Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:10][C:11](=[O:12])[CH:13]=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1]
Reactant: CC(C)=O
Reactant: O=Cc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1ccccc1F)C=Cc1ccccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.5 %

Procedure:
2-Fluorobenzaldehyde (it, 0.5 ml, 4.7 mmol) and acetone (19, 0.18 ml, 2.4 mmol) were combined in ethanol (20 ml) and stirred for 10 min at room temperature. A solution of sodium hydroxide (0.29 g, 7.3 mmol) and water (15 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting mixture was filtered and chromatographed on silica gel with ethyl acetate/hexane to give a solid. The crude solid was recrystallized from ethanol to afford 0.27 g (41%) of yellow crystals: mp 68-72° C. [expected mp 68-70° C.]; 1H NMR: δ 7.13 (m, 6H), 7.36 (m, 2H), 7.61 (dt, 2H, J=7.6 Hz, 1.4 Hz), 7.84 (d, 2H, J=16.3 Hz); 13C NMR: δ 116.2, 122.8, 124.4, 127.6, 129.3, 131.8, 135.9, 161.5, 188.7.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)c1ccc(OCCCCl)cc1
Yield: 96.8 %

Procedure:
A mixture of 50 g (0.365 mole) of 4-hydroxybenzamide, 114.8 g (0.729 mole) of 1-bromo-3-chloropropane and 151.3 g (1.1 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 20 hr. The mixture was concentrated under reduced pressure and the residue was stirred with 1.2 liter of water to remove inorganic solids. The mixture was filtered and te filter cake was washed with water and petroleum ether and dried to yield 75.5 g (97%) of white solid. The solid was recrystallized from ethylacetate, m.p. 142°-143° C.
Reaction SMILES: [O:1]([C:8]1[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:28])[C@@H:18]([CH:19]=[C:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C@H:17]1[C:25](Cl)=[O:26].N1C=CC=CC=1.Cl>C1C=CC=CC=1>[CH3:15][C:16]1([CH3:28])[C@@H:18]([CH:19]=[C:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[C@H:17]1[C:25]([O:14][CH2:13][C:10]1[S:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:12][CH:11]=1)=[O:26]
Reactant: OCc1cnc(Oc2ccccc2)s1
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C1CCCC1
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C(=O)OCc2cnc(Oc3ccccc3)s2)[C@@H]1C=C1CCCC1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
3.1 g of (2-phenoxy-5-thiazolyl)-methanol were added to a solution of (1R,3S) 2,2-dimethyl-3-(cyclopentylidenemethyl)-cyclopropane-1-carboxylic acid chloride prepared from 2.9 g of the corresponding acid [described in French Pat. No. 70-00265 published under No. 2.076.204] in 45 ml of benzene and 1.2 ml of pyridine were added dropwise thereto at 10° C. The mixture was stirred at 20° C. for 17 hours and was poured into dilute aqueous hydrochloric acid solution. The decanted aqueous phasewas extracted with ether and the combined organic phases were washed with water, dried and evaporated to dryness under reduced pressure. The residuewas chromatographed over silica gel and was eluted with a 7-3 hexane-isopropyl ether mixture to obtain 1.3 g of (2-phenoxy-5-thiazolyl)-methyl (1R,3S) 2,2-dimethyl-3-(cyclopentylidenemethyl)-cyclopropane-1-carboxylate meltingat less than 50° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(Cl)Cl.Cl.