Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:16][CH2:15][CH2:14][N:13](CC2C=CC=CC=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:41]([O:43][CH2:44][C:45]([Cl:48])([Cl:47])[Cl:46])=[O:42]>C(Cl)(Cl)Cl>[CH2:27]([O:26][C:24]([C:11]1([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:16][CH2:15][CH2:14][N:13]([C:41]([O:43][CH2:44][C:45]([Cl:48])([Cl:47])[Cl:46])=[O:42])[CH2:12]1)=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: O=C(OCc1ccccc1)C1(C(=O)OCc2ccccc2)CCCN(Cc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(OCC(Cl)(Cl)Cl)N1CCCC(C(=O)OCc2ccccc2)(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-benzylpiperidine-3,3-dicarboxylic acid 3,3-dibenzyl ester (19.6 g 41.8 mmol) and sodium carbonate (5.1 g, 48.1 mmol) in chloroform cooled with a water/ice bath, is added 2,2,2-trichloroethyl chloroformate (11 g, 51.8 mmol). The mixture is stirred overnight at room temperature and concentrated under reduced pressure. The residue is dissolved in diethyl oxide, washed with water, dried over magnesium sulphate and concentrated under reduced pressure to give piperidine-1,3,3-tricarboxylic acid 1-(2,2,2-trichloroethyl) 3,3-dibenzyl ester which cristallizes upon standing.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:14][CH2:15][CH3:16])(=[O:13])C(C)C.[CH3:17][O:18][C:19]1[C:27]([CH3:28])=[C:26]2[C:22]([C:23](=[O:29])[O:24][CH2:25]2)=[C:21]([O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[C:20]=1[CH2:37][CH2:38][CH:39]([CH3:54])[CH2:40][C@H:41]([CH3:53])[C:42](N1[C@H](C(C)C)COC1=O)=O.[NH4+].[Cl-]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:36][O:35][CH2:34][CH2:33][O:32][CH2:31][O:30][C:21]1[C:20]([CH2:37]/[CH:38]=[C:39](\[CH3:54])/[CH2:40][C:41]([CH3:53])([CH3:42])[C:9]([O:14][CH2:15][CH3:16])=[O:13])=[C:19]([O:18][CH3:17])[C:27]([CH3:28])=[C:26]2[C:22]=1[C:23](=[O:29])[O:24][CH2:25]2
Reactant: CCOC(=O)C(C)C
Reactant: COCCOCOc1c(CCC(C)C[C@H](C)C(=O)N2C(=O)OC[C@H]2C(C)C)c(OC)c(C)c2c1C(=O)OC2
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(C)(C)C/C(C)=C/Cc1c(OC)c(C)c2c(c1OCOCCOC)C(=O)OC2
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 74 %

Procedure:
A freshly prepared solution of lithium diisopropylamide (2.8 mmol/10 ml THF) was cooled to -78° C. and ethyl isobutyrate (0.75 ml) was added slowly. The solution was stirred at -78° C. for 40 minutes and then a solution of (E) 4-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2-methylbut-2-enyl bromide (0.6 g) in THF (2 ml) and HMPA (1.5 ml) was added via syringe at such rate that the temperature was maintained below -60° C. After stirring for 30 minutes at -78° C., the mixure was poured onto 100 ml of a concentrated solution of NH4Cl. The organic and aqueous phases were separated and the aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over NaSO4 and evaporated to give a residue which was passed through a column (silica gel, CHCl2 --EtOAc 95:5) to afford 480 mg (74%) of ethyl (E) 6-(4-methoxyethoxymethoxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2,2,4-trimethyl-4-hexenoate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH2:18])=[O:5].[C:24]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25]1.O>CN(C)C=O>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH:18][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5]
Reactant: O=C1CCC(=O)O1
Reactant: NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCC(=O)NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 27.4 %

