Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][Li])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](COCC1C=CC=CC=1)(CCCC)(CCCC)CCCC.[Li]CCCC.[Br:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:46]2[C:47]([CH:56]=[O:57])=[CH:48][C:49]3[NH:53][CH:52]=[N:51][C:50]=3[C:54]=2[F:55])=[C:41]([Cl:58])[CH:40]=1>C1COCC1>[CH2:1]([O:8][CH2:9][CH:56]([C:47]1[C:46]([NH:45][C:42]2[CH:43]=[CH:44][C:39]([Br:38])=[CH:40][C:41]=2[Cl:58])=[C:54]([F:55])[C:50]2[N:51]=[CH:52][NH:53][C:49]=2[CH:48]=1)[OH:57])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Reactant: [Li]COCc1ccccc1
Agent: CCCC[Sn](CCCC)(CCCC)COCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(COCc1ccccc1)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of benzyloxymethyllithium in THF (2 mL, prepared from n-Bu3SnCH2OBn (505 mg, 1.23 mmol) and n-BuLi (0.49 mL, 1.22 mmol, 2.5 M solution in hexane) by the procedure reported in J. Am. Chem. Soc. 1978, 100, 1481) is added a solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde 10f (51 mg, 0.14 mmol) in THF (3 mL) at −78° C. The resulting solution is stirred for 1 hour at −78° C. The reaction is quenched with saturated aqueous NH4Cl, and extracted with EtOAc. The organic layer is dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography (100% CH2Cl2 to 3% MeOH in CH2Cl2) to afford the desired product (46 mg, 68%): MS APCI (+) m/z 490, 492 (M+, Br pattern) detected.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[NH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)=[O:23])[CH2:18][CH2:17]1>>[CH2:9]([O:8][C:7]1[C:6](=[O:11])[C:5](=[O:12])[C:4]=1[NH:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)=[O:23])[CH2:18][CH2:17]1)[CH3:10]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: NCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Product: CCOc1c(NCCC2CCN(C(=O)OCc3cc(Cl)cc(Cl)c3)CC2)c(=O)c1=O

Procedure:
The title compound was prepared from 3,4-diethoxycyclobut-3-ene-1,2-dione and 3,5-dichlorobenzyl 4-(2-aminoethyl)piperidine-1-carboxylate (step 1) analogously to Example 2;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:12](=[O:13])[NH:11][CH:10]1[C:14](OC)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C.[BH4-]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C:12](=[O:13])[NH:11][C@H:10]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1NC(=O)C1NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1C(=O)N[C@H]1CO
Reaction time: 0.33 h
Yield: 50.8 %

Procedure:
A solution of 2.0 g (8.2 mmole) of methyl 3-t-butoxycarbonylamino-4-oxoazetidine-2-carboxylate in 20 ml of tetrahydrofuran is cooled in ice and a solution of 0.75 g (20 mmole) of sodium borohydride in 10 ml of water is added. The mixture is stirred 20 min at 0° and then 1.5 hr at room temperature. Acetic acid is added drop-wise to decompose the excess borohydride and the mixture is concentrated in vacuum. The residue is diluted with brine and extracted with ethyl acetate. The organic phase is washed with brine and 5% NaHCO3 ; dried over magnesium sulfate and evaporated to dryness to give 0.9 g (50%) of the title product as white crystals, mp 128°-131°.
Reaction SMILES: CS(Cl)(=O)=[O:3].C(N(CC)CC)C.[NH:13]1[CH:17]=[CH:16][C:15]([C:18]([OH:20])=O)=N1.N1C=[CH:25][CH:24]=[CH:23][CH:22]=1>>[O:20]1[C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=2[CH2:16][C:17](=[O:3])[NH:13]1
Reactant: O=C(O)c1cc[nH]n1
Reactant: c1ccncc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: O=C1Cc2ccccc2ON1

