Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[O:9][CH2:10][C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[CH:20]1([CH2:26][C@H:27]([NH:40][C:41](=O)[O:42]C2C=CC([N+]([O-])=O)=CC=2)[CH2:28][N:29]([CH3:39])[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:9][CH2:10][C:11](=[O:13])[CH3:12])[C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:41]([NH:40][C@@H:27]([CH2:26][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[CH2:28][N:29]([CH3:39])[C:30](=[O:31])[O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:38])[CH3:36])=[O:42])[CH2:15]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C[C@H](CC1CCCCC1)NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)OCC[Si](C)(C)C
Reactant: CC(=O)CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.4 %

Procedure:
A mixture of 1-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)propan-2-one, obtained as described above, (S)-4-nitrophenyl 1-cyclohexyl-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)propan-2-ylcarbamate (0.390 g, 0.81 mmol), and DIPEA (2.5 mL) in CH2Cl2 was stirred at rt for 16 h. After the reaction mixture was evaporated under reduced pressure, the crude product was purified by reversed-phase HPLC to afford 0.0487 g (11.4% in three steps) of 2-(trimethylsilyl)ethyl (S)-2-((R)-3-((R)-(3-chlorophenyl)(2-oxopropoxy)methyl)piperidine-1-carboxamido)-3-cyclohexylpropyl(methyl)carbamate. MS ESI +ve m/z 624 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([OH:40])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].[N:43]1[CH:48]=[CH:47][CH:46]=[N:45][C:44]=1[CH2:49]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1.O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:27]=3)[C:22]([O:40][CH2:49][C:44]3[N:45]=[CH:46][CH:47]=[CH:48][N:43]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: OCc1ncccn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(OCc3ncccn3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (150 mg) is dissolved in tetrahydrofuran (1 ml), then thereto are added pyrimidin-2-ylmethanol (41 mg) and triphenylphosphine (98 mg). After adding dropwise 40% diethyl azodicarboxylate-toluene solution (163 μl) under ice-cooling, the mixture is stirred at room temperature for 1 hour and 30 minutes. Water is added to the reaction mixture and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=2:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(pyrimidin-2-ylmethoxy)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (118 mg). MS (m/z): 692 [M+H]+
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.Br[CH2:11][CH2:12][CH2:13][Cl:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:14][CH2:13][CH2:12][CH2:11][N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][CH:9]=2.[Cl:14][CH2:13][CH2:12][CH2:11][N:7]1[C:8]2[C:4](=[N:3][CH:2]=[N:1][CH:9]=2)[N:5]=[CH:6]1
Reactant: c1ncc2[nH]cnc2n1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCn1cnc2cncnc21
Product: ClCCCn1cnc2ncncc21
Temperature: 20 °C
Reaction time: 24 h
Yield: 23 %
Yield: 68 %

Procedure:
To a solution of purine (360 mg, 3.00 mmol) and 1-bromo-3-chloropropane (1.42 g, 9.0 mmol) in DMF (10 mL) was added K2CO3 (622 mg, 4.5 mmol) at 20° C. The reaction mixture was stirred for 24 h at 20° C. and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed to give 9-(3-chloropropyl)purine (400 mg, 68%) and 7-(3-chloropropyl)purine (136 mg, 23%) as colorless oils.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH:18][C:19]([C:21]2[N:22]([CH3:31])[N:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=2[Cl:26])=O)[C:3]=1[N+:32]([O-])=O>CC(O)=O.CCOC(C)=O.[Fe]>[C:27]([C:24]1[C:25]([Cl:26])=[C:21]([C:19]2[NH:32][C:3]3[C:4](=[N:5][C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[C:14]([F:17])([F:16])[F:15])=[N:7][C:2]=3[CH3:1])[N:18]=2)[N:22]([CH3:31])[N:23]=1)([CH3:28])([CH3:30])[CH3:29]
Reactant: Cc1nc(-c2ccccc2C(F)(F)F)nc(NC(=O)c2c(Cl)c(C(C)(C)C)nn2C)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1nc(-c2ccccc2C(F)(F)F)nc2nc(-c3c(Cl)c(C(C)(C)C)nn3C)[nH]c12