[OH:12][C:13]1[CH:37]=[C:36]([O:38][CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:35]=[CH:34][C:14]=1[C:15]([NH:17][C:18]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])=[O:16]>N1C=CC=CC=1>[C:1]([N:42]1[CH2:41][CH2:40][CH:39]([O:38][C:36]2[CH:35]=[CH:34][C:14]([C:15]([NH:17][C:18]3[CH:27]=[C:26]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:25]=[CH:24][C:19]=3[C:20]([O:22][CH3:23])=[O:21])=[O:16])=[C:13]([OH:12])[CH:37]=2)[CH2:44][CH2:43]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OC2CCNCC2)cc1O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OC2CCN(C(C)=O)CC2)cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under ice-cooling, pyridine (0.010 mL) and acetic anhydride (4.0 μL) were sequentially added to a methylene chloride (1 mL) suspension of the obtained methyl 2-(2-hydroxy-4-(piperidin-4-yloxy)benzamido)-4-phenylbenzoate hydrochloride (0.017 g), followed by stirring at room temperature for 1 hour. Pyridine (0.49 mL) and acetic anhydride (4.0 μL) were sequentially added to the reaction mixture, followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and a 10% aqueous solution of citric acid and ethyl acetate were added to the residue. The organic layer was separated, washed with a 10% aqueous solution of citric acid, and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 0.016 g of methyl 2-(4-((1-acetylpiperidin-4-yl)oxy)-2-hydroxybenzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([C:13](Cl)=[O:14])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][O:24][CH:25]([O:28][CH3:29])[CH2:26][NH2:27]>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([C:13]([NH:27][CH2:26][CH:25]([O:28][CH3:29])[O:24][CH3:23])=[O:14])[CH:5]=1
Reactant: COC(=O)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1
Reactant: COC(CN)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(=O)NCC(OC)OC)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Under ice cooling a solution of 22.1 g (90.7 mmol) of 3-chlorocarbonyl-5-nitro-benzoic acid methyl ester (U.S. Pat. No. 4,120,891) in 200 ml of DCM is added dropwise to a stirred suspension of 11.2 g (181 mmol) of K2CO3 and 11.7 ml (109 mmol) of aminoacetaldehyde dimethylacetal in 200 ml of DCM. The mixture is stirred at ambient temperature for 2 days, diluted with ethyl acetate and extensively washed with water. The organic phase is dried over sodium sulfate and evaporated to yield the product in the form of a yellow oil.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[C:17]([CH2:19][C:20]([NH2:22])=[O:21])#[N:18].N1CCCCC1>C(O)C>[C:17]([C:19]1[C:20](=[O:21])[NH:22][C:1]([CH3:2])=[C:4]2[C:5]=1[CH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[CH2:9]2)#[N:18]
Reactant: N#CCC(N)=O
Reactant: CC(=O)C1CC(c2ccncc2)CCC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(=O)c(C#N)c2c1CC(c1ccncc1)CC2
Yield: 34.7 %