Procedure:
Coupling of a pyrazolecarboxylic acid of Formula 6 wherein R4 is H with an anthranilic acid of Formula 7 provides the benzoxazinone of Formula 8. In Scheme 7, a benzoxazinone of Formula 8 is prepared directly via sequential addition of methanesulfonyl chloride in the presence of a tertiary amine such as triethylamine or pyridine to a pyrazolecarboxylic acid of Formula 6 wherein R4 is H, followed by the addition of an anthranilic, acid of Formula 7, followed by a second addition of tertiary amine and methanesulfonyl chloride.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].ClC[C:16]1[CH:17]=[N:18][O:19][C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1.Cl>O1CCCC1.O>[F:30][C:27]([F:28])([F:29])[C:24]1[CH:23]=[CH:22][C:21]([C:20]2[O:19][N:18]=[CH:17][C:16]=2[CH2:3][CH2:2][C:1]([OH:9])=[O:8])=[CH:26][CH:25]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: FC(F)(F)c1ccc(-c2oncc2CCl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1cnoc1-c1ccc(C(F)(F)F)cc1
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
To a solution of diethyl malonate (4.71 g) in tetrahydrofuran (40 ml) was gradually added sodium hydride (60%, oil, 1.07 g) at 0° C. The mixture was stirred for 10 min and a solution of 4-chloromethyl-5-(4-trifluoromethylphenyl)isoxazole (3.50 g) in tetrahydrofuran (40 ml) was added dropwise at 0° C. The mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in a mixture of 6N hydrochloric acid (40 ml) and acetic acid (60 ml) and heated under reflux for 8 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated, dried and recrystallized from ethyl acetate to give a colorless prism (3.00 g, yield 79%) of 3-[5-(4-trifluoromethylphenyl)-4-isoxazolyl]propionic acid. melting point: 171–172° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([Cl:30])[CH:24]=[CH:23]2.C1COCC1.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[C:25]([Cl:30])[CH:24]=[CH:23]3)[C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc2cc(CBr)ccc2n1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1ccc2nc(Cl)ccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a solution of 3-oxopiperazine-1-carboxylic acid benzyl ester (4.65 g, 19.8 mmol) and 6-bromomethyl-2-chloroquinoline (5.40 g, 21.0 mmol) in 80 mL of a 3:1 mixture of THF:DMF at 0° C. is added sodium hydride (0.81 g, 20.2 mmol, 60% mineral oil dispersion). The resulting mixture is stirred for 1 hour at 0° C. then at room temperature for 18 hours. The reaction mixture is quenched with saturated NH4Cl solution, then diluted with EtOAc. The organic layer is washed sequentially with 1N HCl, water, saturated NaHCO3 and saturated NaCl, then dried over MgSO4, filtered and concentrated. The crude product is triturated in Et2O/hexanes/EtOAc and filtered to afford the title compound (6.96 g, 17.0 mmol) as a white solid. 1H NMR (CDCl3, 300 MHz) δ8.08 (d, 1H), 8.00 (d, 1H), 7.69 (s, 1H), 7,63 (dd, 1H), 7.41 (d, 1H), 7.35 (s, 5H), 5.15 (s, 2H), 4.78 (s, 2H), 4.28 (s, 2H), 3.70 (m, 2H), 3.32 (bs, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].[Cl:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Cl:26][CH2:27][CH2:28][C:29]([NH:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23])=[O:30]
Reactant: O=C(Cl)CCCl
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NC(=O)CCCl)c1SC(F)(F)F

Procedure:
To a mixture of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthiopyrazole (10.0 g, 19.0 mmol) in toluene was added 3-chloropropionyl chloride (3.92 g, 30.9 mmol), then zinc chloride (0.97 g, 7.1 mmol). The mixture was heated at reflux for 4 hours. After extractive workup and recrystallisation with heptane-ethyl acetate (1:1) the title product was obtained (9.05 g), 19F-NMR: −43.3; −63.7 ppm.
Reaction SMILES: C(OC1C=CC([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([F:26])([F:25])([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=CC=1)CCCC.[C:27]1([CH3:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>[Pd]>[CH2:33]([C@H:27]1[CH2:32][CH2:31][C@H:30]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([F:25])([F:26])([F:23])([F:24])[F:22])=[CH:17][CH:16]=2)[CH2:29][CH2:28]1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCOc1ccc(C#Cc2ccc(S(F)(F)(F)(F)F)cc2)cc1
Reactant: Cc1ccccc1
Agent: [Pd]
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(S(F)(F)(F)(F)F)cc2)CC1

Procedure:
A mixture of 11.4 g of 4-(2-(4-trans-pentylcyclo-hexyl)-ethynyl)-phenyl sulfur pentafluoride (prepared as in EXAMPLE 7), 50 ml of toLuene and 10 mg of palladium-on-active charcoal is hydrogenated at room temperature under normal pressure. The solid constituents are filtered off and the filtrate is concentrated and worked up in the customary manner to give 4-(2-(trans-4-pentyl-cyclohexyl)-ethyl)-phenyl-sulfur pentafluoride.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]([F:11])([F:10])[F:9])=[N:3]1.[C:12](OC(=O)C)(=[O:14])[CH3:13].OS(O)(=O)=O>>[C:12]([C:5]1[C:4]([C:8]([F:10])([F:9])[F:11])=[N:3][N:2]([CH3:1])[C:6]=1[CH3:7])(=[O:14])[CH3:13]
Reactant: Cc1cc(C(F)(F)F)nn1C
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)c1c(C(F)(F)F)nn(C)c1C
Yield: 21.7 %

