Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11].C([O-])(O)=[O:15].[Na+].ClCC1C=NC=CC=1C(F)(F)F.C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[Cl:2][CH2:3][C:4]1[CH:5]=[N+:6]([O-:15])[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:11])[F:12]
Reactant: FC(F)(F)c1ccncc1CCl
Reactant: O=C([O-])O
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc(C(F)(F)F)c(CCl)c1
Reaction time: 29 h

Procedure:
3-Chloromethyl-4-trifluoromethylpyridine hydrochloride (204 mg, 0.88 mmol) from step 2 above was dissolved in CHCl3 (50 mL) and treated with saturated aqueous NaHCO3. The organic layer was removed, dried (Na2SO4), and concentrated to give the free pyridine. This 3-chloromethyl-4-(trifluoromethyl)pyridine was dissolved in CHCl3 (10 mL) and MCPBA was added (0.19 g of 80% MCPBA by weight; 0.88 mmol). After 29 h, the solution was extracted with saturated aqueous NaHCO3 (10 mL), dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue was purified by pressurized silica gel column chromatography eluting with EtOAc. 3-Chloromethyl-4-trifluoromethylpyridine-N-oxide was obtained as a solid (TLC: Rf = 0.35 (EtOAc); FAB MS m/z 212 (M+ +H)).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[N:12]=[C:13]([CH:16]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][Si](C(C)C)(C(C)C)C(C)C)=[CH:25][CH:24]=2)[CH2:17][C:18]([O:20][CH3:21])=[O:19])[O:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.[NH4+].[Cl-]>[CH2:1]([O:8][C:9]([C:11]1[N:12]=[C:13]([CH:16]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH2:17][C:18]([O:20][CH3:21])=[O:19])[O:14][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1)c1nc(C(=O)OCc2ccccc2)co1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)CC(Cc1ccc(O)cc1)c1nc(C(=O)OCc2ccccc2)co1
Yield: 87.6 %

Procedure:
To a solution of methyl (±)-3-[4-(benzyloxycarbonyl)-1,3-oxazol-2-yl]-4-[4-(triisopropylsilyloxy)phenyl]butanoate (2.23 g, 4.04 mmole) in dry THF (20 mL) at 0° C. was added a solution of TBAF in THF (1.0 M, 6.06 mL, 6.06 mmole). After 2 hr the mixture was diluted with saturated NH4Cl (10 mL) and extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel (40% EtOAc/hexanes) to give the title compound (1.4 g. 88%) as an off-white foam: MS (ES) m/e 396 (M+H)+.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][CH2:15][C@@H:14]([F:17])[C@@H:13]3[C@H:9]2[CH2:10][NH:11][CH2:12]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.F[B-](F)(F)F.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:44][C:45](=[NH:49])OCC.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:18]1([C:8]2([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:16][CH2:15][C@@H:14]([F:17])[C@@H:13]3[C@H:9]2[CH2:10][N:11]([C:45](=[NH:49])[CH2:44][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[O:37][CH3:36])[CH2:12]3)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: F[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: CCOC(=N)Cc1ccccc1OC
Agent: Cl
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=N)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Yield: 27.8 %

Procedure:
A solution of 0.6 g of (3aR,7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride and 0.51 cm3 of triethylamine in 10 cm3 of dry dichloromethane is added to a solution of 0.41 g of ethyl (2-methoxyphenyl)-acetimidate tetrafluoroborate in 10 cm3 of dry dichloromethane. The reaction mixture is refluxed for 3 hours. It is then treated, after re-equilibrating to room temperature, with 5 cm3 of a 10% aqueous solution of potassium carbonate; the organic phase is washed with 10 cm3 of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 20 cm), eluting under a nitrogen pressure of 0.6 bar with an ethyl acetate, acetic acid and water mixture (15/1/1 by volume) and collecting fractions of 25 cm3. Fractions 24 to 38 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 40 cm3 of dichloromethane, washed with 10 cm3 of a saturated aqueous solution of potassium carbonate and then with 10 cm3 of a saturated aqueous solution of sodium chloride. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from isopropyl oxide. The crystals are drained and dried. 0.18 g of (3aR,7R,7aR)-4,4-diphenyl-7-fluoro-2-[1-imino-2-(2-methoxyphenyl)ethyl]perhydroisoindole is obtained in the form of white crystals, melting point 184° C., with decomposition.
Reaction SMILES: FC1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[N:38]1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[CH:4]=[CH:3][N:38]=[CH:7][CH:6]=4)[CH2:19][CH2:18]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:35])([F:33])[F:34]
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccncc2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 4-pyridylboronic acid pinacol ester instead of 4-fluorophenylboronic acid. LC-MS: (M+1=498, obsd.=498).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[C:12]([O:14][CH3:15])=[O:13].C1C(=O)N([Br:24])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[C:12]([O:14][CH3:15])=[O:13])[Br:24]
Reactant: COC(=O)Cc1ccc(Cl)cc1C(=O)OC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Cl)ccc1C(Br)C(=O)OC
Yield: 120.8 %