Procedure:
To a solution of 8-(2,6-dichlorobenzoylamino)-4-hydrazinoquinoline (298 mg) in dimethylformamide (4 ml) was added succinic anhydride (94 mg), and the mixture was stirred at ambient temperature for 12 hours. To the mixture was added water (10 ml) and the precipitate was collected. The solid was treated with hot ethanol (5 ml), allowed to cool to ambient temperature, filtered and washed with water to give 8-(2,6-dichlorobenzoylamino)-4-[2-(3-carboxypropanoyl)hydrazino]quinoline as a yellow crystal (105 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH:26]1([N:29]2[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:28][CH2:27]1>>[CH:26]1([N:29]2[CH2:35][CH2:34][CH2:33][N:32]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([N:12]4[C:13]([OH:14])=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=5[CH3:24])[CH:10]=[N:11]4)=[N:16][CH:17]=3)=[O:20])[CH2:31][CH2:30]2)[CH2:28][CH2:27]1
Reactant: C1CNCCN(C2CC2)C1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCCN(C5CC5)CC4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-cyclopropyl-1,4-diazepane. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.66-1.06 (m, 4H) 1.94-2.23 (m, 2H) 2.33 (d, J=2.02 Hz, 3H) 2.81-3.07 (m, 1H) 3.41-4.30 (m, 8H) 7.54-7.70 (m, 1H) 7.75 (t, J=7.45 Hz, 1H) 7.98-8.65 (m, 4H). ESI-MS m/z [M+H]+ 461.3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].C1OCCOCCOCCOCCOCCOC1.[CH3:36][O:37][C:38](=[O:53])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][C:40]=1[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>COCCOC.C1(C)C=CC=CC=1.O>[CH3:36][O:37][C:38](=[O:53])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45][O:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:41][C:40]=1[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: Oc1cccnc1
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1
Reaction time: 0.25 h
Yield: 48.4 %

Procedure:
To a mechanically-stirred 0° C. solution of 3-hydroxypyridine (4.4 g, 46 mmol) in DME (20 mL) was added potassium hexamethyldisilazide (0.5 M in toluene, 88.5 mL, 44 mmol) and the mixture was stirred for 15 minutes. 18-Crown-6 (1.46 g, 5.5 mmol) and a solution of 4-bromomethyl-2-phenylbenzoic acid methyl ester (6.8 g, 22 mmol) in toluene (25 mL) was added and the reaction mixture was vigorously stirred overnight. The reaction mixture was poured into 200 mL of water and the layers were separated. The aqueous phase was extracted with 2 portions of ethyl acetate and the combined organic phases were extracted with water and brine, dried (MgSO4), filtered and concentrated. The resulting oil was purified by flash chromatography (65% ethyl acetate-hexane) to give 4-(3-pyridyloxymethyl)-2-phenylbenzoic acid methyl ester (3.4 g).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][NH:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1)[CH3:2].[CH:21]1[C:33]2[CH:32]([CH2:34][O:35][C:36]([NH:38][C@@H:39]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=3)[C:40](O)=[O:41])=[O:37])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1>>[C:51]([O:50][C:47]1[CH:46]=[CH:45][C:44]([CH2:43][C@H:39]([NH:38][C:36](=[O:37])[O:35][CH2:34][CH:32]2[C:33]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:40]([N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:18][CH2:19][CH3:20])[CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[O:41])=[CH:49][CH:48]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: CCOC(CNCc1ccnc2ccccc12)OCC
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: CCOC(CN(Cc1ccnc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Yield: 76.3 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, 2,2-diethoxy-N-(quinolin-4-ylmethyl)ethanamine (Compound IX-4) (274 mg, 1.0 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid (689 g, 1.5 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=5:1 to 2:1) to obtain the title compound (546 mg, 76%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[C:5]([C:10]([O:19][CH2:20][O:21][CH3:22])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:31]([NH:34][CH2:35][CH:36]=[CH2:37])[CH:32]=[CH2:33]>C(#N)C>[CH2:31]([N:34]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[C:5]([C:10]([O:19][CH2:20][O:21][CH3:22])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])[CH:4]=1)[CH2:35][CH:36]=[CH2:37])[CH:32]=[CH2:33]
Reactant: COCOC(c1cc(CBr)ccc1I)(C(F)(F)F)C(F)(F)F
Reactant: C=CCNCC=C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN(CC=C)Cc1ccc(I)c(C(OCOC)(C(F)(F)F)C(F)(F)F)c1
Temperature: 80 °C
Yield: 84.8 %

