(C(F)(F)F)nc2)cc1OC

Procedure:
This compound is prepared by reaction of 3,4-dimethoxyphenylethylamine and 3-(6-trifluoromethyl-pyridin-3-yl)-propionic acid.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([NH:8][C:9]2[CH:10]=[C:11]3[C:21](=[CH:22][CH:23]=2)[O:20][C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:13][C:12]3=[O:24])=[CH:6][CH:5]=[N:4]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[N:48]1([C:53]2[CH:54]=[C:55]([CH:59]=[C:60]([C:62]3[NH:66][N:65]=[N:64][N:63]=3)[CH:61]=2)[C:56](O)=[O:57])[CH2:52][CH2:51][CH2:50][CH2:49]1>O.CN(C=O)C.C(N(CC)CC)C>[CH3:2][N:3]1[C:7]([NH:8][C:9]2[CH:10]=[C:11]3[C:21](=[CH:22][CH:23]=2)[O:20][C:14]2([CH2:15][CH2:16][N:17]([C:56]([C:55]4[CH:59]=[C:60]([C:62]5[NH:63][N:64]=[N:65][N:66]=5)[CH:61]=[C:53]([N:48]5[CH2:52][CH2:51][CH2:50][CH2:49]5)[CH:54]=4)=[O:57])[CH2:18][CH2:19]2)[CH2:13][C:12]3=[O:24])=[CH:6][CH:5]=[N:4]1
Reactant: Cn1nccc1Nc1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Reactant: O=C(O)c1cc(-c2nnn[nH]2)cc(N2CCCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1nccc1Nc1ccc2c(c1)C(=O)CC1(CCN(C(=O)c3cc(-c4nnn[nH]4)cc(N4CCCC4)c3)CC1)O2
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
6-[(1-Methyl-1H-pyrazol-5-yl)amino]spiro[chroman-2,4′-piperidin]-4-one hydrochloride (46 mg), 1-hydroxybenzotriazole monohydrate (17 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27 mg), triethylamine (34 μL) and water (660 μL) were added in that order to a DMF (2 mL) solution of 3-(pyrrolidin-1-yl)-5-(tetrazol-5-yl)benzoic acid (27 mg), and stirred at 90° C. for 2 hours and 30 minutes. Water was added to the reaction liquid, and the formed precipitate was taken out through filtration, once dried, then washed with hexane/ethyl acetate=3/2, and taken out through filtration. After dried, the title compound was obtained as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ: 7.92 (1.0H, s), 7.32 (1.0H, d, J=2.0 Hz), 7.21 (2.0H, s), 7.18-7.13 (2.0H, m), 6.99 (1.0H, d, J=9.2 Hz), 6.67 (1.0H, s), 5.89 (1.0H, s), 4.30-4.22 (1.0H, m), 3.61 (3.0H, s), 3.65-3.20 (3.0H, m), 2.81 (2.0H, s), 2.05-1.85 (9.0H, m), 1.85-1.70 (3.0H, m). MS [M+H]+=554.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:32])[C@@H:15]([NH:24]C(OC(C)(C)C)=O)[CH2:16][CH2:17][C:18]2[N:19]=[N:20][N:21]([CH3:23])[N:22]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:32])[C@@H:15]([NH2:24])[CH2:16][CH2:17][C:18]2[N:19]=[N:20][N:21]([CH3:23])[N:22]=2)[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCc2nnn(C)n2)NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCc2nnn(C)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 806 mg 4-[(S)-2-tert-Butoxycarbonylamino-4-(2-methyl-2H-tetrazol-5-yl)-butyryl]-piperazine-1-carboxylic acid butyl ester in 8 ml dichloromethane were added 1.3 ml TFA. After 12 h stirring at RT the solvents were removed and the residue was codistilled twice with toluene. Yield: 1.18 g.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[OH:31][CH:32]([CH:36]([OH:40])[C:37]([O-:39])=[O:38])[C:33]([O-:35])=[O:34].C>O>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[OH2:31].[OH:31][CH:32]([CH:36]([OH:40])[C:37]([OH:39])=[O:38])[C:33]([OH:35])=[O:34]
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: O=c1[nH]c2ccccc2n1CCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Solvent: O
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
10.2 parts of 5-chloro-1-{1-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one are converted into the (+)-2,3-dihydroxybutanedioate salt in 100 parts of water at reflux temperature. The solution is treated for 10 minutes with a mixture of 0.5 parts of activated charcoal and 0.2 parts of hyflo. The latter is filtered off over hyflo and the filtrate is cooled till an oily precipitate is formed. The oily product solidifies upon heating for a while. The whole is allowed to cool to room temperature and stirred for 3 hours at this temperature. The product is filtered off, washed with water and dried in vacuo for 18 hours at 60° C, yielding 10.24 parts (85.3%) of 5-chloro-1-{1-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one hemi-[R-(R*,R*)](+)-2,3-dihydroxybutanedioate hydrate; mp. 184.1° C; [α] = + 5.13° (c = 1% CH3OH).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:34]3[C:29]([F:28])=[N:30][CH:31]=[CH:32][CH:33]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cccnc1F
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cccnc2F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 133 using (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1) and (2-fluoropyridin-3-yl)boronic acid to afford a white solid. HPLC (Condition 4) tR=5.22 min, UPLC-MS (Condition 3) tR=1.07 min, m/z=479.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.63-1.76 (m, 1H) 1.78-1.88 (m, 1H) 2.84-2.97 (m, 1H) 3.15 (m, J=4.70 Hz, 2H) 3.31-3.43 (m, 1H) 4.14-4.24 (m, 1H) 4.86 (br. s, 1H) 7.32 (d, J=8.99 Hz, 2H) 7.42-7.54 (m, 1H) 7.76-7.89 (m, 2H) 8.00 (d, J=2.35 Hz, 1H) 8.03-8.13 (m, 1H) 8.28 (d, J=4.69 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:3]=1[C:4]([O:6]C1C=CC=CC=1)=O.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[N:26]=1.CO>C1(C)C(C)=CC=CC=1>[CH3:30][O:29][C:27]([C:25]1[N:26]=[C:22]([NH:21][C:4](=[O:6])[C:3]2[CH:13]=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:2]=2[OH:1])[S:23][CH:24]=1)=[O:28]
Reactant: COc1cc(O)c(C(=O)Oc2ccccc2)cc1OC
Reactant: COC(=O)c1csc(N)n1
Solvent: Cc1ccccc1C
Solvent: CO
Product: COC(=O)c1csc(NC(=O)c2cc(OC)c(OC)cc2O)n1
Temperature: 140 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
In 250 mg of xylene were suspended 250 mg of phenyl 2-hydroxy-4,5-dimethoxybenzoate (3a) and 144 mg of methyl 2-amino-1,3-thiazole-4-carboxylate (4a) in a stream of argon, which was then heated to reflux (at 140° C.) for 7 hours. The reaction was not completed. After cooling, methanol was added, followed by stirring for one hour. The precipitated crystal was collected by filtration and dried under reduced pressure at 60° C. to provide 170 mg of the same compound (5a) as that of Example 4 at a yield of 55%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1.S(Cl)(Cl)=O.[CH3:17]O>O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:17])=[O:11])[CH:3]=1
Reactant: CO
Reactant: Nc1cc(C(=O)O)nc(Cl)c1F
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(N)c(F)c(Cl)n1
Temperature: 50 °C
Yield: 86 %