Procedure:
18E (16.48 mmol) was dissolved in CCl4 (50 mL), and was added NBS (N-bromosuccinimide, 3.23 g, 18.13 mmol), followed by catalytic amount of BPO (benzoyl peroxide). The reaction mixture was refluxed for about 20 hours under stirring. When no more product was produced any more, the reaction mixture was cooled and filtered. To the filtrate was added NBS (1.6 g, 8.24 mmol) and catalytic amount of BPO. The reaction mixture was refluxed for additional 10 hours. After the reaction completed, the mixture was cooled and filtered. The filtrate was concentrated to give 6.4 g of a crude product (19A), which was used directly for the next step.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:20]Br.[C:22]([C:24]1[CH:25]=[C:26]([CH2:40][CH:41]=[CH:42]O)[C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[CH:28][CH:29]=1)#[N:23]>CC#N>[C:22]([C:24]1[CH:25]=[C:26]([CH2:40][CH:41]=[CH:42][Br:20])[C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[CH:28][CH:29]=1)#[N:23]
Reactant: BrBr
Reactant: COc1ccc(COc2ccc(C#N)cc2CC=CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COc1ccc(COc2ccc(C#N)cc2CC=CBr)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 29 %

Procedure:
To a suspension of Ph3P (2.4 g) in 30 mL of MeCN at 0° C. was added bromine (1.5 g) and the mixture was stirred at 0° C. for 15 minutes and then warmed to ambient temperature. To the suspension of Br2PPh3 was then added 3-cyano-6-((4-methoxybenzyl)oxy)-1-(3-hydroxyprop-2-en-1-yl)benzene (2.3 g) in 20 mL MeCN drop-wise. The resulting solution was stirred at ambient temperature for 1 hour, cooled to ambient temperature and concentrated. The residue was purified on silica gel column (ethyl acetate/hexane, 1:9) to afford 3-cyano-6-((4-methoxybenzyl)oxy)-1-(3-bromoprop-2-en-1-yl)benzene (0.81 g) as a yellow oil.
Reaction SMILES: FC(F)(F)[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:30]=[C:29]([NH:31][C:32]([NH:34][C:35](=[O:43])[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:33])[CH:28]=[CH:27][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])[CH:13]=1>>[F:8][C:9]1[CH:30]=[C:29]([NH:31][C:32]([NH:34][C:35](=[O:43])[CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:33])[CH:28]=[CH:27][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([CH:21]2[CH2:26][CH2:25][N:24]([C:3]([O:5][C:21]([CH3:26])([CH3:22])[CH3:19])=[O:4])[CH2:23][CH2:22]2)=[O:20])[CH:13]=1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)C3CCNCC3)c2)c(F)c1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1