Procedure:
22.6 g (0.138 mol) of 1,5-dimethyl-3-trifluoromethyl-1H-pyrazole are added dropwise at 0° C. to a solution of 156 ml (1.65 mol) of acetic anhydride and 0.5 ml of conc. H2SO4. The reaction mixture is stirred under reflux for approx. 8 days. After each 24 h of reaction time, 0.5 ml of H2SO4 each time is added to the reaction mixture. On completion of the reaction, excess acetic anhydride is distilled off under reduced pressure, the residue is taken up in 500 ml of CH2Cl2 and the organic phase is washed 3 times with 300 ml of water each time. The organic phase is dried over MgSO4 and concentrated by rotary evaporation. Distillation of the oily residue results in 6.20 g (0.030 mol; 21.8%) of 4-acetyl-1,5-dimethyl-3-trifluoromethyl-1H-pyrazole (b.p.: 142° C./0.4 mbar).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]1=[CH:8][C:7](=[O:23])[CH2:6][C@H:5]2[CH3:24].[CH3:25][O:26][CH2:27][C@@:28]12[C@@H:45]3[C@H:36]([C@H:37]4[C@@:41]([CH2:43][CH2:44]3)([CH3:42])[C:40](=[O:46])[CH2:39][CH2:38]4)[CH2:35][C@H:34]([CH3:47])[C:33]1=[CH:32][C:31](=[O:48])[CH2:30][CH2:29]2>>[CH3:1][O:2][CH2:3][C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]([OH:22])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]1=[CH:8][C@@H:7]([OH:23])[CH2:6][C@H:5]2[CH3:24].[CH3:25][O:26][CH2:27][C@@:28]12[C@@H:45]3[C@H:36]([C@H:37]4[C@@:41]([CH2:43][CH2:44]3)([CH3:42])[C@@H:40]([OH:46])[CH2:39][CH2:38]4)[CH2:35][C@H:34]([CH3:47])[C:33]1=[CH:32][C@@H:31]([OH:48])[CH2:30][CH2:29]2
Reactant: COC[C@]12CCC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: COC[C@@]12C(=CC(=O)C[C@H]1C)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: COC[C@@]12C(=C[C@@H](O)C[C@H]1C)CC[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Product: COC[C@]12CC[C@H](O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12

Procedure:
Substituting 19-methoxy-1β-methyl-4-androstene-3,17-dione and 19-methoxy-6α-methyl-4-androstene-3,17-dione results in the preparation of 19-methoxy-1β-methyl-4-androstene-3β,17β-diol and 19-methoxy-6α-methyl-4-androstene-3β,17β-diol.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:15][OH:16]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[N:15][OH:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NO
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc2c(c1)C(=NO)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 7-nitro-3,4-dihydro-2H-naphthalen-1-one (500 mg, 2.62 mmol) in pyridine (2 mL) was added hydroxylamine solution (1 mL, ˜50% solution in water). The reaction was stirred at room temperature for 1 h, then concentrated and purified by column chromatography (10-50% ethyl acetate-hexanes) to yield 7-nitro-3,4-dihydro-2H-naphthalen-1-one oxime (471 mg, 88%). HPLC ret. time 2.67 min, 10-99% CH3CN, 5 min run; ESI-MS 207.1 m/z (MH+).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:43]1[CH:44]=[C:45]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[C:46]([Cl:48])=[CH:47][C:42]=1[O:41][C@H:40]2[OH:58])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:59]1(C)C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>CO.COC(OC)OC>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]21[C:43]1[CH:44]=[C:45]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[C:46]([Cl:48])=[CH:47][C:42]=1[O:41][C@H:40]2[O:58][CH3:59])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)O[C@@H](O)[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1ccc(Cc2cc3c(cc2Cl)O[C@@H](OC)[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: 70 °C
Yield: 70 %