Procedure:
To a solution of 4-amino-6-chloro-5-fluoropicolinic acid (23.8 g, 125 mmol) in MeOH (400 ml), cooled in an ice water bath, thionyl chloride (11.78 ml, 162 mmol) was added. The reaction mixture was heated to an internal temperature of 50° C., for 8 hours. The reaction mixture was then diluted with H2O, and extracted with EtOAC (3×100 mL). The combined organics were washed with Sat. NaCl, dried over Mg Sulfate, filtered and concentrated under vacuum to give methyl 4-amino-6-chloro-5-fluoropicolinate (21.9 g, 107 mmol, 86% yield).
Reaction SMILES: [C:1]([NH:9][C:10]([N:12]1[C:16]2([C:30]3[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:31]=3[F:37])[CH2:17][N:18]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:19][CH:15]2[CH2:14][O:13]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.C(OCC)(=O)C.[Zn]>[C:1]([NH:9][C:10]([NH:12][C:16]1([C:30]2[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:31]=2[F:37])[CH:15]([CH2:14][OH:13])[CH2:19][N:18]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH2:17]1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(=S)N1OCC2CN(C(=O)OCc3ccccc3)CC21c1cc(Br)ccc1F)c1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(NC(=S)NC1(c2cc(Br)ccc2F)CN(C(=O)OCc2ccccc2)CC1CO)c1ccccc1
Yield: 85.6 %