Procedure:
2-Acetyl-4-(4-pyridyl)cyclohexanone (1.65 g) and cyanoacetamide (0.64 g) were dissolved in ethanol, and a small amount of piperidine was added. The reaction mixture was heated under reflux for 7 hours. After the reaction was completed, deposited crystals were filtered out to obtain 0.7 g of 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-3-oxo-7-(4-pyridyl)isoquinoline.
Reaction SMILES: C12BC(CCC1)CCC2.[CH2:10]([O:17][CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:19][CH:20]=[CH2:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[O:37]1CCCC1>>[CH2:10]([O:17][CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:19][CH2:20][CH2:21][OH:37])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1CCOC1
Reactant: C=CCC(CCCCCCCCCc1ccccc1)OCc1ccccc1
Agent: B1C2CCCC1CCC2
Product: OCCCC(CCCCCCCCCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a 0.5M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (253 ml) was added dropwise, under nitrogen, a solution of 41.8 g of 4-benzyloxy-13-phenyl-1-tridecene in 100 ml of dry tetrahydrofuran. The mixture was stirred at room temperature for 3 hours, quenched by the sequential addition of 72 ml of ethanol, 24 ml of 6 N solution of sodium hydroxide, and 48 ml of a 30% solution of hydrogen peroxide. The mixture was heated at 50° for 2.5 hours. Upon standing at room temperature overnight, the mixture separated into aqueous and organic layers. The organic layer was washed with 100 ml of a 10% aqueous solution of sodium sulfite and 100 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous potassium carbonate and concentrated. The concentrate was taken up in 20% diethyl ether/hexane, filtered and concentrated to an oil. The oil was purified by high pressure liquid chromatography using as an eluent hexane/diethyl ether (2:1 by volume) to give 32.7 g (75%) 4-benzyloxy-13-phenyl-tridecan-1-ol as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][OH:20])[CH2:11][CH2:10]2)[O:6][N:5]=1.[F:21][C:22]1[CH:27]=[C:26](O)[CH:25]=[CH:24][C:23]=1[CH2:29][C:30]([O:32][CH3:33])=[O:31].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:21][C:22]1[CH:27]=[C:26]([O:20][CH2:19][CH2:18][C@@H:16]2[CH2:17][C@@H:15]2[CH:12]2[CH2:11][CH2:10][N:9]([C:7]3[O:6][N:5]=[C:4]([CH2:3][O:2][CH3:1])[N:8]=3)[CH2:14][CH2:13]2)[CH:25]=[CH:24][C:23]=1[CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: COCc1noc(N2CCC([C@H]3C[C@H]3CCO)CC2)n1
Reactant: COC(=O)Cc1ccc(O)cc1F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCc1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)OC)c(F)c3)CC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[(1S,2R)-2-{1-[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}cyclopropyl]ethanol (0.900 g, 3.20 mmol) in 5 ml anhydrous dichloromethane at RT was added a solution of methyl (2-fluoro-4-hydroxyphenyl)acetate (Intermediate 1, 0.707 g, 3.84 mmol) in 10 ml anhydrous dichloromethane, triphenylphosphine, polymer-bound (2.52 g, 12.6 mmol), and di-tert-butyl azodicarboxylate (1.47 g, 6.40 mmol). The reaction mixture was stirred at RT for 3 hours. It was filtered by Celite and concentrated. The residue was purified on Biotage column (100 g silica gel) using a gradient eluent of 0-50% ethyl acetate in hexanes (700 ml) to afford the title compound. LC/MS (m/z) 448.2 (M+H)+.
Reaction SMILES: C([SiH](CC)CC)C.B(F)(F)F.CCOCC.O[CH:18]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)[C:19]([CH3:30])([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20]([OH:22])=[O:21].B(F)(F)F>C(Cl)Cl>[CH3:30][C:19]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH2:18][C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)[C:20]([OH:22])=[O:21]
Reactant: CC(Oc1ccccc1)(C(=O)O)C(O)c1cccs1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(Cc1cccs1)(Oc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of triethylsilane (56.4 g, 77.4 mL, 485 mmol) in 100 mL of CH2Cl2 at −20° C., boron trifluoride diethyl etherate (68.8 g, 61.5 mL, 485 mmol) was added. A solution of 3-hydroxy-2-methyl-2-phenoxy-3-thiophen-2-yl-propionic acid (45.0 g, 162 mmol) in CH2Cl2 (600 mL) was then added dropwise to the BF3 solution over 1 h, keeping the temperature at −15° C. The reaction was stirred at 0° C. for 2 h. The reaction was quenched with 1 N NaOH (approx. 360 mL) diluted with 180 mL of water and the pH was adjusted to pH=4.0 using 1 N HCl and 1 N NaOH. The organic layer was separated and the aqueous layer was further extracted with CH2Cl2 (2×300 mL). The combined organic layers were then washed with 0.1 N HCl (300 mL) and water (2×300 mL). Xylene (150 mL) and NaCl were added and the organics were concentrated to dryness to yield 40.0 g of crude product. The product was used in the next step without further purification: 1H NMR (400 MHz, CDCl3) δ 6.86-7.29 (m, 8 H), 3.53 (d, 2 H), 3.37 (d, 2 H), 1.44 (s, 3 H); MS (EI) 263.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:8])[CH2:5][CH2:6][OH:7].S=[C:10]1[CH2:14][S:13][C:12](=[O:15])[NH:11]1>C(O)C>[OH:7][CH2:6][CH2:5][N:4]([CH3:8])[CH2:3][CH2:2][NH:1][C:10]1[CH2:14][S:13][C:12](=[O:15])[N:11]=1
Reactant: O=C1NC(=S)CS1
Reactant: CN(CCN)CCO
Solvent: CCO
Product: CN(CCO)CCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98 %

