Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:19][CH:18]([O:20][C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([CH3:29])[CH:22]=4)[CH2:17]3)=[O:15])=[N:11][N:10]=2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.[CH2:37]([C:39]1([OH:43])[CH2:42][NH:41][CH2:40]1)[CH3:38]>>[CH2:37]([C:39]1([OH:43])[CH2:42][N:41]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH:18]3[CH2:19][N:16]([C:14]([C:12]4[O:13][C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)=[N:10][N:11]=4)=[O:15])[CH2:17]3)=[CH:22][C:23]=2[CH3:29])[CH2:40]1)[CH3:38]
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)c(C)c4)C3)o2)cc1
Reactant: CCC1(O)CNC1
Solvent: O=C(O)C(F)(F)F
Product: CCC1(O)CN(Cc2ccc(OC3CN(C(=O)c4nnc(-c5ccc(OC)cc5)o4)C3)cc2C)C1
Yield: 41 %

Procedure:
Using a similar protocol as described in Example 70 employing 73C and 70A as starting materials afforded 100 mg (41%) of 73 as a solid. 1H NMR (500 MHz, CDCl3): δ 0.98 (t, 3H), 1.80 (q, 2H), 2.30 (s, 3H), 2.98 (m, 2H), 3.33 (d, 2H), 3.57 (s, 2H), 3.89 (s, 3H), 4.32 (m, 1H), 4.63 (m, 1H), 4.73 (m, 1H), 5.05 (m, 1H), 5.11 (m, 1H), 6.54 (d, 1H), 6.59 (s, 1H), 7.03 (d, 2H), 7.16 (d, 1H), 8.10 (d, 2H), MS (APCI+) m/z 479 [M+H]+, LC purity: 96%.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].Cl.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH2:27].C(N(CC)CC)C.O>C(#N)C>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:27][CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: NCc1ccccn1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCNc1nc(NCc2ccccn2)nc2ccc([N+](=O)[O-])cc12
Yield: 93.9 %

Procedure:
150 mg (0.57 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline was dissolved in 10 ml of acetonitrile, and then 165 mg (1.14 mmol) of 2-pyridylmethylamine hydrochloride and 0.40 ml (2.85 mmol) of triethylamine were added thereto, followed by heating under reflux overnight. To the reaction solution was added water, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 180 mg (93.9%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH:10]2[CH:6]([N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8](=[O:11])[O:9]2)[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N+:25]([O-])=O)[CH2:3]1>CO.[Pd]>[NH2:25][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:19]=1[CH:4]1[CH2:5][CH:6]2[N:7]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[C:8](=[O:11])[O:9][CH:10]2[CH:2]([CH3:1])[CH2:3]1
Reactant: CC1CC(c2ccncc2[N+](=O)[O-])=CC2C1OC(=O)N2C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC1CC(c2ccncc2N)CC2C1OC(=O)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of (+/−)-tert-butyl 7-methyl-5-(3-nitropyridin-4-yl)-2-oxo-3a,6,7,7a-tetrahydrobenzo[d]oxazole-3(2H)-carboxylate (1.0 equiv.) in MeOH and ethyl:acetate (1:1, 0.07 M) was added 10% Pd/C (0.1 equiv.) and the reaction was stirred at room temperature under an atmosphere of hydrogen. Upon completion of the reaction, the solution was filtered through a pad of Celite, washed with MeOH and ethyl acetate, the filtrate was concentrated to dryness under vacuo to give (+/−)-tert-butyl 5-(3-aminopyridin-4-yl)-7-methyl-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate as a mixture of diastereomers in >99% yield. LC/MS=348.2 (M+H), Rt=0.50 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:32]5[CH:31]=[N:30][C:29]([O:28][CH3:27])=[N:34][CH:33]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: COc1ncc(B(O)O)cn1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5cnc(OC)nc5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-methoxy-5-pyrimidineboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 2): tR=1.10 min; Mass spectrum (ESI+): m/z=467 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:3]=1/[C:14](/[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[CH3:28])=[CH:15]\[CH2:16][C:17]([O:19]C)=[O:18].[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:3]=1/[C:14](/[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[CH3:28])=[CH:15]\[CH2:16][C:17]([OH:19])=[O:18]
Reactant: COC(=O)C/C=C(/c1ccc(Cl)cc1C)c1c(-c2ccccn2)nn(C)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(Cl)ccc1/C(=C/CC(=O)O)c1c(-c2ccccn2)nn(C)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.6 %

