Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:36]=[CH:35][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=3)[N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].[Li+].[OH-].O.Cl>C1COCC1.C(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=[C:14]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=3)[N:13]=2)=[CH:35][CH:36]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCOc1ccc(CNc2nc(Nc3ccc(C(=O)OC)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: C=CCCOc1ccc(CNc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 60 °C
Yield: 101 %

Procedure:
methyl 4-(4-(4-(but-3-enyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (46 mg, 0.091 mmol) was dissolved in THF (2 mL). LiOH (10.94 mg, 0.457 mmol) and Water (2 mL) were added to the solution and the reaction was warmed to 60° C. for 16 h. The reaction was diluted with DCM and acidified with 1 N HCl. The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum to give 4-(4-(4-(but-3-enyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (45 mg).
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=CC=2)=CC=1.[F:35][C:36]1[CH:37]=[C:38]([NH:42][C:43](=[O:69])[NH:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:59]=[C:58]4[C:54]([CH2:55][N:56]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([O:64]C)=[O:63])[C:57]4=[O:60])=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)[CH:39]=[CH:40][CH:41]=1>>[F:35][C:36]1[CH:37]=[C:38]([NH:42][C:43](=[O:69])[NH:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:59]=[C:58]4[C:54]([CH2:55][N:56]([C@@H:61]([CH:66]([CH3:67])[CH3:68])[C:62]([OH:64])=[O:63])[C:57]4=[O:60])=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)[CH:39]=[CH:40][CH:41]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)cc2C1=O
Yield: 95.8 %

Procedure:
The compound of example 14 was prepared analogous to compound of example 8 by hydrolysis of compound of example 13.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:11][C:12]1[CH:20]=[CH:19][C:15]2=[N:16][O:17][N:18]=[C:14]2[CH:13]=1)C.[Li+].[OH-]>O1CCCC1>[N:16]1[O:17][N:18]=[C:14]2[CH:13]=[C:12]([O:11][C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4]([OH:21])=[O:3])[CH:20]=[CH:19][C:15]=12
Reactant: CCOC(=O)c1cccnc1Oc1ccc2nonc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cccnc1Oc1ccc2nonc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
A mixture of 2.2 g (7.7 mmol.) 2-[benzo[2,1,3]oxadiazol-5-yloxy]-nicotinic acid ethyl ester and 23.1 ml (23.1 mmol.) 1M LiOH in 75 ml tetrahydrofuran was stirred overnight at room temperature. The tetrahydrofuran was evaporated in vacuo and the aqueous mixture acidified with 1N HCl. The resulting precipitate was filtered and dried to give 1.9 g (96%) solid.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].[C:13]1([N:23]=[C:24]=[O:25])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[C:13]1([NH:23][C:24]([NH:4][C:3]2[CH:5]=[C:6]([C:9]([F:10])([F:11])[F:12])[CH:7]=[CH:8][C:2]=2[OH:1])=[O:25])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cc(C(F)(F)F)ccc1O
Reactant: O=C=Nc1cccc2ccccc12
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(C(F)(F)F)ccc1O)Nc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
2-hydroxy-5-(trifluoromethyl)aniline (0.12 g, 0.7 mmol) in toluene (3 ml) was added to a solution of alpha-naphthyl isocyanate (0.11 g, 0.7 mmol) in toluene (3 ml). The reaction was stirred at RT overnight and the product filtered off. 0.17 g (72%) of the title compound was isolated. M.p. 205°-207° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][N:35]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29].C(#N)C.C(N(CC)CC)C>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:24][C:25]3[CH:26]=[C:27]([CH:33]=[CH:34][N:35]=3)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:15][CH2:16]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: CCOC(=O)c1ccnc(CCl)c1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccnc(CN2CCC(OC(c3ccccc3)c3ccc(OC)cc3)CC2)c1
Reaction time: 8 h
Yield: 67 %