Procedure:
To a solution of 2-[(2-aminoethyl)(methyl)amino]ethanol (1.00 g) in ethanol (30 mL) was added 4-thioxo-1,3-thiazolidin-2-one (1.07 g). The reaction mixture was stirred at room temperature for 3 days, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (1.71 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([SH:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:13][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(F)ccc1S
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(F)ccc1Sc1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 97.9 %

Procedure:
To a solution of ethyl 5-fluoro-2-mercaptobenzoate (I) (25.0 g, 124.9 mmol) and 1-fluoro-2-nitrobenzene (13.2 mL, 124.9 mmol) in acetone (700 mL) was added K2CO3 (34.5 g, 249.7 mmol) at ambient temperature. The yellow suspension was heated to reflux (60° C.) for 5 hours. The reaction mixture was quenched with 1N HCl (500 mL), diluted with EtOAc (1000 mL) and filtered through a bed of diatomaceous earth. The aqueous layer was removed, the EtOAc layer was washed with 1N HCl (250 mL×2) and brine (200 mL×1), dried and the solvent removed under reduced pressure. The material was carried forward with no further purification to yield ethyl 5-fluoro-2-(2-nitrophenylthio)benzoate (II) (39.3 g, 95%) as a dark yellow solid. m/z (ES+) M+1=322.1; HPLC tR=0.88 min. 1H NMR (300 MHz, DMSO-d6): δ 1.09 (t, 3H, J=7.2 Hz), 4.16 (q, 2H, J=7.2 Hz), 7.07 (d, 1H, J=7.2 Hz), 7.40-7.75 (m, 5H), 8.20 (d, 1H, J=7.2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[O:21][C:20]([CH:22]=O)=[CH:19][CH:18]=3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[CH3:36][S:37]([CH2:40][CH2:41][NH2:42])(=[O:39])=[O:38]>>[F:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[CH2:28][O:27][C:26]1[CH:25]=[CH:24][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([CH2:22][NH:42][CH2:41][CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:19][CH:18]=4)[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(Nc2ncnc3ccc(-c4ccc(C=O)o4)cc23)ccc1OCc1cccc(F)c1
Reactant: CS(=O)(=O)CCN
Product: COc1cc(Nc2ncnc3ccc(-c4ccc(CNCCS(C)(=O)=O)o4)cc23)ccc1OCc1cccc(F)c1

Procedure:
Prepared according to Procedure D from 5-(4-{3-methoxy-4-(3-fluorobenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1H NMR 400 MHz (DMSO-d6) 9.22 (s, 1H); 8.78 (s, 1H); 8.31 (d, 1H); 7.88 (d, 1H); 7.50-7.08 (m, 8H); 6.84 (d, 1H); 5.13 (s, 2H); 4.42 (s, 2H); 3.80 (s, 3H); 3.60 (m, 2H); 3.40 (m, 2H, obscured by water peak); 3.10 (s, 3H); MS m/z 577 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[NH:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1.O.[N+:23]([O-])([OH:25])=[O:24]>S(=O)(=O)(O)O>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=[C:2]([Cl:1])[C:3]=1[C:13]1[NH:14][C:15]([N+:23]([O-:25])=[O:24])=[C:16]([C:18]([F:21])([F:19])[F:20])[N:17]=1
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)c1cc(Cl)c(-c2nc(C(F)(F)F)c[nH]2)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(F)(F)F
Temperature: 120 °C

Procedure:
A mixture of 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylimidazole (1.0 g, 0.0027 mol) in fuming nitric acid (95%, 1 ml) and fuming sulphuric acid (30% free SO3,1 ml) was stirred and heated at 120° C. for 3.5 hours. THe mixture was poured into cold water (50 ml) and the solid was filtered off and washed with water. The resultant solid was purified by chromatography on silica gel, eluting with with a mixture of ethyl acetate and n-hexane (1:5) to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-5-nitro 4-trifluoromethylimidazole (0.7 g) as an off-white solid, m.p. 244°-252° C.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:18](=[O:19])[N:17]([CH3:20])[C:12]2[N:13]=[CH:14][N:15]([CH3:16])[C:11]=2[C:9]1=[O:10])=[O:3].C(Cl)Cl.[BH4-].[Na+]>CO>[OH:3][CH:2]([CH3:1])[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:9](=[O:10])[C:11]2[N:15]([CH3:16])[CH:14]=[N:13][C:12]=2[N:17]([CH3:20])[C:18]1=[O:19]
Reactant: CC(=O)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(O)CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 2 h
Yield: 71.5 %