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [6-methyl-5-nitro-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amide (138 mg, 0.278 mmol, prepared as described in STEP A above) in AcOH (10 mL) was treated with iron powder (77.5 mg, 1.39 mmol), and the mixture was heated to 100° C. for 4 h. The cooled mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (50 mL). The aqueous layer was extracted again with EtOAc (50 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 24-g SEPRA Si 50 SPE column (Flow rate=20 mL/min; Eluent=EtOAc-hexanes, 1:9 for 15 min, then 1:9 to 2:3 over 40 min) to yield 8-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-6-methyl-2-(2-trifluoromethyl-phenyl)-7H-purine as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 10.66 (br. s., 1H), 7.82 (d, J=7.6 Hz, 1H), 7.72-7.77 (m, 1H), 7.66 (t, J=7.5 Hz, 1H), 7.54-7.62 (m, 1H), 4.40 (s, 3H), 2.95 (s, 3H), 1.45 (s, 9H). Mass Spectrum (LCMS, ESI pos.): Calculated for C21H20N6ClF3: 449.1 (M+H). Measured: 449.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:5]=[C:4]([CH3:17])[C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])=[C:28]([F:41])[CH:27]=2)[CH:19]=1.FC(F)(F)C(O)=O.[CH3:49][S:50]([OH:53])(=[O:52])=[O:51]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:49][S:50]([OH:53])(=[O:52])=[O:51].[CH3:17][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[C:28]([F:41])[CH:27]=2)[CH:19]=1
Reactant: Cc1cc(OCCN2CCCC2=O)cc(C)c1-c1cccc(CNc2ccc(CCC(=O)OC(C)(C)C)c(F)c2)c1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCCN2CCCC2=O)cc(C)c1-c1cccc(CNc2ccc(CCC(=O)O)c(F)c2)c1
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of tert-butyl 3-{4-[({2′,6′-dimethyl-4′-[2-(2-oxopyrrolidin-1-yl)ethoxy]biphenyl-3-yl}methyl)amino]-2-fluorophenyl}propanoate (0.51 g, 0.91 mmol) in toluene (5 mL) was added trifluoroacetic acid (5 mL) under stirring at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with saturated aqueous sodium hydrogencarbonate. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1-ethyl acetate-ethyl acetate/methanol=10/1) to give a colorless amorphous powder. The obtained amorphous powder was dissolved in ethyl acetate, and methanesulfonic acid (0.82 mL) was added. The precipitated crystals were collected by filtration, washed, and dried to give the title compound (0.44 g, yield 88%) as colorless crystals.
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[Cl:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1.C(#N)C.C([O-])(=O)C.[K+]>O.ClCCl>[Cl:32][C:33]1[CH:38]=[C:37]([C:2]2[C:6]3[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=3[N:4]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:3]=2)[CH:36]=[CH:35][N:34]=1
Reactant: COc1nccc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: COc1nccc2c1c(-c1ccnc(Cl)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 79.8 %

Procedure:
To a microwave vial was charged 3-iodo-4-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.14 g, 2.21 mmol), 2-chloropyridin-4-ylboronic acid (0.366 g, 2.32 mmol) and bis(diphenylphosphino)ferrocenepalladium chloride (181 mg, 0.221 mmol). Acetonitrile (14 mL, 270 mmol) and 1.0 M of potassium acetate in water (5.3 mL) were then added and the reaction mixture was degassed with nitrogen for 10 minutes and then heated to 100° C. under microwave irradiation for 40 minutes. Upon reaction completion, the reaction mixture was diluted with dichloromethane, filtered through Celite® and concentrated in vacuo. The crude residue was purified by column chromatography eluting with 0-2% EtOAc in DCM to give the title compound (0.887 g, 80%). LC-MS (Method H): m/z=503.3 [M+H]+, 1.55 min. 1H-NMR (400 MHz, CDCl3): δ 8.38 (d, J=4.6, 1H), 8.06 (s, 1H), 7.86 (d, J=4.8, 1H), 7.58 (d, J=6.0, 1H), 7.35-7.28 (m, 9H), 7.23-7.14 (m, 6H), 5.91 (d, J=6.2, 1H), 4.11 (s, 3H.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)SC)[C:4]([NH2:6])=[O:5])#[N:2].[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][C:18]#[N:19])=[CH:15][CH:14]=1.O.[NH2:23][NH2:24]>CCO>[NH2:2][C:1]1[NH:24][N:23]=[C:7]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([CH2:17][C:18]#[N:19])=[CH:15][CH:14]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(SC)=C(C#N)C(N)=O
Reactant: NN
Reactant: N#CCc1ccc(N)cc1
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(Nc2n[nH]c(N)c2C(N)=O)cc1
Temperature: 75 °C

Procedure:
Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added 4-Aminobenzyl cyanide (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-(cyanomethyl)phenyl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:15][CH3:16])[CH:10]([OH:14])[C:11]([OH:13])=O)=O)(C)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN1CCOCC1>ClCCl>[CH2:31]([NH:38][C:11](=[O:13])[C@@H:10]([OH:14])[CH:9]([NH2:8])[CH2:15][CH3:16])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C(=O)O
Reactant: NCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC(N)[C@H](O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-tert-Butoxycarbonylamino-2-hydroxy-pentanoic acid (300 mg, 1.2 9 mmol) was combined with EDC (400 mg, 2.1 mmol) and HOBt (400 mg, 2.6 mmol). A solution of benzylamine (0.22 mL) and 4-methylmorpholine (0.5 mL) in dichloromethane (4 mL) was added in one portion. The reaction mixture was stirred at ambient temperature for 2 h. After dilution with ethyl acetate (150 mL), the solution was washed with 1 N aqueous HCl, water, saturated aqueous NaHCO3 solution and brine. The resultant mixture was dried with magnesium sulfate and evaporated under vacuum to yield (S)-3-amino-2-hydroxy-pentanoic acid benzylamide (380 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[NH2:25][C@@H:26]1[CH2:30][CH2:29][N:28]([CH2:31][C@H:32]([OH:34])[CH3:33])[CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:34][C@H:32]([CH3:33])[CH2:31][N:28]1[CH2:29][CH2:30][C@@H:26]([NH:25][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:21])[CH2:27]1
Reactant: C[C@@H](O)CN1CC[C@@H](N)C1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](O)CN1CC[C@@H](NC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(Cl)cc4s2)n3C)C1
Yield: 24.7 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [(R)-1-((R)-2-hydroxy-propyl)-pyrrolidin-3-yl]amide (20 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (60 mg), (R)-1-((R)-3-amino-pyrrolidin-1-yl)-propan-2-ol (100 mg), HBTU (180 mg), and DIEA (100 uL) in DMF (1 mL). LC/MS: m/z 484.7. 1H NMR (DMSO-d6, 400 MHz): δ 8.43 (m, 1H), 8.08 (s, 1H), 7.93-7.92 (d, 1H), 7.75 (br. m, 1H), 7.47-7.45 (br. d, 1H), 7.40-7.37 (m, 1H), 4.52-4.42 (m, 2H), 3.77-3.73 (m, 1H), 3.66 (s, 3H), 2.92-2.78 (m, 2H), 2.63-2.60 (m, 2H), 2.46-2.43 (m, 2H), 2.19-2.14 (m, 1H), 1.86-1.78 (m, 1H) 1.07-1.06 (d, 3H) —NH and OH proton signal was not observed.
Reaction SMILES: CN(C)C=O.[CH2:6]([N:13]1[C:23]2[C:18](=[CH:19][C:20]([OH:24])=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:14]1=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[CH2:31]([N:33]([CH2:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1)[C:34](=[O:40])[CH2:35][CH2:36][CH2:37][CH2:38]Cl)[CH3:32]>C(Cl)(Cl)Cl.CO>[CH2:6]([N:13]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH2:38][CH2:37][CH2:36][CH2:35][C:34]([N:33]([CH2:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)[CH2:31][CH3:32])=[O:40])=[CH:21][CH:22]=2)[CH2:17][CH2:16][C:14]1=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCN(CC1CCCCO1)C(=O)CCCCCl
Reactant: O=C1CCc2cc(O)ccc2N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCN(CC1CCCCO1)C(=O)CCCCOc1ccc2c(c1)CCC(=O)N2Cc1ccccc1

Procedure:
Into 50 ml of dimethylformamide were added 1.9 g of 1-benzyl-6-hydroxy-3,4-dihydrocarbostyril, 1.8 g of K2CO3 and 0.5 g of KI. The mixture was heated at 60°-70° C. under stirring, then 3.4 g of N-ethyl-N-(2-tetrahydropyranylmethyl)-5-chloropentanic acid amide was added dropwise gradually thereto. After the addition operation, the reaction mixture was further stirred at the same temperature for 4 hours. Then the solvent was removed by distillation and the residue thus obtained was dissolved in 200 ml of chloroform and the chloroform layer was washed with a diluted hydrochloric acid, 1% NaOH aqueous solution and water in this order, then dried with anhydrous sodium sulfate. The drying agent was removed by filtratoon, and the mother liquor was concentrated, then the residue thus obtained was treated by a silica-gel column chromatography [solvent used was a mixture of chloroform:methanol=20:1 (v/v)]. 0.6 Grams of 1-benzyl-6-{4-[N-(2-tetrahydropyranylmethyl)-N-ethylaminocarbonyl]butoxy}-3,4-dihydrocarbostyril was obtained as in the form of a colorless syrupy substance.