Procedure:
A mixture of 297 mg of a known compound (±)-4-[(4-methoxyphenyl)phenylmethoxy]piperidine, 240 mg of a known compound ethyl 2-chloromethylisonicotinate, 2.3 mL of acetonitrile, and 0.28 mL of triethylamine was stirred overnight. The mixture was poured into salt water and extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over sodium sulfate. The solvent was distilled off, and then the residue was purified by p-TLC to give the title compound (309 mg (67%)).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[N:25]1([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[CH2:33][NH2:34])[CH:29]=[N:28][CH:27]=[N:26]1.C(N(C(C)C)CC)(C)C.O.C(#N)C>CN1C(=O)CCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[CH:9]=[CH:8][C:6]3[N:7]=[C:2]([NH:34][CH2:33][C:32]4[CH:35]=[CH:36][CH:37]=[C:30]([N:25]5[CH:29]=[N:28][CH:27]=[N:26]5)[CH:31]=4)[N:3]=[C:4]([NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])[C:5]=3[N:11]=2)=[CH:13][CH:14]=1
Reactant: NCc1cccc(-n2cncn2)c1
Reactant: Fc1ccc(-c2ccc3nc(Cl)nc(NCC(F)(F)F)c3n2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: Fc1ccc(-c2ccc3nc(NCc4cccc(-n5cncn5)c4)nc(NCC(F)(F)F)c3n2)cc1
Temperature: 160 °C
Yield: 59.5 %

Procedure:
A mixture of [2-Chloro-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-4-yl]-(2,2,2-trifluoro-ethyl)-amine (108 mg) and 3-[1,2,4]Triazol-1-yl-benzylamine (124 mg) was dissolved in NMP (1.9 mL) and treated with diisopropylethylamine (0.060 mL). The reaction mixture was sealed and heated by microwave to 160° C. for 1 h. After cooling, the reaction mixture was added dropwise to a stirred solution of water:acetonitrile (1:1). The resulting precipitate was filtered and purified by silica gel chromatography (0-10% EtOH (containing 11% NH4OH sat aq):DCM) to afford 89 mg (60% yield) of the title compound, which was characterized by its NMR and mass spectrum as follows: 1H NMR (d6-DMSO): d 4.29-4.41 (m, 2H), 4.63-4.66 (m, 2H), 7.29-7.35 (m, 2H), 7.40-7.51 (m, 2H), 7.70-7.75 (m, 3H), 7.87 (s, 1H), 8.19-8.22 (m, 2H), 8.36-8.39 (m, 2H), 8.61-8.64 (m, 1H), 9.25 (s, 1H); MS (m/z): 495.3 ([M+H]+, 100).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[O:23]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34](=[O:35])[C:33]2[CH:32]=[CH:31][C:30]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:38][CH:37]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.28 mmol) in acetonitrile (20 ml) were added 4-phenoxybenzoic acid (274 mg, 1.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (368 mg, 1.92 mmol) and 1-hydroxy-1H-benzotriazole (196 mg, 1.28 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (451 mg, 69%).
Reaction SMILES: [C:1]([NH:6][N:7]=[C:8](OCC)[CH2:9][CH2:10][CH2:11][CH3:12])([O:3]CC)=O.[NH2:16][CH2:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1>C(O)C>[CH2:9]([C:8]1[N:16]([CH2:17][C:18]2[CH:36]=[CH:35][C:21]([O:22][CH:23]([C:24]([O:26][CH3:27])=[O:25])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])=[CH:20][CH:19]=2)[C:1](=[O:3])[NH:6][N:7]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCC(=NNC(=O)OCC)OCC
Reactant: COC(=O)C(Oc1ccc(CN)cc1)c1ccccc1Cl
Solvent: CCO
Product: CCCCc1n[nH]c(=O)n1Cc1ccc(OC(C(=O)OC)c2ccccc2Cl)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of approximately equimolar quantities of ethyl valerimidate carbethoxyhydrazone (from Step A) and methyl 2-[4-(aminomethyl)phenoxy]-2-(2-chlorophenyl)acetate (Step F) in ethanol is stirred at 80° C. under N2. After about 2 hours, or when TLC indicates complete reaction, the mixture is cooled and concentrated to dryness. The residue is re-concentrated from CH2Cl2 and then chromatographed on silica gel to yield the title compound.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][C:4]1[CH:8]=[CH:7][O:6][C:5]=1[C:9](Cl)=[O:10]>>[CH3:3][C:4]1[CH:8]=[CH:7][O:6][C:5]=1[C:9]([NH2:2])=[O:10]
Reactant: Cc1ccoc1C(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1ccoc1C(N)=O

