Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=2)=[CH:4][CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:31](=[O:32])[CH2:30][N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)[CH:18]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: Nc1ccc2nc(NC3CCc4ccc(F)cc43)ccc2c1
Product: CN1CCN(CC(=O)Nc2ccc3nc(NC4CCc5ccc(F)cc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(6-fluoro-indan-1-yl)-quinoline-2,6-diamine and (4-methyl-piperazin-1-yl)-acetic acid; MS: m/e=434.5 (M+H+).
Reaction SMILES: [CH2:1]([Li])CCC.[O:6]([C:13]1[CH:14]=[C:15]([C:19]23[CH2:26][CH2:25][C:22]([CH:27]=O)([CH2:23][CH2:24]2)[O:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[O:6]([C:13]1[CH:14]=[C:15]([C:19]23[CH2:26][CH2:25][C:22]([CH:27]=[CH2:1])([CH2:23][CH2:24]2)[O:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: O=CC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)CO2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)CO2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
To a solution of (methyl)triphenylphosphonium bromide (80 mg, 0.224 mmol) in THF (1 mL) at 0° C. was added n-butyllithium (0.140 ml, 0.224 mmol). The reaction mixture was stirred at 0° C. for 30 min. A solution of 4-(3-Phenoxyphenyl)-2-oxabicyclo[2.2.2]octane-1-carbaldehyde (23 mg, 0.075 mmol) in THF (0.5 mL) was then added at 0° C. The reaction was warmed to rt and stirred for 4 h. The reaction was then quenched with saturated aq. NH4Cl, diluted with EtOAc, washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography on SiO2 (0 to 50% EtOAc:hexanes) to afford the title compound (14 mg, 61% yield) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.37-7.29 (m, 3H), 7.14-7.10 (m, 1H), 7.01 (d, J=7.7 Hz, 4H), 6.84 (ddd, J=8.0, 2.4, 0.8 Hz, 1H), 5.89 (dd, J=17.5, 10.9 Hz, 1H), 5.20 (d, J=17.3 Hz, 1H), 5.07 (d, J=10.7 Hz, 1H), 4.08-4.03 (m, 2H), 2.13-1.91 (m, 6H), 1.87-1.80 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[NH:12]1[CH:16]=[N:15][C:14]([SH:17])=[N:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([S:17][C:14]2[N:15]=[CH:16][NH:12][N:13]=2)=[C:3]([NH2:9])[CH:4]=1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Sc1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Sc2nc[nH]n2)c(N)c1
Temperature: 25 °C
Yield: 30.5 %

Procedure:
The title compound was prepared from 1-Chloro-4-methyl-2-nitro-benzene (3.00 g, 17.5 mmol), 1H-[1,2,4]Triazole-3-thiol (1.94 g, 19.2 mmol), and K2CO3 (4.22 g, 30.6 mmol) heated in DMF at 100° C. for 16 hrs. Reaction mixture was then cooled to room temperature and diluted with water and extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (1.1 g, 26%).
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[CH2:9][CH2:8][C@H:3]1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>CO.O>[CH3:1][N:2]1[C:10](=[O:11])[CH2:9][CH2:8][C@H:3]1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)[C@@H]1CCC(=O)N1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1C(=O)CC[C@H]1C(=O)O
Yield: 106.9 %