Procedure:
Pentoxifylline (1.0 g, 3.59 mmol) was dissolved in methanol (20 mL) and DCM (3 mL) then cooled to 0° C. To the reaction was added sodium borohydride (0.41 g, 10.8 mmol) portionwise over 30 min. The reaction was stirred in the cold for 2 h; then it was evaporated to dryness under reduced pressure, diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to give 1-(5-hydroxyhexyl)-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione (0.72 g, 71% yield) as a white solid. LCMS retention time=1.849 min and 98% purity, LCMS MH+ 281. 1H NMR (DMSO-d6) δ 8.00 (s, 1H), 4.31 (d, 1H, J=4 Hz), 3.88 (s, 3H), 3.84 (t, 2H, J=8 Hz), 3.51-3.59 (m, 1H), 1.45-1.56 (m, 2H), 1.25-1.37 (m, 4H), 1.02 ( d, 3H, J=4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[CH3:24][S:25]([NH:28][C:29]1[CH:38]=[CH:37][C:32]([C:33](=[O:36])[CH2:34]Br)=[CH:31][CH:30]=1)(=[O:27])=[O:26]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:34]=1[C:33](=[O:36])[C:32]1[CH:31]=[CH:30][C:29]([NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:38][CH:37]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CBr)cc1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2ccc(NS(C)(=O)=O)cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 8 (Method B) from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 4-(methylsulfonylamino)phenacyl bromide*.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.C(N(CC)CC)C.[C:31](Cl)(=[O:37])[CH2:32][CH2:33][CH2:34][C:35]#[CH:36]>ClCCl>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH:23][C:31](=[O:37])[CH2:32][CH2:33][CH2:34][C:35]#[CH:36])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]=[N:3]1
Reactant: C#CCCCC(=O)Cl
Reactant: Cn1nnnc1C(=NOCc1cccc(N)n1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCCC(=O)Nc1cccc(CON=C(c2ccccc2)c2nnnn2C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.2 %

Procedure:
To a solution of 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine (251 mg, 0.81 mmol) in dichloromethane (10 mL) was added triethylamine (0.22 mL, 1.62 mmol), hex-5-ynoyl chloride (211 mg, 1.62 mmol). The reaction mixture was stirred for 5 hours at room temperature, concentrated in vacuo, and then purified by silica gel chromatography to yield to N-{6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}hex-5-ynamide [200 mg; 95% of purity; 58% of theory; HPLC/MS: m/z=404 (M+H); log P(HCOOH)=2.98].
Reaction SMILES: [N:1]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:3][CH:2]=1.[Cl:24]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:24][C:8]1[S:7][C:6]2[N:1]=[CH:2][N:3]=[C:4]([NH:10][CH:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]3)[C:5]=2[CH:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3sccc23)CC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3sc(Cl)cc23)CC1
Yield: 70.5 %

Procedure:
A mixture of t-butyl 4-(thieno[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (1.00 g, 3.00 mmol) and N-chlorosuccinimide (0.39 g, 3.00 mmol) were heated in 50 mL of acetic acid for 3 h. After cooling to room temperature acetic acid was removed under reduced pressure and the remaining residue was partition in 1 M NaOH and DCM. The DCM layer was dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by silica chromatography in 5% MeOH-DCM to collect 0.78 g of product (71% yield). 1H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 7.01 (s, 1H), 4.94 (d, 1H), 4.32 (m, 1H), 4.15 (m, 2H), 2.94 (m, 2H), 2.11 (m, 2H), 1.48 (s, 9H), 1.44 (m, 2H); MS (ESI) m/z: Calculated for C16H21ClN4O2S, 368.11; Observed: 368.8 (M++1).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:17]([CH3:26])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>>[ClH:1].[ClH:1].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH:17]([C:18](=[O:19])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:26])[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(Br)C(=O)c1ccccc1
Agent: Cl
Product: CC(C(=O)c1ccccc1)N1CCN(Cc2ccccc2)CC1
Yield: 142.9 %

Procedure:
A mixture of N-benzylpiperazine dihydrochloride (7 mmol) and 2-bromo-1-phenylpropan-1-one (8.4 mmol) was treated according to the general preparation 2 to obtain N1-benzyl-N4-(1-benzoylethyl) piperazine dihydrochloride (2.6 g, 5 mmol), which was reduced according to the general preparation 3 to obtain 1.28 g of the title compound, yield 67%, mp 244-246° C.).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[BrH:14].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O>[Br:14][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: OCc1ccc2c(Cl)ccnc2c1
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1ccnc2cc(CBr)ccc12
Temperature: 120 °C

Procedure:
7-Hydroxymethyl-4-chloroquinoline (0.2 g, 0.97 mmol) is treated with 48% HBr and heated to 120° C. for 1 h. The resulting solution is cooled with ice, diluted with water and treated with ethyl acetate and sodium bicarbonate until basic to pH paper. The layers are separated and the organic layer is washed with water, dried (Na2SO4) and concentrated to give 7-Bromomethyl-4-chloroquinoline (0.23 g, 0.9 mmol). MS m/z: M+=255; 1H NMR (CDCl3, 300 MHz) δ8.75 (d, 1H), 8.1 (s, 1H), 7.7 (d, 1H), 7.5 (d, 1H), 4.7 (s. 2).