Procedure:
To a stirred flask containing excess concentrated ammonium hydroxide was added gradually 50 g of 3-methyl-2-furoyl chloride. The resulting mixture was extracted with dichloromethane. The extracts were dried, then evaporated to provide solid 3-methylfuran-2-carboxamide.
Reaction SMILES: FC1C=C(OC)C=C(F)C=1[C:11]1=[C:12]([CH:42]=[CH:43][C:44]2[C:52]([CH3:54])([CH3:53])[C:51]3[C:46](=[CH:47][CH:48]=[C:49]([S:55]([O-:58])(=[O:57])=[O:56])[CH:50]=3)[N+:45]=2[CH2:59][CH2:60][CH2:61][CH2:62][S:63]([O-:66])(=[O:65])=[O:64])[CH2:13][CH2:14][CH2:15]/[C:16]/1=[CH:17]\[CH:18]=[C:19]1\[N:20]([CH2:34][CH2:35][CH2:36][CH2:37][S:38]([O-:41])(=[O:40])=[O:39])[C:21]2[C:26]([C:27]\1([CH3:29])[CH3:28])=[CH:25][C:24]([S:30]([O-:33])(=[O:32])=[O:31])=[CH:23][CH:22]=2.[Na+:67].[Na+].[Na+].B([C:73]1[C:74]([F:87])=[C:75]([CH:83]=[CH:84][C:85]=1[F:86])[O:76][CH2:77][CH2:78][CH2:79][C:80]([OH:82])=[O:81])(O)O>>[C:80]([CH2:79][CH2:78][CH2:77][O:76][C:75]1[C:74]([F:87])=[C:73]([C:11]2=[C:16]([CH:17]=[CH:18][C:19]3[C:27]([CH3:29])([CH3:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([S:30]([O-:33])(=[O:31])=[O:32])[CH:25]=4)[N+:20]=3[CH2:34][CH2:35][CH2:36][CH2:37][S:38]([O-:41])(=[O:40])=[O:39])[CH2:15][CH2:14][CH2:13]/[C:12]/2=[CH:42]\[CH:43]=[C:44]2\[N:45]([CH2:59][CH2:60][CH2:61][CH2:62][S:63]([O-:66])(=[O:65])=[O:64])[C:46]3[C:51]([C:52]\2([CH3:54])[CH3:53])=[CH:50][C:49]([S:55]([O-:58])(=[O:56])=[O:57])=[CH:48][CH:47]=3)[C:85]([F:86])=[CH:84][CH:83]=1)([OH:82])=[O:81].[Na+:67].[Na+:67].[Na+:67]
Reactant: COc1cc(F)c(C2=C(C=CC3=[N+](CCCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC/C2=C\C=C2\N(CCCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c(F)c1
Reactant: O=C(O)CCCOc1ccc(F)c(B(O)O)c1F
Agent: CC1(C)C(/C=C/C2=C(c3c(F)ccc(OCCCC(=O)O)c3F)/C(=C/C=C3/N(CCCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC2)=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21
Agent: COc1cc(F)c(C2=C(/C=C/C3=[N+](CCCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC/C2=C\C=C2\N(CCCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c(F)c1
Agent: [Na+]
Product: CC1(C)C(C=CC2=C(c3c(F)ccc(OCCCC(=O)O)c3F)/C(=C/C=C3/N(CCCCS(=O)(=O)[O-])c4ccc(S(=O)(=O)[O-])cc4C3(C)C)CCC2)=[N+](CCCCS(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc21

Procedure:
Compound 37 is prepared analogously to compound 17, except with 4-(3-borono-2,4-difluorophenoxy)butanoic acid as a starting material.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:17]3[S:18][CH:19]=[C:20]([C:22]([O:24]CC)=[O:23])[N:21]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[CH2:30]([OH:32])[CH3:31]>>[CH2:30]([O:32][C:2]1[N:7]=[C:6]2[N:8]([C:17]3[S:18][CH:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:5]2=[CH:4][CH:3]=1)[CH3:31]
Reactant: CCO
Reactant: CCOC(=O)c1csc(-n2nc(-c3ccccc3)c3ccc(Cl)nc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccc2c(-c3ccccc3)nn(-c3nc(C(=O)O)cs3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ethanol (2 mL, manufactured by Wako Pure Chemical Industries, Ltd.) solution of ethyl 2-(6-chloro-3-phenyl-1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole-4-carboxylate (33 mg), which had been synthesized from the compound of Reference Example 33 according to the method of Example 3, 5 M sodium hydroxide (500 μL, manufactured by Kanto Chemical Co., Inc.) was added, and the mixture was stirred for one hour at room temperature. 5 M hydrochloric acid (500 μL, manufactured by Kanto Chemical Co., Inc.) was added to neutralize the mixture, and then the mixture was extracted with chloroform (3×3 mL), washed with brine (3 mL), and dried (MgSO4). The solvent was then evaporated, to give 17.6 mg of the title compound. LC-MS: HPLC retention time 1.38 minutes, m/z (M+H) 367, condition C-1.
Reaction SMILES: [BH4-].[Li+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:26](OC)=[O:27])=[C:8]2[C:12]=1[N:11]=[C:10]1[N:13]([C:17]3[CH:18]=[N:19][C:20]([O:24][CH3:25])=[CH:21][C:22]=3[CH3:23])[CH2:14][CH2:15][CH2:16][N:9]21>O1CCCC1>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:18]=[N:19][C:20]([O:24][CH3:25])=[CH:21][C:22]=4[CH3:23])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH2:26][OH:27])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1cnc(OC)cc1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C)c(N2CCCn3c2nc2c(Cl)ccc(CO)c23)cn1
Temperature: 40 °C
Reaction time: 24 h
Yield: 99.7 %