Reaction SMILES: [OH:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:14][CH3:15].[OH:16]OS([O-])=O.[K+]>CN(C=O)C.CCOC(C)=O>[OH:1][C:2]1[C:9]([C:10]([F:12])([F:13])[F:11])=[CH:8][C:5]([C:6]([OH:16])=[O:7])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: COc1cc(C=O)cc(C(F)(F)F)c1O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)cc(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A suspension of 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzaldehyde (1.03 g, 4.68 mmol) and Oxone™ (3.45 g, 5.61 mmol) in DMF (10 mL) was stirred at RT for 2 h. The reaction mixture was diluted with EtOAc (40 mL) and the solution was washed sequentially with 1M HCl (40 mL) and brine (4×40 mL). The solvent was removed in vacuo and the residue was purified by silica gel chromatography (80 g, 0-10% MeOH in DCM) to afford 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzoic acid (4) (392 mg, 35%) as a white solid: m/z 235 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 13.01 (1H, br s), 10.74 (1H, br s), 7.68 (2H, dd), 3.92 (3H, s).
Reaction SMILES: ClC1C=C(Cl)C=CC=1[O:4]CC(Cl)=O.[Cl:14][C:15]1[CH:52]=[C:51]([C:53]([F:56])([F:55])[F:54])[CH:50]=[CH:49][C:16]=1[O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:46]([O-:48])=[O:47])=[C:22]([CH:45]=1)[C:23]([O:25][CH2:26][CH2:27]OC(=O)CCOC1C=CC([N+]([O-])=O)=CC=1C#N)=[O:24].[Cl:57][C:58]1[CH:68]=[C:67]([Cl:69])[CH:66]=[C:65]([Cl:70])[C:59]=1[O:60][CH2:61][C:62](Cl)=[O:63]>>[Cl:14][C:15]1[CH:52]=[C:51]([C:53]([F:54])([F:56])[F:55])[CH:50]=[CH:49][C:16]=1[O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:46]([O-:48])=[O:47])=[C:22]([CH:45]=1)[C:23]([O:25][CH2:26][CH2:27][O:63][C:62](=[O:4])[CH2:61][O:60][C:59]1[C:58]([Cl:57])=[CH:68][C:67]([Cl:69])=[CH:66][C:65]=1[Cl:70])=[O:24]
Reactant: O=C(Cl)COc1c(Cl)cc(Cl)cc1Cl
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Reactant: N#Cc1cc([N+](=O)[O-])ccc1OCCC(=O)OCCOC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Product: O=C(COc1c(Cl)cc(Cl)cc1Cl)OCCOC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Other compounds of this type are also prepared according to this example by proper substitution of the 2,4-dichlorophenoxyacetyl chloride reactant. For instance, 2-[(2-cyano-4-nitrophenoxy)-propionyloxy]ethyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate is prepared by substituting 2-[(2-cyano-4-nitrophenoxy)propionyl]chloride; 2-(2,4,6-trichlorophenoxyacetoxy)ethyl 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate is prepared by substituting 2-(2,4,6-trichlorophenoxyacetyl chloride; etc.