Procedure:
To a solution of (Z)-methyl 4-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(4-chloro-2-methylphenyl)but-3-enoate (13.34 g, 32.0 mmol) in dioxane (150 mL) was added 2 N aqueous NaOH (32 mL, 64 mmol). The mixture was stirred at rt for about 16 h then partitioned between EtOAc (300 mL) and 10% citric acid (200 mL). The layers were separated and the aqueous layer was extracted with EtOAc (300 mL). The combined organic layers were washed with water (300 mL) followed by brine (300 mL) then concentrated in vacuo. The residue was triturated in Et2O to give (Z)-4-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(4-chloro-2-methylphenyl)but-3-enoic acid (12.31 g, 95%) as an off-white solid: LC-MS (Table 1, Method g) Rt=2.20 min, m/z 402/404 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 12.18 (s, 1H), 8.42-8.39 (m, 1H), 7.80-7.68 (m, 2H), 7.26-7.19 (m, 1H), 7.16 (d, J=2.2 Hz, 1H), 7.08-7.04 (m, 1H), 7.01-6.97 (m, 1H), 5.91 (t, J=7.2 Hz, 1H), 3.92 (s, 3H), 2.95 (s, 2H), 2.34 (s, 3H). To a suspension of (Z)-4-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(4-chloro-2-methylphenyl)but-3-enoic acid (12.31 g, 30.6 mmol) in THF (50 mL) was added 2-methylpropan-2-amine (6.46 mL, 61.2 mmol). The mixture was stirred at rt for about 10 min then concentrated in vacuo to give 2-methylpropan-2-aminium (Z)-4-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(4-chloro-2-methylphenyl)but-3-enoate (14.40 g, 95%): LC-MS (Table 1, Method g) Rt=2.20 min, m/z 402/404 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 8.41-8.38 (m, 1H), 7.78-7.67 (m, 2H), 7.24-7.17 (m, 1H), 7.13 (d, J=2.1 Hz, 1H), 7.05-7.01 (m, 1H), 6.99-6.96 (m, 1H), 6.01 (t, J=7.1 Hz, 1H), 3.91 (s, 3H), 2.81-2.59 (m, 2H), 2.32 (s, 3H), 1.16 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([CH2:17][OH:18])=[CH:10][C:9]=1[O:19][CH3:20].[OH-].[Na+].O.Cl>CO.C(Cl)(Cl)Cl.C(O)(=O)C>[OH:18][CH2:17][C:11]1[C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]([O:7][CH2:6][CH2:5][CH2:4][C:3]([OH:21])=[O:2])=[C:9]([O:19][CH3:20])[CH:10]=1
Reactant: COC(=O)CCCOc1cc([N+](=O)[O-])c(CO)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(CO)c([N+](=O)[O-])cc1OCCCC(=O)O
Yield: 90.1 %