Procedure:
Lithium borohydride (290 mg, 13.3 mmol) was added to a stirred solution of methyl 9-chloro-1-(6-methoxy-4-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (1.29 g, 3.33 mmol) in tetrahydrofuran (25 mL) at room temperature, and the mixture was stirred at 40° C. for 24 hr. The reaction was quenched by aqueous saturated ammonium chloride at 0° C. and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a colorless powder (1.19 g, 3.32 mmol, 99%).
Reaction SMILES: C([O:3][CH2:4][CH3:5])=O.[CH3:6][Si:7]([CH2:10][Mg]Cl)([CH3:9])[CH3:8].Cl.[NH4+]>C(OCC)C>[CH3:6][Si:7]([CH3:10])([CH3:9])[CH2:8][CH:4]([OH:3])[CH2:5][Si:7]([CH3:9])([CH3:8])[CH3:6]
Reactant: C[Si](C)(C)C[Mg]Cl
Reactant: CCOC=O
Agent: Cl
Agent: [NH4+]
Solvent: CCOCC
Product: C[Si](C)(C)CC(O)C[Si](C)(C)C
Yield: 70 %

Procedure:
Ethyl formate (0.1 mol) was slowly added to 0.3 mol of trimethylsilylmethyl magnesium chloride solution dissolved in diethyl ether which was contained in a 500 ml flask. The mixture was allowed to react under reflux for about 24 hours. After hydrolyzing the reactant using ammonium hydrochloride solution, the obtained reaction product was separated and purified by a vacuum distillation and a 70 percent yield was obtained. The structure of the obtained distillates was analyzed using NMR and a spectroscopic method of FT-IR spectroscopy.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][N:3]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)[Cl:15]>>[Cl:15][CH2:14][CH:16]([OH:18])[CH2:17][N:3]1[C:2](=[O:1])[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:4]1
Reactant: ClCC1CO1
Reactant: Cc1c(O)noc1-c1ccccc1
Product: Cc1c(-c2ccccc2)on(CC(O)CCl)c1=O
Temperature: 75 °C
Yield: 71.1 %

Procedure:
A mixture of 6.00 g (34.2 mmoles) of 3-hydroxy-4-methyl-5-phenylisoxazole and 6.33 g (68.4 mmoles) of epichlorohydrin was stirred, whilst heating at 75° C., for 5 hours. At the end of this time, the excess epichlorohydrin was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of cyclohexane and ethyl acetate as eluent, to give 6.51 g (yield 71.1%) of the title compound as a colorless powder, melting at 82°-83° C.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][CH:3]=1.[OH-].[Na+].[CH:11](=[O:13])[CH3:12].Cl>O>[OH:13][CH:11]([C:3]1[O:4][CH:5]=[CH:6][C:7](=[O:8])[C:2]=1[OH:1])[CH3:12]
Reactant: O=c1ccocc1O
Reactant: CC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(O)c1occc(=O)c1O
Reaction time: 8 h

Procedure:
3-Hydroxy-pyran-4(1H)-one (5.6 g, 50 mmol, 1 eq.) was added to 50 ml water and the pH of the solution was adjusted to 10.5 using 50% aqueous sodium hydroxide. Acetaldehyde (2.64 g, 60 mmol, 1.25 eq.) dissolved in 20 ml water was slowly added dropwise over 1 hour and the solution allowed to stir overnight. The reaction mixture was acidified to pH 1 with 37% w/v hydrochloric acid and concentrated in vacuo to dryness. The residue was extracted with 2×70 ml of isopropanol at 90° C. The isopropanol extracts were combined and concentrated to yield after recrystallisation from toluene, the pure product (3.7 g, 47.4%) as a pale yellow crystalline solid. m.p. 131-132° C. [lit. 130-131° C. (Ichimoto, 1970)].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[CH:18][C:13]3=[C:12]([N:24]3[CH2:29][CH:28]4[CH2:30][CH2:31][CH:25]3[CH2:26][O:27]4)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.C12OC(CC1)CN(C1N=C(C3C=CC(N)=CC=3)N=C3N(CC(F)(F)F)N=CC=13)C2.Cl.C12OC(CC1)CNC2>>[CH:28]12[CH2:30][CH2:31][CH:25]([N:24]([C:12]3[N:11]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=4)[N:15]=[C:14]4[N:16]([CH2:19][C:20]([F:22])([F:23])[F:21])[N:17]=[CH:18][C:13]=34)[CH2:29]1)[CH2:26][O:27]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(N3CC4CCC3CO4)c3cnn(CC(F)(F)F)c3n2)cc1
Agent: C1CC2CNCC1O2
Agent: Cl
Agent: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(CC(F)(F)F)c3n2)cc1
Product: Nc1ccc(-c2nc(N3CC4CCC3CO4)c3cnn(CC(F)(F)F)c3n2)cc1

