Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].N1C=CC=CC=1.[CH3:24][O:25][C:26]1[C:27]([O:46][CH3:47])=[C:28]([CH:43]=[CH:44][CH:45]=1)[C:29](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C1C=CN=CC=1.CO>[CH3:24][O:25][C:26]1[C:27]([O:46][CH3:47])=[C:28]([CH:43]=[CH:44][CH:45]=1)[C:29]([O:9][CH2:8][C@H:5]1[O:4][C@@H:3]([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[C@H:2]([F:1])[C@@H:6]1[OH:7])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1OC
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: c1ccncc1
Product: COc1cccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](F)[C@@H]2O)(c2ccccc2)c2ccccc2)c1OC
Reaction time: 3 h

Procedure:
0.5 g (about 2 mmol) of 2′-fluoro-2′-deoxyuridine is coevaporated with 10 ml of abs. pyridine twice in a 50 ml Schlenk flask. The dried nucleoside is taken up in 25 ml of abs. pyridine and, at room temperature, 0.66 g (about 2.2 mmol) of dimethoxytrityl chloride and 10 mg of 4-dimethylaminopyridine are added. After three hours, 1 ml of methanol was added to the mixture, which was then evaporated to dryness in vacuo. The remaining oil is taken up in 50 ml of methylene chloride (deacidified over aluminum oxide) and extracted three times with 50 ml of water. The organic phase is dried over sodium sulfate. After the methylene chloride had been stripped off, the crude product remained as a solid foam. To remove more highly tritylated components and the tritanol, the crude product was digested with 30 ml of abs. benzene at 40-50° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([O:19][C@H:20]4[CH2:25][CH2:24][N:23]([CH3:26])[C@@H:22]([C:27](O)=[O:28])[CH2:21]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:34][NH2:35]>>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:30][CH3:31])=[C:16]([O:19][C@H:20]4[CH2:25][CH2:24][N:23]([CH3:26])[C@@H:22]([C:27]([NH:35][CH3:34])=[O:28])[CH2:21]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C)[C@@H](C(=O)O)C1
Agent: Cl
Product: CNC(=O)[C@H]1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C

Procedure:
(2R,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-1-methylpiperidine-2-carboxylic acid (20) was coupled with methylamine hydrochloride analogously as for the equivalent step in Example 7 to give the title compound (2R,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N,1-dimethylpiperidine-2-carboxamide: 1H NMR Spectrum: (DMSO-d6) δ1.63-1.72 (2H, m), 2.15-2.21 (6H, m), 2.55-2.62 (4H, m), 2.93-2.98 (1H, m), 3.94 (3H, s), 4.43-4.51 (1H, m), 7.23 (1H, s), 7.28-7.33 (1H, m), 7.49-7.56 (2H, m), 7.68-7.72 (1H, m), 7.86 (1H, s), 8.39 (1H, s), 9.57 (1H, s); Mass Spectrum: (M+H)+ 474.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:6][C:5]([CH3:17])=[CH:4][C:3]=1[CH:18](SCCC)[C:19]([NH2:21])=[O:20]>O1CCCC1.[Ni]>[NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)=[CH:6][C:5]([CH3:17])=[CH:4][C:3]=1[CH2:18][C:19]([NH2:21])=[O:20]
Reactant: CCCSC(C(N)=O)c1cc(C)cc(C(=O)c2ccc(F)cc2)c1N
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1cc(CC(N)=O)c(N)c(C(=O)c2ccc(F)cc2)c1

Procedure:
A mixture of 60.0 (0.167 mole) of 2-amino-3-(4-fluorobenzoyl)-5-methyl-α-(propylthio)phenylacetamide in 2.4 liters of tetrahydrofuran was treated with 400 g of wet Raney nickel (washed with water and titrated to constant pH 7 with acetic acid, washed again with water and then washed 3 times with tetrahydrofuran). The mixture was filtered and the filtrate was concentrated. The residue was triturated with hot isopropyl ether and recrystallized from isopropyl alcohol to give 43.6 (91%) of the titled compound as bright yellow crystals, m.p. 203°-206° C.
Reaction SMILES: C([NH:9][C:10](=[S:23])[NH:11][C:12]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:14][N:13]=1)(=O)C1C=CC=CC=1.[OH-].[K+].Cl.[OH-].[NH4+].C(O)(=O)C1C=CC=CC=1>>[C:17]1([C:15]2[S:14][N:13]=[C:12]([NH:11][C:10]([NH2:9])=[S:23])[N:16]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(NC(=S)Nc1nsc(-c2ccccc2)n1)c1ccccc1
Agent: Cl
Agent: O=C(O)c1ccccc1
Agent: [K+]
Product: NC(=S)Nc1nsc(-c2ccccc2)n1
Temperature: 60 °C