Procedure:
Compound 5 (1.07 g, 2.11 mmol) was dissolved in anhydrous acetonitrile (20 mL) under nitrogen atmosphere. Potassium carbonate (583 mg, 4.22 mmol), potassium iodide (350 mg, 2.11 mmol) and diallylamine (2.6 mL, 21.1 mmol) were added and the reaction mixture heated at 80° C. overnight. After cooling to room temperature, the salts were filtered and the filtrate ware evaporated under reduced pressure. The residue was purified over silica gel using heptane/acetone (9/1) as eluant to give 936 mg (1.79 mmol, 85% yield) of a yellowish oil.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH2:28][CH2:29]O[SiH](C)C)[CH2:23]C(C)(C)C)=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:52]1CCCC1>>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH:22]([CH2:28][CH3:29])[CH2:23][OH:52])=[CH:19][CH:20]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: C[SiH](C)OCCC(CC(C)(C)C)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCC(CO)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reaction time: 1.5 h
Yield: 80 %

Procedure:
To the product of Example 3D (0.3 g, 0.6 mmol) in a 10 mL round bottom flask was added tetrahydrofuran (2 mL). Upon solution, tetrabutylammonium fluoride (1.8 mmol, 1.8 mL, 1 M solution in THF) was added and the reaction mixture was stirred for 90 minutes. The contents were then concentrated under reduced pressure and the crude mixture purified by flash chromatography using silica gel (hexanes:ethyl acetate) to obtain 185 mg (80%) of pure desired product. 1H (CDCl3) δ (ppm): 7.74 (s, 1H), 7.3 (d, 2H), 6.9 (d, 2H), 5.2 (s, 2H), 4.3 (m, 1H), 3.81-3.77 (two br s, 2H), 1.84 (hr t, 1H), 1.77-1.69 (m, 2H), 1.64 (s, 9H), 0.98 (t, 3H); 13C (CDCl3) δ (ppm): 159.2, 158.9, 153.9, 129.2, 127.5, 125.4, 116.6, 80.4, 71.9, 66.5, 64.2, 28, 23.5, 9.7.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:11]=[C:12]([CH3:18])[C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[C:6]=2[CH:19]=1.CN(C)[C:22]1[O:23][C:24](=[O:32])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:27]=1.C(O)(=O)C>O>[CH3:17][O:16][C:13]1[C:12]([CH3:18])=[CH:11][C:10]([C:7]2[C:6]3[CH:19]=[C:2]([N:1]4[C:24](=[O:32])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[NH:27][C:22]4=[O:23])[CH:3]=[CH:4][C:5]=3[O:9][N:8]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(-c2noc3ccc(N)cc23)cc1C
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2noc3ccc(-n4c(=O)cc(C(F)(F)F)[nH]c4=O)cc23)cc1C

Procedure:
A mixture of 5-amino-3-(6-methoxy-m-tolyl)-1,2-benzisoxazole (8.40 g, 0.033 mol), 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazin-6-one (7.60 g, 0.036 mol), and acetic acid is refluxed for three hours, cooled, poured onto ice, and diluted with water. The resultant aqueous mixture is filtered to obtain a solid. The solid is washed with water and dried to give the title product as a pink solid which is identified by NMR spectral analyses.
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:24][CH3:25])([CH3:3])[CH3:2]
Reactant: CC(C)Br
Reactant: COc1cc2c(Nc3cccc(C)c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Nc3cccc(C)c3)ncnc2cc1OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
Isopropyl bromide (0.246 g) was added to a stirred mixture of 7-hydroxy-6-methoxy-4-(3'-methylanilino)quinazoline (0.281 g), potassium carbonate (0.414 g) and DMA (3 ml). The mixture was stirred at ambient temperature for 30 minutes and then heated to 70° C. for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated to give 7-isopropoxy-6-methoxy-4-(3'-methylanilino)quinazoline (0.28 g), m.p. 218°-221° C. NMR Spectrum: (CD3SOCD3) 1.36 (d, 6H), 2.34 (s, 3H), 3.94 (s, 3H), 4.83 (m, 1H), 6.94 (d, 1H), 7.17 (s, 1H), 7.27 (t, 1H), 7.57 (s, 1H), 7.64 (d, 1H), 7.82 (s, 1H), 8.43 (s, 1H); Elemental Analysis: Found C, 69.4; H, 6.7; N, 12.0; C19H21N3O2. 0.3H2O. 0.1EtOAc requires C, 69.0; H, 6.6; N, 12.4%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=3)[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:7]([CH3:35])[C:6]=2[CH:36]=1.C(N(CC)CC)C.[C:44](OC(=O)C)(=[O:46])[CH3:45].C(=O)([O-])O.[Na+]>O1CCCC1>[C:44]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=3)[CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)=[C:7]([CH3:35])[C:6]=2[CH:36]=1)(=[O:46])[CH3:45]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(N)cc3c2C)C2CCCCC2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(NC(C)=O)cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 70 %