Procedure:
Methyl 1-methyl-5-oxo-prolinate (0.308 g, 1.96 mmol) was dissolved in methanol (˜10 ml) and to this was added a solution of sodium hydroxide (0.157 g, 3.92 mmol) in water (˜10 ml). The mixture was heated at reflux for 3 hrs, then cooled and evaporated to leave a minimal amount of water. This was acidified to pH 1 using 2M aqueous hydrogen chloride. The aqueous layer was washed with dichloromethane and then separated and evaporated to give 1-methyl-5-oxo-proline as a white solid (0.300 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[CH:14][N:15](C)C)[C:11](=O)[C:10]([CH3:20])([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:22]N>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([CH3:20])([CH3:19])[C:11]2[NH:22][N:15]=[CH:14][C:12]=2[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CC(C)(C)C1=O
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2cn[nH]c2C(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-dimethylaminomethylene-3,3-dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (6.35 g, 22 mmol) in methanol (15 mL) was added hydrazine hydrate (1.2 mL, 1.1 equiv). The solution was stirred at room temperature overnight and concentrated to give 5.3 g (94%) which was used without purification. Mass spec.: 252.19 (MH)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.CCN(CC)CC.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[C:16]1([S:22]([O:1][CH2:2][CH:3]2[CH2:4][CH2:5][C:6](=[O:8])[NH:7]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCC(CO)N1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C1CCC(COS(=O)(=O)c2ccccc2)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 5-(hydroxymethyl)pyrrolidin-2-one (1.0 g, 8.7 mmol) in acetone (80 mL) was added Et3N (1.8 g, 17.4 mmol) and benzenesulfonyl chloride (3.1 g, 17.4 mmol). The mixture was stirred for 3 h at room temperature. Then the reaction mixture was filtered and concentrated, and the crude product was purified by column chromatography to give the desired product. MS (ESI): 256 (MH+).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.ClCCl.P(Br)(Br)[Br:17].N>O>[Br:17][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)c1ccc(CO)cc1
Agent: N
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
11.5 g (70 mmol) of methyl 4-hydroxymethylbenzoate are added to 120 ml of dichloromethane and 47.3 ml of phosphorus tribromide are added thereto. The mixture is stirred for one hour at ambient temperature and a semi-concentrated solution of ammonia in water is carefully added, whilst cooling with ice, until a pH of 8 to 9 is achieved. The organic phase is separated off and dried and the solvent is distilled off. 13.4 g (84% of theory) of the methyl 4-bromomethylbenzoate are obtained (analogously to Compound 6).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[O:24][C:23]([C:25]([O:27]C)=[O:26])=[CH:22][CH:21]=3)=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[O:24][C:23]([C:25]([OH:27])=[O:26])=[CH:22][CH:21]=3)=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)o1
Solvent: CO
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)o1
Yield: 90.7 %

Procedure:
The title compound was prepared from methyl 5-(2-(7-phenylheptanoyl)oxazol-5-yl)furan-2-carboxylate (7 mg, 0.018 mmol) following General Procedure E. Preparative thin layer chromatography (10% MeOH/CH2Cl2) yielded the title compound as a white solid (6 mg, 85%): 1H NMR (THF-d8, 500 MHz) δ 7.68 (s, 1H), 7.27 (d, 1H, J=3.5 Hz), 7.22-7.07 (m, 5H), 7.04 (d, 1H, J=4.0 Hz), 3.05 (t, 2H, J=7.0 Hz), 2.60 (t, 2H, J=7.5 Hz), 1.73-1.71 (m, 2H), 1.65-1.61 (m, 2H), 1.42-1.40 (m, 4H); 13C NMR NMR (THF-d8, 125 MHz) δ 187.6, 164.6, 158.3, 146.2, 145.8, 143.5, 129.1, 128.9, 128.9, 126.3, 126.0, 119.7, 111.7, 39.6, 36.7, 32.4, 30.0, 30.0, 24.6; MALDI-FTMS m/z 368.1501 (M+H+, C21H22NO5, requires 368.1492).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1>>[F:36][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][N:17]1[C:9]2=[N:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:12][C:11](=[O:13])[N:10]2[CH2:14][CH2:15][C@H:16]1[C:18]([F:20])([F:21])[F:19]
Reactant: Fc1cccc(CBr)c1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2Cc1cccc(F)c1

Procedure:
The product is prepared according to the procedure described in Example 22, using 100 mg of (8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, 214 mg of caesium carbonate and 68 mg of 1-(bromomethyl)-3-fluorobenzene. After purification by preparative HPLC/MS (Method C), 102 mg of (8S)-9-(3-fluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]-pyrimidin-4-one are obtained in the form of an oil, the characteristics of which are the following:
Reaction SMILES: [CH:1]12[O:6][CH:2]1[CH2:3][CH2:4][CH2:5]2.Br[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=1>>[CH3:15][O:14][C:12]1[CH:13]=[C:8]([C@@H:2]2[CH2:3][CH2:4][CH2:5][C@H:1]2[OH:6])[CH:9]=[C:10]([O:16][CH3:17])[CH:11]=1
Reactant: COc1cc(Br)cc(OC)c1
Reactant: C1CC2OC2C1
Product: COc1cc(OC)cc([C@@H]2CCC[C@H]2O)c1