Procedure:
A solution of the ester (50)(10.00 g, 33.4 mmol) in methanol (100 mL) was added dropwise to a stirring solution of 1M NaOH (100 mL) and H2O (50 mL). TLC (1:10:100 Acetic acid: MeOH: CHCl3) after 16 hours revealed the complete loss of starting material. The solution was acidified to pH1 with conc. HCl. The resulting yellow precipitate was collected by vacuum filtration to provide the product (51) as a yellow solid (8.58 g, 90%). MP=172-175° C. 1H NMR (250 MHz, CDCl3) δ 7.71 (s, 1H), 7.40 (s, 1H), 4.99 (s, 2H), 4.13 (t, J=6.3 Hz, 2H), 3.98 (s, 3H), 2.52 (t, J=7.1 Hz, 2H), 2.15 (pent, J=6.7 Hz, 2H). 13C NMR (67.8 MHz, CDCl3) 174.5 (C12), 154.2 (Cquat.), 146.4 (Cquat.), 138.5 (Cquat.), 134.7 (Cquat.), 109.8 (C6), 109.3 (C3), 68.3 (C9), 60.9 (C1), 56.2 (C8), 30.2 (C11), 24.3 (C10). IR (cm−1) 3533, 2976, 2634, 1709, 1617, 1577, 1520, 1411, 1286, 1214, 1019, 990, 888, 876, 814, 756, 677. MS (M+ —OH) 268.0. Anal. Calcd for C12H15NO7: C, 50.53; H, 5.30; N, 4.91. Found: C, 50.48; H, 5.22; N, 4.88.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][OH:9].[C:10](OC)(=[O:14])[C:11]([CH3:13])=[CH2:12].C1(C=CC(O)=CC=1)O.C[O-].[Na+]>CN(C)C=O.O>[C:10]([O:9][CH2:8][CH:2]1[CH2:3][CH:4]2[CH2:7][CH:1]1[CH:6]=[CH:5]2)(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: OCC1CC2C=CC1C2
Reactant: C=C(C)C(=O)OC
Agent: C[O-]
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)C(=O)OCC1CC2C=CC1C2

Procedure:
5-norbornen-2-ylmethyl methacrylate monomer was prepared in a flask fitted with a vertical condenser with water at 75° C circulating through the jacket, attached at the top to a downwards cold water-cooled condenser. There were refluxed for 2 hours 372 grams (3.0 moles) of 5-norbornen -2-methanol, 450 grams (4.5 moles) of methyl methacrylate, 526 grams of N,N-dimethylformamide, 28.8 grams of hydroquinone, and 8.1 grams (0.15 mole) of sodium methoxide. A total of 252 ml of distillate was collected (theoretical methanol equals 121 ml.). The flask contents were cooled, diluted with ether, and washed with water, excess dilute hydrochloric acid, water, 5% aqueous sodium hydroxide until the washes were colorless, and again with water. The ether solution was dried with anhydrous sodium sulfate, 11.5 grams of p-(p-tolylsulfonyl-amido) diphenylamine were added, and the ether was removed in a rotary evaporator at 60° C and about 15 mm pressure. To the residual oil 0.58 gram of hydroquinone was added and the product was distilled through a Vigreux column to give 431 grams of product having a boiling point of 770 C/1.4 mm, nD20 = 1.4848. The monomer was then passed through a column of activated sodium aluminum silicate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:23][NH2:24])=[O:22])[C:9]=2[S:25][CH3:26])=[CH:4][CH:3]=1.[C:27](O)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:23][NH:24][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:22])[C:9]=2[S:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)O
Reactant: CSc1c(C(=O)NN)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CSc1c(C(=O)NNC(=O)C(C)(C)C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.4 %

