Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:19]=[CH:18][C:17](=[O:20])[C:16]([C:21]3[N:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:24]=[CH:23][CH:22]=3)=[N:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[C:26]1([N:25]2[C:21]([C:16]3[C:17](=[O:20])[CH:18]=[CH:19][N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[N:15]=3)=[CH:22][CH:23]=[N:24]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=c1ccn(C2CCN(Cc3ccccc3)CC2)nc1-c1ccnn1-c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=c1ccn(C2CCNCC2)nc1-c1ccnn1-c1ccccc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 36.9 %

Procedure:
To a solution of 1-(1-benzylpiperidin-4-yl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (2.6 g) in methanol (30 mL) was added palladium hydroxide on carbon (10% wet, 0.30 g). The reaction mixture was stirred at 50° C. for 4 hr under a hydrogen atmosphere. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the obtained crystals were recrystallized from methanol/ethyl acetate to give the title compound (0.75 g).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]([O:15][CH2:16][CH2:17][CH:18]([OH:22])[CH2:19][CH2:20][OH:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)=O.CC(C)=O>N1C=CC=CC=1.CO.C(Cl)Cl>[C:1]([O:21][CH2:20][CH2:19][CH:18]([OH:22])[CH2:17][CH2:16][O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: OCCC(O)CCOCc1ccccc1
Agent: O=C=O
Solvent: ClCCl
Solvent: CO
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)OCCC(O)CCOCc1ccccc1
Reaction time: 15 h

Procedure:
Pivaloyl chloride (2.070 ml, 17.1 mmol) was added slowly to a solution of 5-benzyloxy-1,3-pentanediol (39, 16.3 mmol) in anhydrous pyridine (35 ml) at -18° C. (dry ice-acetone bath). The mixture was kept without stirring in a -20° freezer for 15 hours. The reaction mixture was then diluted with methanol (1 ml) and CH2Cl2 (50 ml), and extracted with 10% HCl containing copper sulfate (10 g/l) until the blue color in the organic layer was removed. The aqueous layer was re-extracted with methylene chloride, the combined organic layers are dried (magnesium sulfate), the solvent evaporated, and 1-pivaloyloxy-5-benzyloxy-3-pentanol (40) isolated as a colorless oil by flash chromatography on silica gel (hexane/EtOAc 7:3 as eluant; yield 4.05 g, 86% as a colorless oil).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[I:8].[S:9]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10]1.O1CCCC1.CN(C)C=O.[H-].[Na+]>O>[I:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[O:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][S:9][CH:10]=1
Reactant: Clc1ccncc1I
Reactant: OCCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Ic1cnccc1OCCc1ccsc1
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a solution of 4-chloro-3-iodo-pyridine (4.79 g, 20.0 mmol) and 2-(3-thienyl)ethanol (2.43 mL, 22.0 mmol) in a mixture of tetrahydrofuran (60 mL, 700 mmol) and N,N-dimethylformamide (20 mL, 200 mmol) was added sodium hydride, 60% dispersion in mineral oil (0.960 g, 24.0 mmol) portionwise over 30 min. The mixture was stirred for 2 hours, poured carefully into 200 ml of cold water and extracted with diethylether twice. The organic extract was washed with water and brine, and dried over MgSO4. After concentration under vacuum, the crude residue was purified on silica gel column, eluting with 50% ethyl acetate in hexane to give 3-iodo-4-(2-(thiophen-3-yl)ethoxy)pyridine (yield 5.34 g, 81%). 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.35 (d, J=5.6, 1H), 7.29 (dd, J=3.0, 4.8, 1H), 7.19 (s, 1H), 7.12 (d, J=4.9, 1H), 6.70 (d, J=5.6, 1H), 4.26 (t, J=6.5, 2H), 3.21 (t, J=6.5, 2H). MS (ESI+) 332.0, 221.9.
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[CH2:17][CH2:18]O.C([N:22](CC)CC)C.N>C(Cl)Cl.C1COCC1.C1(C)C=CC=CC=1>[N+:14]([C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[CH2:7][NH:22][CH2:18][CH2:17]2)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(CO)c(CCO)c1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)CCNC2
Temperature: 24 °C
Yield: 79.8 %