Procedure:
To a solution (10 mL) of ethyl 3-{[(4-{[(5-amino-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (480 mg) synthesized above in tetrahydrofuran were added triethylamine (204 μL) and acetic anhydride (138 μL), and the mixture was stirred at room temperature for 2.5 days. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (90% ethyl acetate/hexane) to give the title object compound (366 mg, 70%) as a pale-brown oil
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])[CH:5]=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:26][C:25]3[C:20]([O:19][CH3:18])=[N:21][CH:22]=[CH:23][CH:24]=3)[N:7]=2)[CH3:10])=[N:12][CH:13]=1
Reactant: COc1ncccc1N
Reactant: C[C@H](Nc1ccnc(Cl)n1)c1ccc(F)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ncccc1Nc1nccc(N[C@@H](C)c2ccc(F)cn2)n1
Temperature: 100 °C
Yield: 19 %

Procedure:
An oven-dried resealable Schlenk tube was charged with (S)-2-chloro-N-(1-(5-fluoropyridin-2-yl)ethyl)pyrimidin-4-amine (Preparation 1a, 43 mg, 0.17 mmol), 2-methoxypyridin-3-amine (23 mg, 0.19 mmol), cesium carbonate (111 mg, 0.34 mmol) and 1,4-dioxane (3 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon then tris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.02 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (10 mg, 0.02 mmol) were added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was capped and then stirred and heated to 100° C. After 24 hours the mixture was cooled to ambient temperature and the solvent was evaporated under reduced pressure. Ethyl acetate was added and the organic solution was washed with water (×3) and brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by reverse phase chromatography (C-18 silica from Waters©, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give the title compound (11 mg, 19%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH3:22])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:5][CH:4]=1.[CH3:30][O:31][CH2:32][CH2:33][C:34](Cl)=[O:35]>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]([C:34](=[O:35])[CH2:33][CH2:32][O:31][CH3:30])[CH3:22])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[CH:5][CH:4]=1
Reactant: COCCC(=O)Cl
Reactant: CNCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Product: COCCC(=O)N(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1

Procedure:
Using N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-methylaminomethyl-benzamide and 3-methoxy-propionyl chloride, the title compound was prepared as light yellow crystals (46% yield). MS: m/e=499(M+H+).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](SCC)=[N:12][N:11]=[N:10]2)=[C:5]([F:17])[CH:4]=1.C([OH:20])C>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:20])[NH:12][N:11]=[N:10]2)=[C:5]([F:17])[CH:4]=1
Reactant: CCO
Reactant: CCSc1nnnn1-c1ccc(Cl)cc1F
Agent: [Na]
Solvent: O
Product: O=c1[nH]nnn1-c1ccc(Cl)cc1F