Procedure:
To a solution of 27 (35 mg, 44 μmol) in anhydrous MeOH (1 mL) and trimethylorthoformate (0.5 mL) was added 4-toluenesulfonic acid (15 mg). The mixture was heated in a closed vial at 70° C. overnight, cooled to ambient temperature, loaded onto a preparatory TLC plate, and developed using 15% EtOAc in petroleum ether to give 54 (25 mg, 70% yield). LC/MS m/z 834 (M+Na).
Reaction SMILES: Br[Si](C)(C)C.C([O:8][P:9]([CH2:14][O:15][CH2:16][CH:17]([OH:30])[CH2:18][O:19][N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2[NH2:29])([O:11]CC)=[O:10])C>ClCCl>[OH:30][CH:17]([CH2:16][O:15][CH2:14][P:9]([OH:10])([OH:11])=[O:8])[CH2:18][O:19][N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2[NH2:29]
Reactant: CCOP(=O)(COCC(O)COn1cnc2c(N)ncnc21)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Nc1ncnc2c1ncn2OCC(O)COCP(=O)(O)O
Temperature: 20 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
Bromotrimethylsilane (1.4 ml, 10.6 mmol) was added to a solution of 9-[3-(diethoxyphosphorylmethoxy)-2-hydroxypropoxy]adenine (200 mg, 0.52 mmol) in dichloromethane (8 ml) and stirred under nitrogen for 16 h at 20° C. The solvents were evaporated in vacuo, co-evaporating the residue with methanol and toluene. The residue was recrystallised from water-acetone 1:1, affording 9-[2-hydroxy-3-(phosphonomethoxy)propoxy]adenine (130 mg, 76%) as a white solid m.p. 218°-221° C. λmax (H2O), 259 (ε13,500)nm; νmax (KBr) 3400, 1700 and 1620 cm-1 ; δH [(CD3)2SO] 3.59 (4H, m, CH2OCH2P), 3.95 (1H, m, CH,OH), 4.27 (1H, m, CH2ON), 4.39 (1H, m, CH2ON), 7.43 (2H, br.s, D2O exchangeable, NH2), 8.16 (1H, s, H-2/H-8), 8.39 (1H, s, H-2/H-8); m/z (FAB+ve Ion), 320 (MH+). Found: C, 33.79; H, 4.79; N, 22.00%; C9H14N5O6P requires C, 33.86; H, 4.42; N, 21.94%.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].Cl.[N:9]([O-])=[O:10].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[N:9]([N:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7])=[O:10]
Reactant: O=N[O-]
Reactant: OC[C@@H]1CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=NN1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.9 %

Procedure:
To a stirred mixture of (S)-(+)-2-pyrrolidinemethanol (6.52 g, 64.4 mmol) in THF (120 mL) and 3N hydrochloric acid (33 mL, 99 mmol) at 3° C. was added dropwise a solution of sodium nitrite (5.80 g, 84 mmol) in water (25 mL) over 20 minutes. The reaction mixture was warmed to room temperature and stirred for 15 hours. After being basified with aqueous sodium carbonate, the mixture was extracted with EtOAc twice, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, EtOAc) to give the title compound (8.04 g, 96% yield) as a liquid. 1H NMR (300 MHz, CDCl3) δ 4.53-4.31 (m, 1H), 4.30-4.27 (m, 1H), 4.02-3.93 (m, 2H), 3.70-3.52 (m, 2H), 2.23-1.89 (m, 4H). 13C NMR (75 MHz, CDCl3) δ 63.4, 62.6, 45.9, 26.2, 20.5, LRMS (API-TIS) m/z 131 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=3)[N:18]=[C:17]([OH:28])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(=O)(OC)OC>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[N:24][CH:25]=3)[N:18]=[C:17]([O:28][CH3:29])[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-n2nc(O)cc2-c2ccc(OCc3ccccc3)cc2)cn1
Agent: [K+]
Solvent: COC(=O)OC
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(OC)cc2-c2ccc(OCc3ccccc3)cc2)cn1
Temperature: 120 °C
Reaction time: 5 h
Yield: 128.8 %

Procedure:
A suspension of 5-{5-[4-(benzyloxy)phenyl]-3-hydroxy-1H-pyrazol-1-yl}-2-methoxypyridine (800 mg), dimethyl carbonate (0.9 mg) and potassium carbonate (888 mg) in DMF (8 ml) was stirred at 120° C. for 5 hours. The mixture was poured into ice water and extracted with AcOEt. The organic layer was washed with H2O, saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt/n-hexane=30% to give 5-{5-[4-(benzyloxy)phenyl]-3-methoxy-1H-pyrazol-1-yl}-2-methoxy-pyridine (1.069 g) as a solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:12]([I:13])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7].[F:14][C:15]([F:22])([F:21])[C:16](OCC)=O.Cl>C(O)C.O>[I:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:5]2[C:4]=1[NH:3][C:16]([C:15]([F:22])([F:21])[F:14])=[N:8][C:6]2=[O:7]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NC(=O)c1cccc(I)c1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1nc(C(F)(F)F)[nH]c2c(I)cccc12
Yield: 98.6 %