Procedure:
To a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-(methylthio)-1H-pyrazole-3-carbohydrazide (7) (200 mg, 0.47 mmol), pivalic acid (8) (57 mg, 0.56 mmol) and EDCI (134 mg, 0.70 mmol) dissolved in CH2Cl2 (30 ml) was added DMAP (114 mg, 0.93 mmol) in one portion at room temperature. The reaction mixture was stirred at room temperature for 12 hrs, and then treated with 1N—HCl solution. The organic layer was collected, and evaporated under a vacuum. The crude mixture was further purified by preparative HPLC, to obtain 150 mg (63%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:39][CH3:40])[C:4]([C:6]1[CH:38]=[CH:37][C:9]([CH2:10][C:11]2[CH:36]=[CH:35][CH:34]=[CH:33][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=[C:23]3[CH2:31][OH:32])[CH2:18][CH2:17]2)=[CH:8][CH:7]=1)=O)[CH3:2].COCCO[AlH2-]OCCOC.[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:4][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][C:11]2[CH:36]=[CH:35][CH:34]=[CH:33][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=[C:23]3[CH2:31][OH:32])[CH2:18][CH2:17]2)=[CH:37][CH:38]=1)[CH2:39][CH3:40])[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(Cc2ccccc2OCCN2CCC(n3c(CO)nc4ccccc43)CC2)cc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCN(CC)Cc1ccc(Cc2ccccc2OCCN2CCC(n3c(CO)nc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 49.7 %

Procedure:
The 1-[2-[2-(4-diethylcarbamoylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine (64 mg) obtained in Example 84 was dissolved in tetrahydrofuran (1.3 ml), added with a solution of Red-Al in toluene (65%, 0.18 ml) and stirred at room temperature for 2.5 hours. After the reaction mixture was slowly poured into ice 10 g with ice cooling to quench the reaction and the layers were separated, the aqueous layer was extracted with dichloromethane (30 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: dichloromethane:methanol:aqueous ammonia=9:1:0.1) to obtain 31 mg of the title compound. Yield: 50%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2([CH2:22][CH2:23][CH2:24][N:25]([CH3:35])[CH:26](C)[CH2:27]C3C=CC=CC=3)[S:17](=O)(=O)[CH2:16][CH2:15][CH2:14][S:13]2(=O)=O)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:36][O:37][C:38]1[CH:39]=[C:40]([CH:65]=[CH:66][C:67]=1[O:68][CH3:69])[CH2:41]CN(C)CCCCC1(C2C=CC(OC)=CC=2OC)SCCCS1>CC(C)=O.C(OCC)(=O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2([CH2:22][CH2:23][CH2:24][N:25]([CH2:26][CH2:27][CH2:41][C:40]3[CH:65]=[CH:66][C:67]([O:68][CH3:69])=[C:38]([O:37][CH3:36])[CH:39]=3)[CH3:35])[S:13][CH2:14][CH2:15][CH2:16][S:17]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2(CCCN(C)C(C)Cc3ccccc3)S(=O)(=O)CCCS2(=O)=O)cc1OC
Reactant: COc1ccc(C2(CCCCN(C)CCc3ccc(OC)c(OC)c3)SCCCS2)c(OC)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(CCCN(C)CCCC2(c3ccc(OC)c(OC)c3)SCCCS2)cc1OC

Procedure:
2-(3,4-Dimethoxyphenyl)-N-methyl-N-(-methylphenethyl)-m-dithiane-2-propylamine-1,1,3,3-tetraoxide hydrochloride of melting point 185°-187° C. (from acetone/ethyl acetate), starting from 2-(3,4-dimethoxyphenyl)-N-methyl-N-(α-methylphenethyl)-m-dithiane-2-propylamine (prepared as described in Example 6).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:12].[BH4-].[Na+]>CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([OH:12])[CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(CCc1cccnc1)c1ccc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CCc1cccnc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a solution of (2-naphthyl) [2-(3-pyridyl)ethyl]ketone (2.14 g) in MeOH (40 ml) was added NaBH4 (0.34 g) and the mixture was stirred at room temperature for 30 minutes. After removal of the solvent, the residue was extracted with ethyl acetate. The extract was washed with water and brine, dried and concentrated to give the titled compound (1.56 g) as colorless prisms.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:15][CH2:16][C:17]2[N:18]=[CH:19][N:20]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][C:31]=3[C:32]([F:35])([F:34])[F:33])[NH:28][C:27](=[O:36])[C:26]([C:37]([O:39]CC)=[O:38])=[CH:25]4)[CH:21]=2)=[O:14])=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Li+].O>C(O)C>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:15][CH2:16][C:17]2[N:18]=[CH:19][N:20]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][C:31]=3[C:32]([F:35])([F:33])[F:34])[NH:28][C:27](=[O:36])[C:26]([C:37]([OH:39])=[O:38])=[CH:25]4)[CH:21]=2)=[O:14])=[CH:8][CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(NC(=O)OCc2cn(-c3cc4cc(C(=O)OCC)c(=O)[nH]c4cc3C(F)(F)F)cn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(Nc1ccc(C(=O)O)cc1)OCc1cn(-c2cc3cc(C(=O)O)c(=O)[nH]c3cc2C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.4 %