Procedure:
t-Butyl 4-{4-[2-fluoro-4-(3-phenylacetylureido)phenoxy]pyridin-2-ylcarbamoyl}piperidine-1-carboxylate (60 mg, 0.101 mmol) and trifluoroacetic acid (0.50 ml) gave a crude product of piperidine-4-carboxylic acid {4-[2-fluoro-4-(3-phenylacetylureido)phenoxy]pyridin-2-yl}amide (ESI-MS (m/z):492). The crude product, formalin (37% aqueous solution; 0.0376 ml, 0.505 mmol), acetic acid (0.0231 ml, 0.404 mmol) and sodium triacetoxyborohydride (42.8 mg, 0.202 mmol) gave the titled compound (51.1 mg, 22.5%) as colorless powder.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[CH2:4][NH:5][C:6]1[C:11]([NH:12][CH2:13][C:14](OCC)=[O:15])=[CH:10][CH:9]=[C:8]([O:19][CH3:20])[N:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O=[Mn]=O>[CH3:1][O:2][CH:3]([O:21][CH3:22])[CH2:4][N:5]1[C:14](=[O:15])[CH:13]=[N:12][C:11]2[CH:10]=[CH:9][C:8]([O:19][CH3:20])=[N:7][C:6]1=2
Reactant: CCOC(=O)CNc1ccc(OC)nc1NCC(OC)OC
Agent: O=[Mn]=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2ncc(=O)n(CC(OC)OC)c2n1
Temperature: 107.5 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl N-[2-{[2,2-bis(methyloxy)ethyl]amino}-6-(methyloxy)-3-pyridinyl]glycinate (1 g, 3.2 mmol) and potassium carbonate (1.3 g, 9.6 mmol) in DMF (64 mL, 0.05M) was heated at 105-110° C. for 2 h. The mixture was cooled to room temperature and MnO2 (0.8 g, 11 mmol) was added and the reaction was stirred for 18 h. The reaction was filtered, concentrated, and the residue was dissolved in ethyl acetate and washed with water. The organic extract was concentrated and added to a silica column which was then eluted with 0-100% ethyl acetate in hexane affording the desired compound (0.78 g, 78%).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([N+:22]([O-])=O)[CH:14]=1)=[O:11])(=[O:5])[CH:2]([CH3:4])[CH3:3].[H][H]>[C].[Pd].C(O)C>[C:1]([O:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([NH2:19])[CH:16]=[C:15]([NH2:22])[CH:14]=1)=[O:11])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)OCCNC(=O)Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)C(=O)OCCNC(=O)Nc1cc(N)cc(N)c1
Temperature: 17 °C
Reaction time: 1 h

Procedure:
8.3 g of 5% palladium carbon, 83.0 g (0.244 mol) of 2-(3,5-dinitrophenylureido)ethyl isobutyrate (compound 12) and 800 ml of ethanol were placed in a 5-l autoclave equipped with a thermocouple thermometer and a mixing blade, and the autoclave was sealed. The atmosphere inside the autoclave was replaced by hydrogen and the hydrogen pressure was raised to 5 kg/cm2. The autoclave contents were stirred at room temperature (17° C.). 10 minutes later, the autoclave inside temperature rose to 43° C. and the autoclave inside pressure dropped to 1 kg/cm2. Then, hydrogen was introduced to raise the pressure to 5 kg/cm2, and stirring was continued. 10 minutes later, the temperature became 58° C. and the pressure dropped to 1 kg/cm2. Hydrogen was again introduced to raise the pressure to 5 kg/cm2, and stirring was continued. Since the temperature began to drop and the pressure became constant (4.5 kg/cm2), stirring was continued for 60 minutes (the temperature dropped to 26° C.). The atmosphere inside the autoclave was replaced by nitrogen, and the autoclave contents were taken out and filtered to remove palladium carbon. The filtrate was concentrated by the use of an evaporator, whereby a solid was separated. The solid was recrystallized from 300 ml of butanol to obtain 2-(3,5-diaminophenylureido)ethyl isobutyrate (compound 13). Yield: 55.0 g (81%) Melting point: 89-90° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].CCO>[Pd].CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4/C=C/C(=O)OC)cc3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)OC)cc3)cc2)CC1
Reaction time: 4 h

Procedure:
1-{4′-[4-((E)-2-Methoxycarbonyl-vinyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (1.249 g, 2.89 mmol) and 10% palladium on carbon (0.135 g) were combined in EtOAc (25 mL) and stirred under H2 atmosphere for 4 hours. EtOH (25 mL) was added, along with additional 10% palladium on carbon (one spatula), and the reaction was stirred under H2 for 2 days, replacing the balloon of H2 as needed. When no starting material was seen by analytical LCMS, the mixture was filtered through Celite and the filtrate was concentrated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:13][C:14]2[NH:15][C:16]3[C:21]([N:22]=2)=[C:20]([NH2:23])[N:19]=[CH:18][N:17]=3)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Br[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([CH2:27][CH2:26][CH2:25][N:17]2[C:16]3[C:21]([N:22]=[C:14]([S:13][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)[N:15]=3)=[C:20]([NH2:23])[N:19]=[CH:18]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cc(Sc2nc3c(N)ncnc3[nH]2)cc(OC)c1OC
Reactant: BrCCCc1ccccc1
Product: COc1cc(Sc2nc3c(N)ncn(CCCc4ccccc4)c-3n2)cc(OC)c1OC