Procedure:
3-[N′-(benzoyl)thioureido]-5-phenyl-1,2,4-thiadiazole (BzPTT; 1 kg, 2.94 moles) was placed in a 12-L reaction vessel. A solution of KOH (8.8 L; 3.0 M in water) was added with stirring. The reaction milieu (initially yellow) was heated to 60° C. for about 1 hour or until completion with vigorous stirring. Completion of the reaction was determined either by a color change, e.g., from yellow (BzPTT) to white (PTT), or by monitoring by NMR. Concentrated HCl (2.2 L) was added with stirring at 0-10° C. to lower the pH to about 2-3 by Litmus paper. Concentrated ammonium hydroxide (241 mL) was added to the reaction milieu to raise the pH to about 8, which is more than 4 pH units greater than the pKa of the benzoic acid. After cooling in an ice bath for 30 minutes, the PTT was isolated by filtration in a Büchner funnel over filter paper and dried at room temperature overnight until dryness. The yield of PTT was about 97.4% and the product was about 99.7% pure as determined by HPLC. The H1NMR and 13C NMR spectrum of the product was consistent with that of a reference sample. Mp (253-255° C.) and mass spectroscopy were also used to identify the product.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:14]([O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([N:8]1[C:12]([NH:13][C:25]2[CH:26]=[CH:27][C:22]([O:21][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])=[CH:23][CH:24]=2)=[CH:11][CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccnn1Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Nc2ccnn2Cc2ccccc2)cc1
Reaction time: 12 h
Yield: 44.7 %

Procedure:
A suspension of 1-benzyl-1H-pyrazol-5-amine (5.0 g), (4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)boronic acid (15 g), copper acetate (11 g), pyridine (12 mL) and molecular sieves 4A (10 g) in tetrahydrofuran (150 mL) was stirred for 12 hr. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (4.9 g, 45%).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[C:7](Br)[C:6]([F:11])=[C:5]([F:12])[C:3]=1[NH2:4].[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[C:8]([F:9])=[C:7]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[CH:20]=2)[C:6]([F:11])=[C:5]([F:12])[C:3]=1[NH2:4]
Reactant: Nc1c(F)c(F)c(Br)c(F)c1F
Reactant: COc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: COCCOC
Product: COc1cccc(-c2c(F)c(F)c(N)c(F)c2F)c1
Temperature: 90 °C

Procedure:
Alternative procedure: 2,3,5,6-Tetrafluoro-4-bromoaniline (12.0 g, 49.2 mmol) is dissolved in DME (250 mL) and treated with 3-methoxyphenylboronic acid (7.5 g, 49.2 mmol), a catalytic amount of palladium(II) acetate (0.23 g, 1.0 mmol) and tri-o-tolylphosphine (1.22 g, 4.0 mmol). Potassium carbonate (13.6 g in 50 mL water) is added and the reaction mixture stirred, purged with nitrogen, then heated to 90° C. for 24 hours. After cooling to room temperature most of the DME is removed by rotary evaporator under high vacuum. The resulting material is partitioned between EtOAc (200 mL) and water (250 mL). The organic layer is washed with brine, dried (Na2SO4) and concentrated by rotary evaporator. The crude reaction product is purified by flash chromatography (9:1 hexanes/EtOAc, then 6:4 hexanes/EtOAc) to give 2,3,5,6-tetrafluoro-4-(3′-methoxyphenyl)aniline (m.p. 94–96° C.).
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]=1[CH3:3].[H][H]>FC(F)(F)C(O)=O.O=[Pt]=O>[CH3:3][C:2]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[N:1]=1
Reactant: Cc1ccc2ccccc2n1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(n1)CCCC2