Procedure:
Preparation 19 is prepared from cyclopentene oxide and 1-bromo-3,5-dimethoxybenzene in a manner similar to preparation 10. 1H NMR (CDCl3): 6.41 (s, 2H), 6.33(s, 1H), 4.15 (dd, J=7.5 Hz, 1H), 3.78 (s, 6H), 2.81 (dd, J=9.2 Hz, 1H), 2.1 (m, 2H), 1.9-1.5 (m, 6H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Br)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].CC1(C)C(C)(C)OB([C:34]2[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH:35]=2)O1.C([O-])(=O)C.[K+].O>[Pd].CC#N>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:34]3[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH:35]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2ncccc2Br)cc1)c1nc2ccccc2[nH]1
Reactant: CC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)N1CC=C(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 90 °C

Procedure:
(1H-benzo[d]imidazol-2-yl)(4-(3-bromopyridin-2-yloxy)phenyl)methanone (0.895 g, 2.270 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (0.60 g, 2.39 mmol), potassium acetate (1.06 g, 17.9 mmol), and palladium catalyst (0.13 g, 0.18 mmol) were taken up in 24 mL of 3:1 MeCN:water. The mixture was purged with nitrogen and heated to 90° C. for 15 h. The reaction mixture was diluted with water and extracted with EtOAc (3×). The organics were washed with 30 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel [10 to 100% EtOAc (contains 5% MeOH)/hexane] afforded 1-(4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([NH:15][NH:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])=O)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:16]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[NH2:15].[NH:16]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])[NH2:15]
Reactant: CC(C)(CO)NNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CO)NN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (4 mL) was added to a solution of N′-(2-hydroxy-1,1-dimethyl-ethyl)-hydrazinecarboxylic acid tert-butyl ester (490 mg, 2.4 mmol) in dichloromethane (4 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to give the trifluoroacetic acid salt of 2-hydrazino-2-methyl-propan-1-ol (520 mg, quantitative) which was used without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].C([O-])(O)=O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:19]([O:18][C:16]([NH:1][CH:2]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:7]([OH:9])=[O:8])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)C(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 817.3 %

Procedure:
To a solution of L-tert-leucine (1) (50.0 g, 38.0 mmol) and NaHCO3 (96.0 g, 114 mmol) in ice (500 g) and water (500 ml) was added benzyl chloroformate (65.0 ml, 74.0 mmol) and the reaction stirred at 0° C. for 3 hours then at room temperature for 18 hours. 0.1N Na2CO3 was added until the oily layer dissolved and the solution was washed with 10% EtOAc in hexanes (2×500 ml). The iced aqueous phase was acidified to pH 1 using 12N HCl then extracted using EtOAc (3×350 ml). The combined organic extracts were dried over Na2SO4, filtered and evaporated to give the title compound as a colorless oil (82.4 g, 81.5% yield):
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.Cl[S:14]([C:17]1[CH:18]=[C:19]([C:27]([OH:29])=[O:28])[C:20]2[O:25][CH2:24][CH2:23][O:22][C:21]=2[CH:26]=1)(=[O:16])=[O:15]>O>[CH2:1]([N:3]([CH2:4][CH3:5])[S:14]([C:17]1[CH:18]=[C:19]([C:27]([OH:29])=[O:28])[C:20]2[O:25][CH2:24][CH2:23][O:22][C:21]=2[CH:26]=1)(=[O:16])=[O:15])[CH3:2]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc2c1OCCO2
Reactant: CCNCC
Solvent: O
Solvent: CCN(CC)CC
Product: CCN(CC)S(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Temperature: 25 °C
Yield: 74 %