Procedure:
4-(4-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline was prepared from 5-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.2]octane according to the method used for 4-[4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenylamine, except in step 5,2-oxa-5-azabicyclo[2.2.2]octane hydrochloride replaced 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:23][O:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1.C(OCC)C>O>[CH2:1]([O:19][CH2:20][CH:21]([CH2:23][O:24][C:25]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:22][S:50]([C:47]1[CH:48]=[CH:49][C:44]([CH3:54])=[CH:45][CH:46]=1)(=[O:52])=[O:51])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OS(=O)(=O)c1ccc(C)cc1
Temperature: 4 °C

Procedure:
A solution of 1-O-octadecyl-3-O-tritylglycerol (173.51 g, 295.63 mmol) in 895 mL water free pyridine is added to a solution of p-toluenesulfonyl chloride (88.49 g, 464.15 mmol) in 670 mL water-free pyridine with constant stirring. The reaction mixture is kept at ambient temperature (20°-23° C.) for two days. Diethyl ether (2.8 L) is added to this reaction mixture and the organic phase is washed six times with water, twice with diluted aqueous sodium carbonate, and then washed with water until neutral. After drying the organic phase over sodium sulfate, the solvent is removed under reduced pressure. The residue is triturated with isopropanol (1140 mL) with stirring until the product crystallizes. After cooling to 4° C., the product, 1-O-octadecyl-2-O-p-toluenesulfonyl-3-O-tritylglycerol, is isolated by filtration, washed with isopropanol and dried under vacuum.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[C@@H:30]([CH3:31])[C@H:29]([CH2:32][CH2:33][C:34]([O:36]C)=[O:35])[C:15]([C:16]5[CH2:27][C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:28])=[CH:20]2)=[N:14]4)=[C:9]([CH3:38])[C:8]=3[CH:39]=[CH2:40])[C:4]=1[CH3:41].Cl.CO.ClCCl>O1CCCC1>[CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[C@@H:30]([CH3:31])[C@H:29]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:15]([C:16]5[CH2:27][C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:28])=[CH:20]2)=[N:14]4)=[C:9]([CH3:38])[C:8]=3[CH:39]=[CH2:40])[C:4]=1[CH3:41]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4)[C@@H](CCC(=O)OC)[C@@H]3C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4)[C@@H](CCC(=O)O)[C@@H]3C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl pyropheophorbide-a (2, 250 mg) was dissolved in distilled tetrahydrofuran (50 ml) and 4N HCl (125 ml) was added in one lot. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 4 hours. The reaction was monitored by analytical tlc (silica plates), using 10% methanol/dichloromethane as a mobile phase. The reaction mixture was then poured in ice water, extracted with dichloromethane. The dichloromethane layer was washed several times with water (3×200 ml). The organic layer was separated and dried over anhydrous sodium sulfate. Evaporation of the solvent gave a residue, which was crystallized from dichloromethane/hexane. Yield, 225 mg. The purity of the compound was ascertained by tlc and the structure was confirmed by NMR spectroscopy. The NMR data were similar as described for 2 except the resonances for the --OCH3 protons of the propionic ester (--CH2CH2CO2CH3) were missing.
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.[OH:18][CH:19]([CH3:26])[CH2:20][O:21][N:22]=[C:23]([CH3:25])[CH3:24]>>[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:18][CH:19]([CH3:26])[CH2:20][O:21][N:22]=[C:23]([CH3:25])[CH3:24])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: CC(C)=NOCC(C)O
Product: CC(C)=NOCC(C)OC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and acetone (2-hydroxypropyl) oxime, there is obtained 2-[(isopropylideneamino)oxy]-1-methylethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 351 (12), 295 (4), 237 (81), 194 (100), 114 (35), 56 (78);