Reaction SMILES: Cl.C[OH:3].[C:4]([CH2:6][C:7]1[N:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[N:8]=1)#N.C([O:19][CH2:20]C)C>C(OC)(=O)C>[CH3:16][O:15][C:9]1[CH:10]=[C:11]([O:13][CH3:14])[N:12]=[C:7]([CH2:6][C:4]([O:19][CH3:20])=[O:3])[N:8]=1
Reactant: CO
Reactant: CCOCC
Reactant: COc1cc(OC)nc(CC#N)n1
Agent: Cl
Solvent: COC(C)=O
Product: COC(=O)Cc1nc(OC)cc(OC)n1
Temperature: 5 °C
Reaction time: 5 h

Procedure:
A powerful stream of hydrogen chloride gas is passed for 15 minutes into a solution of 230 ml of methyl acetate and 6.45 ml of methanol, at 0° C. to 10° C. 23.8 g of 2-cyanomethyl-4,6-dimethoxypyrimidine in 250 ml of methyl acetate are not added dropwise while more hydrogen chloride is passed in, and the passing-in of gas is stopped when the dropwise addition is complete, and stirring is continued for 5 hours at 10° C. to 15° C. 200 ml of absolute diethyl ether are added, the mixture is cooled to 5° C., and the precipitate is filtered off with suction under nitrogen. The residue is washed with ether and filtered off with suction until dry. This gives 31.5 g of the imidomethyl ester hydrochloride of melting point 110°-112° C., to which 250 ml of water are added, and the mixture is stirred for 4 hours at 40° C. The mixture is cooled to room temperature and extracted four times using four 150 ml portions of diethyl ether. The organic phase is dried over magnesium sulfate, and the solvent is distilled off. This gives 19.5 g of methyl (4,6-dimethoxypyrimidin-2-yl)acetate of boiling point 110° C./0.04 mbar (ball tube distillation).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.Br[CH2:11][C:12]1[C:13]([Cl:22])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2.C(N(CC)CC)C>C(O)C>[Cl:22][C:13]1[C:12]([CH2:11][S:8][C:6]2[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Clc1nc2ccccc2cc1CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2cc3ccccc3nc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a mixture of 6-methyl-2-sulfanylpyrimidin-4-ol (0.492 g, 3.46 mmol) and 3-(bromomethyl)-2-chloroquinoline (1.27 g, 4.95 mmol) in anhydrous ethanol (30 mL) at room temperature was added triethylamine (1.50 g, 14.85 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated to dryness and water (50 mL) was added. The mixture was sonicated, and a white solid precipitated out. The product was filtered, washed with water, washed with ether, and then dried in vacuo to provide 2-{[(2-chloroquinolin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid (1.03 g, 66% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.24 (s, 3H), 4.57 (s, 2H), 6.00 (bs, 1H), 7.61 (t, 1H), 7.78 (t, 1H), 7.79 (d, J=10.8 Hz, 1H), 8.01 (d, J=10.8 Hz, 1H), 8.67 (s, 1H); M+317.8.
Reaction SMILES: [H][H].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]2[C:18](=[O:19])[CH:17]=[CH:16][CH2:15][C:14]2([CH3:21])[CH3:20])=[CH:8][CH:7]=1)([O-:5])=[O:4]>C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH:13]2[C:14]([CH3:20])([CH3:21])[CH2:15][CH2:16][CH2:17][C:18]2=[O:19])=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: [H][H]
Reactant: CC1(C)CC=CC(=O)C1Cc1ccc([N+](=O)[O-])cc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC1(C)CCCC(=O)C1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.2 %

Procedure:
An atmosphere of hydrogen was introduced to and maintained by a balloon to an evacuated 50 mL round-bottomed flask containing 6-(4'-nitrophenyl)methyl-5,5-dimethylcyclohex-2-en-1-one (39) (14.0 mg, mmol) and tris(triphenylphosphine)rhodium chloride (Wilkinson's catalyst) (8.0 mg) in 6.5 mL anhydrous benzene. The yellow-orange solution was stirred at room temperature for 24 h, and then passed through a short silica gel column (hexanes/ethyl acetate, 3:1) to afford the 6.8 mg (48%) of the desired ketone as a pale yellow oil (Rf0.43, 2:1 hexanes lethyl acetate). 1H NMR (400MHz, CDCl3) δ0.86 and 1.23 (2s, 2×3H, geminal-CH3 's), 2.50 (d, 1H, J=13.0 Hz, 2-H), 2.66 and 3.17 (d of ABq, 2H, JAB =13.0 Hz, JA =1.6 Hz, JB =9.6 Hz, benzylic-CH2), 7.37 (d, 2H, J=9.6 Hz, 2', 6'-H), 8.09 ppm (d, 2H, J=9.6 Hz, 3',5'-H). [Compound 40 is hereinafter also referred to as COMPOUND "V" or 120211]