Procedure:
200 ml of water, 100 ml of diethylamine and 200 ml of triethylamine were introduced into a balloon flask provided with an agitator and a thermometer and then 140 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were added in portions, the temperature being maintained at from 20°-30° C. The mixture was agitated at ambient temperature and then 500 ml of water were added. The solution was filtered and treated with 300 ml of hydrochloric acid. The precipitate was dried off, washed and dried. 117 g of 7-diethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were obtained (M.P: 149° C.; yield: 74%).
Reaction SMILES: [CH:1]1[N:5]([CH2:6][O:7][CH2:8][CH2:9][OH:10])[C:4]2[N:11]=[C:12]([NH2:16])[N:13]=[C:14]([OH:15])[C:3]=2[N:2]=1.N1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:22]=[CH:21]\[CH2:20]/[CH:19]=[CH:18]\[CH2:22]/[CH:21]=[CH:20]\[CH2:19][CH2:18][CH2:4][CH2:3][C:14]([O:10][CH2:9][CH2:8][O:7][CH2:6][N:5]1[C:4]2[NH:11][C:12]([NH2:16])=[N:13][C:14](=[O:15])[C:3]=2[N:2]=[CH:1]1)=[O:15]
Reactant: Nc1nc(O)c2ncn(COCCO)c2n1
Reactant: c1ccncc1
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCOCn1cnc2c(=O)nc(N)[nH]c21

Procedure:
Acyclovir (ACV, 0.5 g, 2.22 mmol, used as a dry white powder) was suspended in anhydrous pyridine (10 ml) and to the mixture stirred under dry nitrogen was added GLA acid chloride (0.788 g, 2.664 mmol). The reaction mixture was stirred overnight at room temperature after which period TLC indicated conversion to the required product. The pyridine was removed in vacuo and the residual syrup was dissolved in chloroform. This was introduced into a column of silica gel (30 g) pre-equilibrated in chloroform:ethanol (30:1, v:v). Elution with chloroform followed by chloroform: ethanol (30:1) , (20:1) and finally (15:1), gave the required product, AK-5, as a TLC homogeneous semi-solid. Yield, 48% (0.517 g, 1.065 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH2:13].[Br:15]Br>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([Br:15])[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH2:13]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a solution of 2.23 g (10.4 mmol) of 2-amino-3-nitro-benzoic acid methyl ester in 12 mL of acetic acid was added dropwise a solution of 0.53 mL (10.4 mmol) of Br2 in 2.0 mL of acetic acid. The mixture was stirred at r.t. for 30 min and poured into 100 g of ice. The solid was collected by filtration and dried to afford 2.5 g (82%) of 2-Amino-5-bromo-3-nitro-benzoic acid methyl ester. 1H NMR (CDCl3, 400 MHz): δ 8.6 (d, 1H), 8.53 (s, 1H), 3.95 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=1)[CH3:19]
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(O)c(F)c1
Temperature: 85 °C

Procedure:
(3-Fluoro-4-hydroxy-phenyl)-acetic acid (20.03 g) was dissolved in ethanol (100 mL), and conc. sulfuric acid (1 mL) was added to the solution. The solution was heated to 85° C. for 16 h. The reaction mixture was allowed to cool and evaporated to dryness in vacuo to yield the crude title compound (24.2 g). An aliquot of the crude product was purified by silica gel chromatography (ethyl acetate:hexanes=3:7) for full characterization of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]2)[CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](SC)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]2)[CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: C1COCCN1
Reactant: CSc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCC(C)CC4)c3)c3ccccc23)n1
Product: CC1CCN(c2cc(F)cc(C(=O)Nc3ccc(Oc4ccnc(N5CCOCC5)n4)c4ccccc34)c2)CC1

Procedure:
Compound is prepared from 3-fluoro-5-(4-methylpiperidin-1-yl)-N-(4-{[2-(methylthio)pyrimidin-4-yl]oxy}-1-naphthyl)benzamide (0.1 g, 0.2 mmol) and morpholine (10 mmol) according to conditions described in Step 4 of Example 3 and general procedure C. A pink solid is produced (15 mg). Mp: 88-89° C.; 1H NMR (300 MHz, CDCl3) δ 0.98 (d, J=6.6 Hz, 3 H), 1.25-1.38 (m, 3H), 1.75 (d, J=12.6 Hz, 2H), 2.78-2.86 (m, 2H), 3.64 (s, 9H), 3.77 (d, J=12 Hz, 1H), 6.07 (d, J=5.7 Hz, 1H), 6.77 (d, J=12 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 2.30-7.33 (m, 2H), 7.49-7.60 (m, 2H), 7.89-7.99 (m, 3 H), 8.13 (s, 1H), 8.18 (d, J=5.7 Hz, 1H); MS 542 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]=2[C:5]([CH3:12])=[C:4]2[C:13]3[CH:19]=[C:18]([O:20]C)[CH:17]=[CH:16][C:14]=3[NH:15][C:3]=12.Cl.N1C=CC=CC=1>>[CH3:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]=2[C:5]([CH3:12])=[C:4]2[C:13]3[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:14]=3[NH:15][C:3]=12
Reactant: COc1ccc2[nH]c3c(C)c4ccncc4c(C)c3c2c1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1c2ccncc2c(C)c2c1[nH]c1ccc(O)cc12