Procedure:
A mixture of benzyl 1-(benzoylcarbamothioyl)-6a-(5-bromo-2-fluoro-phenyl)-3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate (6.05 g 10.4 mmol) and zinc (dust, <10 micron) (6.77 g, 103.5 mmol) is stirred in acetic acid (52 mL) at room temperature overnight under nitrogen. The reaction is diluted with ethyl acetate and filtered through diatomaceous earth. The solvent is removed in vacuo and the residue is diluted with ethyl acetate, water and saturated aqueous sodium bicarbonate. The mixture is extracted with ethyl acetate (3×), the combined organic layers are combined and dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude product is purified over silica gel with a 30 minute 5% to 100% EtOAc in hexanes gradient to give the title compound (5.222 g, 86%). ES/MS (m/e): (79Br/81Br) 586/588 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9](=[O:12])[C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[C:3]1=[O:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:25](O)[CH2:26][OH:27]>>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2([O:27][CH2:26][CH2:25][O:12]2)[C:4]2([CH2:5][CH2:6][CH2:7][CH2:8]2)[C:3]1=[O:13]
Reactant: OCCO
Reactant: CN1CCC(=O)C2(CCCC2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CN1CCC2(OCCO2)C2(CCCC2)C1=O
Yield: 56 %

Procedure:
A solution of 26 g of 7-methyl-7-azaspiro [4.5] decane-6,10-dione in 150 ml of ethylene glycol, containing 100 mg of p-toluenesulphonic acid, is distilled at atmospheric pressure until 110 ml of distillate has been collected. The distillation residue is then shaken with ether and dilute aqueous ammonia. The aqueous layer is extracted with chloroform and the combined organic solutions are dried and evaporated in vacuo. The residue is recrystallized from ether. Melting point 84 -85° C. Yield 56%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[SH:29][C:30]1[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[S:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Reactant: Oc1cccc(S)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Sc3cccc(O)c3)n(-c3ccccc3)c(=O)c12
Yield: 29.4 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.21 mmol) was treated with 3-mercaptophenol (39 mg, 0.31 mmol), potassium carbonate (128 mg, 0.93 mmol) and copper(I) iodide (59 mg, 0.31 mmol) in a microwave vessel with dichloromethane as a solvent according to the method described in Preparation 44. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to give 30 mg (30% yield) of the title compound.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24](O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([F:11])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In an argon atmosphere and while cooling at −78° C., [bis(2-methoxyethyl)amino]sulfur trifluoride (7.33 mL) was added dropwise to 4-hydroxy-1-piperidinecarboxylic acid tert-butyl ester (4.00 g) in methylene chloride (80 mL), followed by stirring for 30 minutes. The resultant mixture was stirred at 0° C. for 30 minutes and then at room temperature for 2 hours. The reaction mixture was partitioned by use of saturated aqueous sodium hydrogencarbonate and chloroform. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform-ethyl acetate) to thereby give 4-fluoropiperidine-N-carboxylic acid tert-butyl ester as an oily product (1.77 g, 44%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.CN1CCNCC1>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Agent: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 188.8 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. The above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Methylpiperazine (9.0 g) and triethylamine (8 ml) are added to the bottle. The above mixture is reacted at the temperature for 1 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum for 5 h at to obtain solid purin (12.0 g). The yield is about 67.4%.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10]([NH2:12])=[O:11])[CH:5]=[CH:4][CH:3]=1.[CH:13](O)=O>>[F:1][C:2]1[N:7]=[C:6]([N:8]2[CH:13]=[N:12][C:10]([OH:11])=[N:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: NC(=O)NNc1cccc(F)n1
Product: Oc1ncn(-c2cccc(F)n2)n1
Temperature: 25 °C
Yield: 60 %