Procedure:
To a stirred solution of 0.12 g (0.0052 mole) of sodium in 16 ml of ethanol was added 1.2 g (0.0046 mole) of (1-(4-chloro-2-fluorophenyl)-1H-tetrazol-5-yl)ethyl sulfide. The resultant solution was heated at reflux for six hours. The reaction mixture was cooled and the solvent was evaporated under reduced pressure leaving a residue. This residue was dissolved in 40 ml of water and the aqueous solution was washed with diethyl ether. The aqueous phase was acidified with concentrated hydrochloric acid forming a precipitate. The precipitate was collected by filtration and dried to yield 0.55 g of 1-(4-chloro-2-fluorophenyl)-1,4-dihydro-5H-tetrazol-5-one as a solid, m.p. 194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[CH:6][C:7]=1[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])O.S(Cl)([Cl:28])=O>ClC(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:18]2[C:23](=[O:24])[NH:22][C:21](=[O:25])[CH:20]=[N:19]2)[CH:5]=[CH:6][C:7]=1[CH:8]([Cl:28])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17]
Reactant: O=c1cnn(-c2ccc(C(O)c3ccc(Cl)cc3Cl)c(Cl)c2)c(=O)[nH]1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3Cl)c(Cl)c2)c(=O)[nH]1
Reaction time: 3 h

Procedure:
To a stirred mixture of 16 parts of 2-[3-chloro-4-[(2,4-dichlorophenyl)hydroxymethyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione and 150 parts of trichloromethane are added dropwise, during a period of 5 minutes, 16 parts of thionyl chloride. Upon completion, stirring is continued for 3 hours at reflux temperature. The reaction mixture is evaporated in vacuo. Methylbenzene is added and the whole is evaporated again, yielding 2-[3-chloro-4-[chloro(2,4-dichlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione.
Reaction SMILES: [CH:1]1([C:7]([OH:33])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:10][CH2:11][C:12]#[C:13][CH2:14][N:15](CC2C=CC(OC)=CC=2)[CH2:16][CH3:17])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)OC(Cl)C.CO>ClC(Cl)C>[CH:27]1([C:7]([OH:33])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:10][CH2:11][C:12]#[C:13][CH2:14][NH:15][CH2:16][CH3:17])=[O:9])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCN(CC#CCOC(=O)C(O)(c1ccccc1)C1CCCCC1)Cc1ccc(OC)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CO
Product: CCNCC#CCOC(=O)C(O)(c1ccccc1)C1CCCCC1

Procedure:
reacting said 4-[N-ethyl-(4-methoxyphenyl)methylamino]-2-butynyl α-cyclohexyl-α-hydroxybenzeneacetate sequentially with α-chloroethyl carbonochloridate in dichloroethane, followed by methanol to produce 4-(ethylamino)-2-butynyl α-cyclohexyl-α-hydroxybenzeneacetate (desethyloxybutyin).
Reaction SMILES: [CH3:1][N:2]([CH2:17][CH:18]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=1)[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]([C:29]2[NH:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[N:30]=2)=[O:28])[CH2:23][CH2:22]1)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1.[CH2:45]([O:47][CH2:48][CH2:49]Cl)[CH3:46]>>[CH3:1][N:2]([CH2:17][CH:18]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=1)[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]([C:29]2[N:30]([CH2:46][CH2:45][O:47][CH2:48][CH3:49])[C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[N:33]=2)=[O:28])[CH2:23][CH2:22]1)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1
Reactant: COc1cc(C(=O)N(C)CC(CCN2CCC(C(=O)c3nc4ccccc4[nH]3)CC2)c2cccc(Cl)c2)cc(OC)c1OC
Reactant: CCOCCCl
Product: CCOCCn1c(C(=O)C2CCN(CCC(CN(C)C(=O)c3cc(OC)c(OC)c(OC)c3)c3cccc(Cl)c3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 21.1 using N-methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3-chlorophenyl)butyl)-3,4,5-trimethoxybenzamide and 2-chloroethyl ethyl ether to give the title compound.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:18][CH:19]([OH:22])[CH2:20][CH3:21]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:22][CH:19]([CH2:20][CH3:21])[CH3:18])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCC(C)O
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: CCC(C)OC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and 2-butanol there is obtained 2-butyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resinous product, 1H-NMR(CDCl3): 1.02 (t, CH2CH3), 1.35 (d, CH--CH3), 1.4-2.0 (m, 2H), 4.23 (s, 4H), 4.83 (m, 1H), 7.3-7.7 (8H);