Procedure:
To a suspension of the compound of Example 18 (1.13 g, 1.97 mmol) in ethanol (30 ml) was added 1 mol/L aqueous solution of lithium hydroxide (9.26 ml, 9.26 mmol) and successively water (15 ml), and, after stirring for 4 hours at room temperature, the mixture was allowed to stand statically overnight. After stirring for 16 hours at 30° C., ice water was added to the reaction mixture and the insolubles were filtered off. Then, the pH value was brought to 4 with 3 mol/L hydrochloric acid and solvent was distilled off. Water was added to the residue obtained, the precipitated crystals were collected by filtration, washed with water, and then dried under reduced pressure. After the powder obtained was suspended into water (40 ml), 1 mol/L aqueous solution of lithium hydroxide (9.26 ml, 9.26 mmol) was added and the mixture was stirred for 30 minutes at 50° C. Ice water was added to the reaction mixture, the insolubles were filtered off, then the pH value was brought to 4 with 3 mol/L hydrochloric acid, and solvent was distilled off. Water was added to the residue obtained, the precipitated crystals were collected by filtration, washed with water, and then dried under reduced pressure, thereby obtaining 757 mg of title compound as pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.[Cl:11]Cl.C(=O)=O.CC(C)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:11])=[N:7][OH:8])=[CH:4][CH:3]=1
Reactant: ClCl
Reactant: ON=Cc1ccc(F)cc1
Agent: O=C=O
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: ON=C(Cl)c1ccc(F)cc1
Reaction time: 1 h
Yield: 48.1 %

Procedure:
A solution of 25 g of 4-fluorobenzaldoxime in 200 ml of chloroform was cooled to 0° to -10°. From a pressure bottle, 14.2 g of chlorine was run into a flask cooled by dry ice-acetone and allowed to distill into the aldoxime solution, the solution being maintained at 0° ± 5°. The reaction mixture was stirred for one hour in an ice bath while nitrogen was bubbled through the solution. The chloroform was evaporated to leave an oil to which hexane was added quickly. The solid which separated was recrystallized from hexane to give 15.0 g of 4-fluorobenzohydroximoyl chloride, m.p. 74.5°-75°. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([O:11][CH2:12]C=C)[CH:5]=1.CI.C([O-])([O-])=O.[K+].[K+].OC1C=C(C=C(O)C=1)C(OC)=O>>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[C:6]([O:11][CH3:12])[CH:7]=[C:8]([OH:10])[CH:9]=1
Reactant: C=CCOc1cc(O)cc(C(=O)OC)c1
Agent: COC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COC(=O)c1cc(O)cc(OC)c1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1a, from methyl iodide (6.44 mL, 104 mmol), K2CO3 (28.8 g, 208.15 mmol), and methyl 3,5-dihydroxybenzoate (17.5 g, 64 mmol). Purification by column chromatography eluting with 15% EtOAc in hexanes gave a pale yellow solid (7.51 g, 40% yield). 1H NMR (400 MHz, CDCl3) δ 7.16 (dd, J=4.80, 2.27 Hz, 2 H) 6.63 (t, J=2.27 Hz, 1 H) 5.36 (s, 1H) 3.92 (s, 3 H) 3.83 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(F)c(F)cc1Cl
Reaction time: 3 h
Yield: 92.9 %