Procedure:
A mixture of one part by weight 9-methoxy-ellipticine obtained by extraction from "yellowwood" (Ochrosia maculate)from the island of Reunion, and from 3 to 11 parts by weight of pyridine hydrochloride, were heated with gentle reflux for 30 to 90 minutes. The reaction mass became a dark brown colour; it was then poured over crushed ice, the precipitate formed was centrifuged and washed several times with iced water and then recrystallized in methanol. The crystals obtained were orange coloured.
Reaction SMILES: [C:1]1([C:7]2([C:13]#[N:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](#[N:18])[CH:16]=[CH2:17]>CO>[C:15]([CH2:16][CH2:17][N:10]1[CH2:9][CH2:8][C:7]([C:13]#[N:14])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][CH2:11]1)#[N:18]
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: C=CC#N
Solvent: CO
Product: N#CCCN1CCC(C#N)(c2ccccc2)CC1

Procedure:
4-Phenyl-4-cyanopiperidine (7 g, 37.6 mmol) and acrylonitrile (2.97 ml ,45.1 mmol) were stirred at room temperature in methanol (34 mL) for 18 hours monitoring the reaction by tlc until complete. The solvent was removed under vacuum and the residue chased with toluene (2x). This residual oil was used directly in the next step
Reaction SMILES: [NH:1]=[C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([I:17])[CH:11]=1)[NH:3][NH:4][C:5]([CH:7]1[CH2:9][CH2:8]1)=O>P(Cl)(Cl)(Cl)=O>[CH:7]1([C:5]2[NH:1][C:2]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([I:17])[CH:11]=3)=[N:3][N:4]=2)[CH2:9][CH2:8]1
Reactant: Cc1ccc(C(=N)NNC(=O)C2CC2)cc1I
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2nnc(C3CC3)[nH]2)cc1I
Reaction time: 14 h
Yield: 19.6 %

Procedure:
A solution of N′-(imino(3-iodo-4-methylphenyl)methyl)cyclopropanecarbohydrazide (preparation 51c, 0.76 g, 2.2 mmol) in phosphorus oxychloride (10 mL) was heated in a sealed tube at 110° C. with stirring. After 14 hours, the mixture was cooled and concentrated in vacuo. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue. The organic layer was dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (2:1 hexanes/ethyl acetate) to give the title compound (0.14 g, 20%) as a white solid.
Reaction SMILES: O.[SH-:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][C:10]=1Cl.Cl>CO>[Cl:4][C:5]1[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][C:10]=1[SH:2]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: [SH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc(S)c(Cl)c1
Reaction time: 16 h
Yield: 53.3 %

Procedure:
A solution of sodium hydrosulfide hydrate (60 g technical; ~0.75 mol) in methanol (200 ml) is added to a solution of 3,4-dichloronitrobenzene (100.0 g; 0.52 mol) in methanol (750 ml) with cooling and at a rate to maintain the temperature of the reaction mixture below 40° C. After the addition is completed, the reaction mixture is stirred an additional 16 hours, and then poured on a mixture of ice and hydrochloric acid. The mixture remains strongly acidic. The precipitated yellow solid is filtered, washed and dried. This solid is purified by dissolving same in 25% aqueous sodium hydroxide, extracting the resultant solution several times with methylene chloride until the methylene chloride solution remains colorless. Next, concentrated hydrochloric acid is added to the aqueous solution dropwise to precipitate a light yellow solid and adjust the pH to 1-2. The thus formed slurry is filtered, the isolated solid is washed with water and dried to afford 52.6 g (55%) of title compound. A sample is recrystallized from cyclohexane, m.p. 77°- 78° C. Lit. 73.5°-74° C. (ref. Nippon Kagaku Kaishi 1972, 756).