Procedure:
A solution was prepared by admixing 17 g (0.10 m) of 2-(6-fluoro-2-pyridinyl)hydrazinecarboxamide and 60 mls of 98 percent formic acid. This mixture was stirred and refluxed for 2 hours and allowed to cool to room temperature. The insolubles were filtered off and dried to produce 3.5 g of the desired 1-(6-fluoro-2-pyridinyl)-1H-1,2,4-triazol-3-ol which melted at 290° C. with decomposition. The excess formic acid in the remaining liquid phase was distilled off under reduced pressure and the solids which precipitated were washed and dried. This product was a second crop of the desired product which also melted at 290° C. The product was recovered in a yield of 60 percent of theoretical and upon analysis, was found to have carbon, hydrogen and nitrogen contents of 46.80, 2.89 and 31.17 percent, respectively, as compared with the theoretical contents of 46.47, 2.80 and 31.10 percent, respectively, as calculated for the above named compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10](OC)(=[O:18])[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[SH:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[C:10](=[O:18])[N:6]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccc(Br)c2)sc2ccccc12
Yield: 20.6 %

Procedure:
A mixture of 3-bromobenzonitrile (2.00 g, 11 mmol), methyl thiosalicylate (2.87 g, 17 mmol), triethylamine (1.95 g, 19 mmol) and toluene (10 ml) was heated and refluxed under a nitrogen flow for 40 hours. The precipitated crystals were taken by filtration and recrystallized from tetrahydrofuran-ethyl acetate to give the title compound (0.72 g, 21%) as crystals.
Reaction SMILES: O.C(=O)([O-])[O-].[K+].[K+].[NH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[C:29](=[O:30])[C:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[CH:27][N:26]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)=[CH:13][C:12](Br)=[CH:11][N:10]=1.[CH3:44][O:45][C:46]1[CH:51]=[C:50](B2OC(C)(C)C(C)(C)O2)[CH:49]=[CH:48][C:47]=1[OH:61]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[NH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[C:29](=[O:30])[C:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[CH:27][N:26]([CH2:38][C:39]([F:42])([F:41])[F:40])[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)=[CH:13][C:12]([C:50]2[CH:49]=[CH:48][C:47]([OH:61])=[C:46]([O:45][CH3:44])[CH:51]=2)=[CH:11][N:10]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: Nc1ncc(Br)cc1-c1ccc(NC(=O)c2cn(CC(F)(F)F)cc(-c3ccc(F)cc3)c2=O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(-c2cnc(N)c(-c3ccc(NC(=O)c4cn(CC(F)(F)F)cc(-c5ccc(F)cc5)c4=O)cc3)c2)ccc1O
Temperature: 100 °C
Reaction time: 4 h
Yield: 42 %

Procedure:
Water (0.1 ml), potassium carbonate (70 mg) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct (6.9 mg) were added to a solution of the compound obtained in Step 1 of Example 31 (95 mg) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (51 mg) in 1,4-dioxane (1.5 ml), and the mixture was stirred at 100° C. for four hours. After leaving to cool, the reaction solution was diluted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->30:1 (v/v)] to give 43 mg of the title compound as a solid.