Procedure:
Into a 300 cc glass reactor, 100 g of 2-chloro-4,5-difluorobenzoic acid and 200 g of thionyl chloride were charged and stirred at about 60° to 70° C. for 3 hours. Unreacted thionyl chloride was distilled off, and the residue was subjected to distillation under reduced pressure to obtain 101.8 g of 2-chloro-4,5-difluorobenzoyl chloride. The physical properties of the obtained 2-choloro-4,5-difluorobenzoyl chloride were as follows.
Reaction SMILES: [H-].[Na+].[N:3]1([C:14](=[O:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:7]([CH3:8])[C:5]1=[O:6])[CH3:4].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27].O>CS(C)=O>[CH2:27]([N:12]1[C:13]2[C:14](=[O:15])[N:3]([CH3:4])[C:5](=[O:6])[N:7]([CH3:8])[C:9]=2[N:10]=[CH:11]1)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=[CH2:17]
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: C=CCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCCCCn1cnc2c1c(=O)n(C)c(=O)n2C
Reaction time: 0.33 h
Yield: 94.2 %

Procedure:
This example illustrates a synthesis of 7-(11,10-Oxidondecyl)-1,3-dimethylxanthine (inventive compound no. 1423). Sodium hydride (95%) (0.575 g, 24 mmol) was added to a solution of theophylline (3.6 g, 20 mmol) in dimethylsulfoxide (100 mL). After 20 minutes of stirring, 1-bromoundec-10-ene (4.66 g, 20 mmol) was added and stirred for 12 hours at room temperature. The reaction mixture was then poured into a separatory funnel containing water (300 mL) and extracted with dichloromethane (5×100 mL). The organic extracts were combined, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 50% hexane/ethyl acetate eluant, yielding 6.26 g (94% yield) of 7-(10-undecenyl)-1,3-dimethylxanthine (inventive compound no. 1420).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:39]([O:41]C)=[O:40])=[C:11]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH2:29][CH2:28]3)[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:13]2)=[CH:8][C:7]=1[S:43]([CH3:46])(=[O:45])=[O:44])[CH3:4].[K]>CO.O>[CH2:3]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:39]([OH:41])=[O:40])=[C:11]([CH2:26][N:27]3[CH2:28][CH2:29][CH:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH2:31][CH2:32]3)[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=3)=[N:13]2)=[CH:8][C:7]=1[S:43]([CH3:46])(=[O:45])=[O:44])[CH3:4]
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)OC)c2cc1S(C)(=O)=O
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)O)c2cc1S(C)(=O)=O
Temperature: 25 °C
Yield: 106.2 %

Procedure:
Potassium hydroxide (1.36 g, 2.42 mmol) was added to a solution of methyl 7-(ethyloxy)-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.54 g, 2.423 mmol) in methanol (60 mL) and water (20 mL). The reaction mixture was heated to reflux overnight. The mixture was cooled to room temperature, diluted with water, and concentrated in vacuo to remove methanol. The solid precipitate was collected by filtration, washed with cold water, and dried to afford 7-(ethyloxy)-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (1.6 g, >99% yield) as the potassium salt. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.92 (d, J=7.53 Hz, 1H), 7.79 (d, J=7.78 Hz, 1H), 7.68 (t, J=7.78 Hz, 1H), 7.52 (s, 1H), 4.34 (q, J=6.94 Hz, 2H), 3.49-3.55 (m, 4H), 3.44 (s, 2H), 3.17 (s, 3H), 2.53 (br. s., 2H), 2.31-2.38 (m, 4H), 1.93-2.02 (m, 1H), 1.85 (t, J=11.29 Hz, 2H), 1.52 (d, J=11.04 Hz, 2H), 1.46 (t, J=7.03 Hz, 3H), 0.94-1.07 (m, 2H); MS (m/z) 622.2 (M+H+).