Procedure:
A solution of quinaldine (available from Aldrich) (25 mL, 176 mmol) in trifluoroacetic acid (140 mL) was hydrogenated at 50 psi hydrogen in the presence of PtO2 (2.62 g, 11.5 mmol) for 1.5 h at rt. (This method was conducted in accordance with Bell, T. W. et. al. J. Am. Chem. Soc. 2002 124, 14092 incorporated herein by reference). The mixture was filtered through filter paper, diluted with water and crushed ice, and made basic by the addition of solid NaOH until the mixture was pH>10. The aqueous layer was extracted with hexane. The pooled organic layers were washed with water and dried over MgSO4. The mixture was filtered and evaporated to give 2-methyl-5,6,7,8-tetrahydro-quinoline (Intermediate 200A1) as a clear, yellow oil ˜25 g (98%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[N:28]=[C:27]([CH2:29][N:30]([CH3:40])[CH2:31][C:32]([NH:34][CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:33])[CH:26]=[CH:25][CH:24]=1>>[CH:35]1([NH:34][C:32](=[O:33])[CH2:31][N:30]([CH2:29][C:27]2[N:28]=[C:23]([NH:1][C:2]3[S:3][C:4]([C:10]4[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=4[F:16])=[CH:5][C:6]=3[C:7]([NH2:9])=[O:8])[CH:24]=[CH:25][CH:26]=2)[CH3:40])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CN(CC(=O)NC1CCCC1)Cc1cccc(Br)n1
Product: CN(CC(=O)NC1CCCC1)Cc1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared by using the procedure listed in Example 1 with 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.12 g, 0.38 mmol) and N2-[(6-bromopyridin-2-yl)methyl]-N-cyclopentyl-N2-methylglycinamide (0.11 g, 0.34 mmol) as the starting materials.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[CH2:15][CH:16]([N:18]=[N+]=[N-])[CH3:17])=[CH:8][CH:7]=1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[CH2:15][C@@H:16]([NH2:18])[CH3:17])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2cnn(CC(C)N=[N+]=[N-])c2c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc2cnn(C[C@H](C)N)c2c1
Yield: 66.5 %

Procedure:
To a solution of the product from Step C (0.20 g, 0.73 mmol) in ethanol (10 mL) was added Pd/C (10%, 0.01 g) under nitrogen atmosphere at room temperature. The resultant suspension was stirred for 18 h under hydrogen atmosphere. The reaction was filtered through a filter aide and the filtrate was concentrated in vacuo to give a residue (0.12 g, 66%) which was purified by chromatography (silica, 10% ethyl acetate in hexane). The oil was converted to the fumaric acid salt and crystallized from methanol/ether to give a solid (0.10 g): mp 150-152° C.; MS (ES) m/z 248 (M+); 1H NMR (DMSO-d6) 8.38 (1H, s), 8.24 (1H, d, J=0.8 Hz), 7.89 (1H, d, J=9.2 Hz), 7.70 (1H, d, J=9.2 Hz), 6.46 (2H, s), 4.44 (2H, m), 4.39 (2H, dd, J=6.8 Hz), 3.60 (1H, m), 1.36 (3H, t, J=7.2 Hz), 1.11 (3H, d, J=6.4 Hz). Analysis. Calculated for C13H17N3O2.C4H4O4.0.5H2O: C, 54.83; H, 5.95; N, 11.28. Found: C, 54.77; H, 5.95; N, 11.46.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][OH:16].[H-].[Na+].[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCOC(C)=O>C1COCC1.O.CCCCCC>[Cl:21][C:22]1[N:23]=[CH:24][N:25]=[C:26]([O:16][CH2:15][C:5]2[N:4]([CH2:3][C:2]([CH3:18])([CH3:17])[CH3:1])[C:8]3[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=3[CH:6]=2)[CH:27]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(C)Cn1c(CO)cc2cnc(C#N)nc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)Cn1c(COc2cc(Cl)ncn2)cc2cnc(C#N)nc21
Reaction time: 0.25 h
Yield: 92 %