Procedure:
The title compounds were prepared from 8-(3,4,5-trimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and (3-bromo-propyl)-benzene by a procedure similar to examples 1 and 2. The isomers were separated by preparative HPLC. 9-(3-Phenyl-propyl)-8-(3,4,5-trimethoxy-phenylsulfanyl)-9H-purin-6-ylamine: Yield 34%, 1H NMR (DMSO-d6) δ 8.30 (s, 1H), 7.26-7.22 (m, 2H), 7.16 (tt, J=7.6, 1.2 Hz, 1H), 7.12-7.10 (m, 2H), 6.78 (s, 2H), 4.24 (t, J=7.2 Hz, 2H), 3.72 (s, 6H), 3.63 (s, 3H), 2.56 (t, J=7.6 Hz, 2H), 1.94 (tt, J=7.6, 7.2 Hz, 2H); LC-MS [M+H]+ 452.0. 3-(3-Phenyl-propyl)-8-(3,4,5-trimethoxy-phenylsulfanyl)-3H-purin-6-ylamine: Yield, 13%, 1H NMR (DMSO-d6) δ 8.61 (s, 1H), 7.27-7.23 (m, 2H), 7.18-7.15 (m, 3H), 7.06 (s, 2H), 4.35 (t, J=7.2 Hz, 2H), 3.77 (s, 6H), 3.71 (s, 3H) 2.64 (t, J=7.2 Hz, 2H), 2.20 (quintet, J=7.2 Hz, 2H); LC-MS [M+H]+ 452.0.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30](Br)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[OH:40][CH:41]1[CH2:44][NH:43][CH2:42]1>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30]([N:43]4[CH2:44][CH:41]([OH:40])[CH2:42]4)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: OC1CNC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CC(O)C4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 199 using Diethyl[4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate and 3-hydroxyazetidine. MS (ES+): m/z 621.25 (100) [MH+]; HPLC: tR=0.89 min (UPLC, purity).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[Br:4][C:5]1[C:15]([O:16][CH3:17])=[C:14](Br)[CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:4][C:5]1[C:15]([O:16][CH3:17])=[C:14]([S:3][CH2:1][CH3:2])[CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCS
Reactant: CCOC(=O)c1ccc(Br)c(OC)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(SCC)c(OC)c1Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ethyl mercaptan (5 ml) was added to a suspension of ethyl 2,4-dibromo-3-methoxybenzoate (10.0 g) and potassium carbonate (9.0 g) in dimethylformamide (DMF). The mixture was stirred at room temperature for 48 hours, water was added and the mixture was extracted with ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by medium pressure chromatography eluted with a mixture of ethyl acetate and cyclohexane to give ethyl 2-bromo-4-(ethylsulphenyl)-3-methoxybenzoate (3.98 g) as an oil NMR (CDCl3) 1.35(m,6H) 2.9(q,2H) 3.8(s,3H) 4.4(q,2H) 7.1-7.4(m,2H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:45])=[C:7]([C:16]([CH2:23][S:24][CH2:25][C@H:26]([NH:31][C:32](=[O:44])[C@@H:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34][OH:35])[C:27]([O:29][CH3:30])=[O:28])=[C:17]([O:19][C:20](=[O:22])[CH3:21])[CH:18]=1)[C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])(=[O:3])[CH3:2].P(=O)(O)(O)O.P([O-])(O)(O)=O.[Na+]>[Zn].O1CCCC1>[C:1]([O:4][C:5]1[C:6]([CH3:45])=[C:7]([C:16]([CH2:23][S:24][CH2:25][C@H:26]([NH:31][C:32](=[O:44])[C@@H:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34][OH:35])[C:27]([O:29][CH3:30])=[O:28])=[C:17]([O:19][C:20](=[O:22])[CH3:21])[CH:18]=1)[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](CSCc1c(OC(C)=O)cc(OC(C)=O)c(C)c1C(=O)OCC(Cl)(Cl)Cl)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Agent: O=P(O)(O)O
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CSCc1c(OC(C)=O)cc(OC(C)=O)c(C)c1C(=O)O)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 1.2 h