Procedure:
EDCI hydrochloride (18.4 g) and 1-hydroxybenzotriazole (9.5 g) were added to a solution of 2-amino-3-iodobenzoic acid (16.4 g) synthesized using the method described in Journal of Medicinal Chemistry, 2004, 47 (6), 1448-1464 in DMF (120 mL), and subsequently ammonia water (21.2 ml) was added thereto. The reaction solution was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the deposit was filtrated and dried under reduced pressure to obtain 2-amino-3-iodobenzamide (12.8 g). 60% sodium hydride (2.29 g) was added to a solution of the obtained 2-amino-3-iodobenzamide (5.0 g) in ethanol (95 ml), then ethyl trifluoroacetate (10.8 g) was added thereto, and the mixture was heated to reflux for 15 hours. After cooling, water was added thereto, and the reaction solution was rendered acidic by the addition of 6 N hydrochloric acid. Then, the deposit was filtrated and dried under reduced pressure to obtain compound (4a) (6.4 g, yield based on 2 steps: 77%).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].Cl.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29](Cl)=[O:30])[CH2:25][CH2:24]1>O1CCCC1>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([NH:9][CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[O:30])[CH2:25][CH2:24]1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: NCC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)NCC(=O)OCc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 43.5 %

Procedure:
4.2 cm3 of triethylamine and 3.02 g of benzyl glycinate hydrochloride are added, at 20° C., to 3 g of 4-methylpiperazin-1-ylcarbonyl chloride hydrochloride in solution in 150 cm3 of tetrahydrofuran. After stirring for 16 hours at 60° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is taken up in 70 cm3 of dichloromethane. The organic phase is successively washed with twice 100 cm3 of a saturated aqueous sodium bicarbonate solution and 70 cm3 of water, and then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.9 g of benzyl N-(4-methylpiperazin-1-ylcarbonyl)-glycinate in the form of a white solid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[C@@H:16]([CH3:27])[CH2:15][NH:14]2.Cl[C:29]([O:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:30]>ClCCCl>[Br:10][C:11]1[CH:12]=[C:13]2[C:18]([N:17]([C:21](=[O:26])[C:22]([F:23])([F:25])[F:24])[C@@H:16]([CH3:27])[CH2:15][N:14]2[C:29]([O:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:30])=[CH:19][CH:20]=1
Reactant: O=C(Cl)OC1CCCC1
Reactant: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(C(=O)OC2CCCC2)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Temperature: 50 °C
Reaction time: 72 h
Yield: 96.6 %

Procedure:
N,N-Diisopropylethylamine (0.486 mL, 2.79 mmol) was added to a solution of (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (0.300 g, 0.928 mmol) and cyclopentyl chloroformate (0.144 mL, 1.114 mmol) in 1,2-dichloroethane (6.0 mL), and the mixture stirred at 50° C. for 3 days. Additional N,N-diisopropylethylamine (0.486 mL, 2.79 mmol) and cyclopentyl chloroformate (0.28 mL, 2.22 mmol) were added, and the mixture stirred at 50° C. for 16 h. The reaction mixture was concentrated to afford an off-white solid. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-25% ethyl acetate-hexane) to afford (S)-cyclopentyl 7-bromo-3-methyl-4-(2,2,2-trifluoroacetyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.390 g, 97%) as a yellow oil. MS (ESI, pos. ion) m/z 435, 437 [M+1]+.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])OC2=O.[NH2:13]CCCO.[O:18]1C[CH2:21][CH2:20][CH2:19]1>>[OH:18][CH2:19][CH2:20][CH2:21][N:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[NH2:13])[CH:5]=[O:12]
Reactant: C1CCOC1
Reactant: NCCCO
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: Nc1ccccc1N(C=O)CCCO
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
Isatoic anhydride (6.0 g) and 3-aminopropanol (2.8 ml) were dissolved in tetrahydrofuran (100 ml) and the mixture was stirred at room temperature for 4 hours. Tetrahydrofuran was removed and the residue was purified by silica gel chromatography (ethyl acetate) to obtain 5.94 g of N-(3-hydroxypropyl)(2-aminophenyl)formamide. Yield: 83%.