Procedure:
To a solution of 7-(2,2-dimethyl-propyl)-6-hydroxymethyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (1.0 mmol) in THF (10 ml) is added NaH (1.2 mmol) at room temperature under nitrogen atmosphere. After 15 min stirring, 4,6-dichloropyrimidine (1.1 mmol) is added and the mixture is stirred at room temperature for 1 h. The reaction mixture is diluted with H2O and extracted with AcOEt. The organic extracts are dried over Na2SO4 and concentrated. The residue obtained is purified by column chromatography on silica gel to give the product in 92% yield. Rf=0.49 (AcOEt:n-hexane=1:2). 1H NMR(400 MHz, CDCl3) δ 1.05 (s, 9H), 4.26(s, 2H), 5.74(s, 2H), 6.83(s, 1H), 6.86(s, 1H), 8.62(s, 1H), 8.97(s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[Cl:22][C:23]1[CH:34]=[CH:33][CH:32]=[CH:31][C:24]=1[CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>>[Cl:22][C:23]1[CH:34]=[CH:33][CH:32]=[CH:31][C:24]=1[CH2:25][CH:26]1[CH2:30][CH2:29][N:28]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:15])[CH2:27]1
Reactant: Clc1ccccc1CC1CCNC1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: O=C(O)C(=O)O
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(Cc3ccccc3Cl)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(2-chlorobenzyl)pyrrolidine oxalate (17.1 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (6.4 mg). Calcd for C22H21ClN2O2: 380.1292, found 380.1300.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:27][C:28]1[CH:43]=[CH:42][C:31]2[N:32]=[C:33]([N:35]3[CH2:41][CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[S:34][C:30]=2[CH:29]=1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:38]2[CH2:39][CH2:40][CH2:41][N:35]([C:33]3[S:34][C:30]4[CH:29]=[C:28]([Cl:27])[CH:43]=[CH:42][C:31]=4[N:32]=3)[CH2:36][CH2:37]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Clc1ccc2nc(N3CCCNCC3)sc2c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCCN(c3nc4ccc(Cl)cc4s3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 6-chloro-2-[1.4]diazepan-1-yl-benzothiazole.
Reaction SMILES: [N+]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:17])=[O:9])=[CH:6][CH:5]=1)([O-])=O.[Cl:20]C1C=C(C=CC=1)C(Cl)=O>>[Cl:20][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][CH:4]=1)[C:8]([N:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:17])=[O:9]
Reactant: O=C1CCCCCN1C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: O=C1CCCCCN1C(=O)c1cccc(Cl)c1

Procedure:
Synthesized as for N-(4-nitrobenzoyl)caprolactam (Example XXIII using 3-chlorobenzoyl chloride (Aldrich) in place of 4-nitrobenzoyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:17])[NH:15][NH2:16])=[N:6]1.[NH2:22][C:23](=S)[C:24](OCC)=[O:25].C(N(CC)CC)C>CO>[NH2:22][C:23]1[N:16]=[N:15][C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=3[F:1])[N:6]=2)=[N:17][C:24]=1[OH:25]
Reactant: CCOC(=O)C(N)=S
Reactant: N=C(NN)c1nn(Cc2ccccc2F)c2ncccc12
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O
Reaction time: 8 h

Procedure:
2.000 g (7.035 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidohydrazide in 50 ml of methanol were initially introduced and admixed with 0.937 g (7.035 mmol) of ethyl amino(thioxo)acetate, and 1.424 g (14.070 mmol) of triethylamine were admixed and the mixture was heated under reflux for 5 h. The reaction mixture was left to stand overnight, and the precipitate was filtered off with suction, washed with a little ethanol and dried under high vacuum. This gave 1.892 g of the target compound (purity 94%; 75% of theory).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:32]=[CH:31][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH2:58][CH:59]2[CH2:61][O:60]2)=[CH:53][CH:52]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[N:25]1([C:23](=[O:24])[CH2:22][CH2:21][NH:20][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:61][C@H:59]([OH:60])[CH2:58][O:57][C:54]4[CH:55]=[CH:56][C:51]([OH:50])=[CH:52][CH:53]=4)=[CH:32][CH:31]=3)[CH2:13][CH2:14]2)=[O:19])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCCC(=O)N3CCOCC3)CC2)cc1
Solvent: O=CO
Product: O=C(CCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1)N1CCOCC1

Procedure:
4-[4-(2-aminoethyl)anilino]-N-[3-(4-morpholinyl)-3-oxopropyl]-1-piperidinecarboxamide formate (0.90 g, 2.0 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane according to Procedure G to yield the title compound (0.39 g, 0.5 mmol).
Reaction SMILES: CC(O)(C)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:7][CH:6]=1.[H-].[Na+].O>C1(C)C=CC=CC=1>[CH2:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4]#[CH:3])=[CH:10][CH:9]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCc1ccc(C#CC(C)(C)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C#Cc1ccc(CCCCC)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 78.3 %