Procedure:
A mixture of 1.90 g of 2,2,2-trichloroethyl 3,5-diacetoxy-6-[[((R)-2-[(S)-2-(1-t-butoxyformamido)-3-hydroxypropionamido]-2-(methoxycarbonyl)ethyl]thio]methyl]-2-methylbenzoate, 50 ml of tetrahydrofuran, 12.5 ml of 1M phosphoric acid, 12.5 ml of 1M aqueous sodium dihydrogen phosphate solution and 3.2 g of zinc powder was stirred at 20° C. for 1.2 hours. The mixture was filtered, and the unsoluble material was washed with water and ethyl acetate. The filtrate was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and evaporated in vacuo to afford 3,5-diacetoxy-6-[[[(R)-2-((S)-2-(1-t-butoxyformamido)-3-hydroxypropionamido]-2-(methoxycarbonyl)ethyl]thio]methyl]-2-methylbenzoic acid as a solidifying oil.
Reaction SMILES: [Li+].[OH-].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:16]([CH:21]=2)[C:17]([O:19]C)=[O:18])=[O:11])[CH2:6][CH2:5]1.Cl>O.O1CCCC1>[CH3:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:16]([CH:21]=2)[C:17]([OH:19])=[O:18])=[O:11])[CH2:8][CH2:9]1
Reactant: COC(=O)c1cc(C(=O)N2CCN(C)CC2)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(C(=O)c2ccc(OCc3ccccc3)c(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of LiOH (393 mg, 9.36 mmol) in water (10 ml) was added to a stirred solution of methyl 5-[(4-methyl-1-piperazinyl)carbonyl]-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 50; 345 mg, 0.94 mmol) in tetrahydrofuran (2.5 ml) at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was acidified by HCl (6 mol/L). The solvent was evaporated in vacuo to afford the crude product. The crude product was used directly in the next step without further purification.
Reaction SMILES: C([N:4]1[C:12]2[C:11]3=[N:13][N:14]=[N:15][N:10]3[C:9](=[O:16])[N:8]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:7]=2[N:6]=[CH:5]1)C=C.N1CCOCC1.N#N.Cl>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl>[CH2:17]([N:8]1[C:7]2[N:6]=[CH:5][NH:4][C:12]=2[C:11]2=[N:13][N:14]=[N:15][N:10]2[C:9]1=[O:16])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C=CCn1cnc2c1c1nnnn1c(=O)n2CCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: N#N
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CCCCCn1c(=O)n2nnnc2c2[nH]cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
A mixture of 9-allyl-6-pentyl-6,9-dihydro-5H-tetrazolo[5,1-i]purin-5-one (0.10 g, 0.35 mmol) and morpholine (0.2 mL, 2.0 mmol) in THF (3 mL) was degassed for 5 min using N2 and tetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.086 mmol) was added to the mixture. After being stirred at room temperature overnight, the reaction mixture was mixed with 2 M HCl aqueous solution and DCM. The organic layer was separated, dried over Na2SO4 and concentrated. The residue was purified using preparative LCMS to provide the product as a white powder (0.030 g, 35%). LCMS calculated for C10H14N7O (M+H): 248.0. found: 248.0.
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH2:10][CH2:11]Cl)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC>C1COCC1>[C:1]([NH:5][S:6]([CH:9]1[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)CCCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)C1CC1
Temperature: 25 °C
Yield: 56.4 %

Procedure:
To a solution of N-tert-butyl-(3-chloro)propylsulfonamide (2.14 g, 10.0 mmol) in THF (100 mL) was added n-BuLi (2.5 M in hexane, 8.0 mL, 20.0 mmol) at −78° C. The reation mixture was allowed to warm up to room temperature over period of 1 h. The volatiles were removed in vacuo. The residue was partitioned between EtOAC and water (200 mL, 200 mL). The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was recrystallized from hexane to yield the desired product as a white solid (1.0 g, 56%).
Reaction SMILES: [NH2:1][NH2:2].O[CH:4]([CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=O)[C:5](OCC)=[O:6]>C(O)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:2]=[N:1][C:5]([OH:6])=[CH:4][CH:10]=2)=[CH:14][CH:15]=1
Reactant: NN
Reactant: CCOC(=O)C(O)CC(=O)c1ccc(OC)cc1
Solvent: CCO
Product: COc1ccc(-c2ccc(O)nn2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 97.6 %

Procedure:
4.91 ml (98.0 mmol) of hydrazine was added to an ethanol solution (50 ml) of 20.62 g (82.0 mmol) of the obtained ethyl 2-hydroxy-4-(4-methoxyphenyl)-4-oxo-butyrate, and the reaction liquid was stirred at 60° C. for 4 h ours. The reaction liquid was concentrated under reduced pressure, and the resulting solid was washed with diethyl ether to obtain 16.18 g (yield: 80%) of 6-(4-methoxyphenyl)-pyridazin-3-ol as a white solid.