Procedure:
3-Methyl-1-(4'-pentylphenyl)-1-butyne-3-ol (82 g) was dissolved in toluene (900 ml) under nitrogen atmosphere, and then sodium hydride (60% in paraffin liquid; 5.6 g) was added thereto, followed by stirring at 60° C. for 6 hours. The reaction solution was poured into water (500 ml), and extracted with chloroform, followed by washing with water three times. After distilling off toluene and chloroform, the resultant was distilled under reduced pressure (b.p. 85° to 90° C./3 mmHg) to give 4-pentylphenylacetylene (48 g).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][C:10]([OH:17])=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:3]=1.[H-].[Na+].Br[CH2:27][CH2:28][O:29][P:30](=[O:47])([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C.CCOC(C)=O>[OH:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[CH:5]=[C:6]2[C:15]=1[C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([O:17][CH2:27][CH2:28][O:29][P:30](=[O:47])([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:9][C:8]=1[O:7]2
Reactant: O=P(OCCBr)(OCc1ccccc1)OCc1ccccc1
Reactant: O=c1c2ccc(O)cc2oc2cc(N3CCOCC3)cc(O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1c2ccc(OCCOP(=O)(OCc3ccccc3)OCc3ccccc3)cc2oc2cc(N3CCOCC3)cc(O)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
A solution of 1,6-dihydroxy-3-morpholin-4-yl-xanthen-9-one in anhydrous DMF (2.0 mL) was treated with sodium hydride (27.7 mg, 0.693 mmol). After 15 minutes, a solution of phosphoric acid dibenzyl ester 2-bromoethyl ester (267.0 mg, 0.693 mmol) in DMF (1.0 mL), was added, and reaction mixture was stirred overnight at room temperature. The reaction mixture then was dissolved in EtOAc (250 mL) and washed with water (6×50 mL) and brine (1×50 mL). The organics were dried. (Na2SO4) and concentrated. The residue then was purified via Biotage chromatography using 80% EtOAc in hexanes as, eluent to yield 132 mg (31%) of phosphoric acid dibenzyl ester 2-(8-hydroxy-6-morpholin-4-yl-9-oxo-9H-xanthen-3-yloxy)-ethyl ester as a white solid. 1H NMR (CDCl3, 400 MHz) δ: 12.82 (s, 1H), 8.12 (d, 1H), 7.34 (m, 10H), 6.82 (d, 1H), 6.73 (s, 1H), 6.24 (s, 1H), 6.22 (s, 1H), 5.04 (m, 4H), 4.38 (m, 2H), 4.18 (m, 2H), 3.83 (m, 4H), 3.38 (m, 4H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[OH:11].O.[N+:13]([O-])([OH:15])=[O:14].S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[I:1][C:2]1[CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[OH:11]
Reactant: Oc1c(I)ccc2c1CCC2
Reactant: O=[N+]([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(I)c(O)c2c1CCC2

Procedure:
To a solution of 5-iodoindan-4-ol (358 mg) in acetic acid (3 mL) was added water (0.5 mL). To the solution was added nitric acid (60%, 0.105 mL) in small portions under ice-cooling, and the mixture was stirred under ice-cooling for 20 min. After adding water (10 mL) and aqueous sodium sulfite (1.5 g/10 mL) successively, the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated sodium hydrogen carbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was crystallized from a small amount of dichloromethane and hexane to give the title compound (70 mg).
Reaction SMILES: [N+:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:16](OC(=O)C)(=[O:18])[CH3:17]>[N+](C1C=CC=CC=1)([O-])=O>[OH:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[C:16](=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1c(O)cccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc(O)c([N+](=O)[O-])c1O
Temperature: 100 °C

Procedure:
2-Nitrobenzene-1,3-diol (24.5 g) was added portionwise over 15 min to a vigorously stirred solution of aluminium chloride (46.3 g) in nitrobenzene (325 mL). Acetic anhydride (15.65 mL) was then added dropwise to the mixture over a further 15 min and the mixture then heated at 100° C. for 5 h. The reaction was cooled to ambient temperature and carefully quenched with ice cold 2M hydrochloric acid (300 mL). The mixture was extracted with ether (2×500 mL) and the combined ether extracts then extracted with 2M aqueous sodium hydroxide (2×400 mL). The combined basic extracts were washed with ether (4×500 mL) and then acidified to pH 1 with 2M hydrochloric acid (700 mL). The resulting precipitate was filtered off, washed with water, and dried under vacuum at 40° C. to afford the subtitled compound as a yellow/brown solid (29.5 g). 1H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 12.31 (s, 1H), 7.98 (d, J=9.2 Hz, 1H), 6.63 (d, J=28.2 Hz, 1H), 2.59 (s, 3H).