Procedure:
Methanesulfonyl chloride (0.9 mL, 11.63 mmol) was added dropwise over 10 min to a solution of 2-(2-hydroxymethyl-5-nitrophenyl)-ethanol (1.0 g, 5.07 mmol), triethyl amine (1.8 mL, 12.91 mmol), in methylene chloride (20 mL). TLC showed complete reaction after 30 min. 1H NMR (CD3Cl) δ 8.17-11 (m, 2H), 7.65 (d, J=9 Hz, 1H), (s, 2H), 4.49 (t, J=6 Hz, 2H), 3.25 (t, J=6 Hz, 2H), 3.08 (s, 3H), 2.98 (s, 3H). reaction mixture was washed with 10% aqueous HCL, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried with magnesium sulfate, methylene chloride removed under vacuum and chased with THF (3×100 mL). The product 1.9 g was employed directly in the next reaction without further purification. Ammonia (50 mL) was added to the dimesylate (1.9 g) in THF (30 mL) at -78° C. The contents were warmed to 24° C. for 60 hrs, ammonia distilled out, and solvent removed under vacuum to give the crude product (786 mg, 82%). Toluene was added and the solution was filtered through magnesium sulfate, and solvent removed under vacuum to yield 721 mg (75%) of an amber oil.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][C:15]([CH3:17])=O.[OH:18][C:19]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:20]=1[C:21]([OH:23])=[O:22]>FC(F)(F)C(O)=O>[OH:28][C:25]1[CH:26]=[CH:27][C:19]2[O:18][C:15]([CH3:17])([CH3:14])[O:22][C:21](=[O:23])[C:20]=2[CH:24]=1
Reactant: CC(C)=O
Reactant: O=C(O)c1cc(O)ccc1O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC(=O)c2cc(O)ccc2O1
Temperature: 55 °C
Reaction time: 23 h

Procedure:
10 mL of trifluoroacetic anhydride and 4 mL of acetone were added to a slurry of 2,5-dihydroxybenzoic acid (available from Aldrich) (2 g, 13 mmol) in 16 mL of trifluoroacetic acid. The mixture was stirred at 55° C. for 23 h and then at 85° C. for 2.5 h under a nitrogen atmosphere. The reaction mixture was concentrated under vacuum, dissolved and re-concentrated from toluene twice, and dried under vacuum. The crude solid was dissolved in ethyl acetate and washed twice with saturated sodium bicarbonate solution and once with brine. The organic fraction was dried over sodium sulfate and concentrated. Crude product was purified by column chromatography (eluting from silica gel with a gradient of 5 to 50% ethyl acetate in hexanes) to provide the title product as a yellow solid 0.47 g. 1H NMR (200 MHz, CDCl3): δ (ppm)=7.43 (d, J=2.8 Hz, 1H), 7.08 (dd, J=9.0, 3.1 Hz, 1H), 6.85 (d, J=9.0 Hz, 1H), 5.45 (s, 1H), 1.71 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH:24]=O)[CH:7]=1)[CH3:2].[CH2:27]([NH2:29])[CH3:28].C([BH3-])#N.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][NH:29][CH2:27][CH3:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2C=O)c1
Reactant: CCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CCNCc1cc([N+](=O)[O-])ccc1Oc1cc(CC(=O)OCC)ccc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
[3-(2-Formyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (1.0 g, 2.79 mmol), ethylamine (2M in THF; 2.8 mL, 5.6 mmol), and sodium cyanoborohydride (0.26 g, 4.2 mmol) were combined in CH2Cl2 (30 mL), and the reaction was stirred at room temperature for 3 hours. After work-up, the mixture was concentrated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.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]>C1COCC1.O>[OH:9][C:4]1[CH:3]=[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[C:6]([OH:8])[CH:5]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cc(O)cc(O)c1)OCc1ccccc1
Reaction time: 3 h

Procedure:
To a mixture of 5-aminobenzene-1,3-diol (0.60 g, 3.7 mmole) and sodium hydrogencarbonate (1.4 g, 16 mmole) in THF/water (15 mL, 1:1 v/v) was added dropwise benzyl chloroformate 1.6 mL, 11 mmole). After 3 h at rt, THF was removed under vacuum and the remaining aqueous layer was extracted with ethyl acetate. Purification by column chromatograpy over silica gel provided benzyl N-(3,5-dihydroxyphenyl)carbamate. 1H NMR (CD3OD): δ 7.42-7.25 (m, 5H), 6.46 (d, 2H, J=2.4 Hz), 5.97-5.94 (m, 1H), 5.14 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[C:11]([OH:13])=[O:12].FC(F)(F)C(O)=O.CO[CH2:23][N:24]([CH2:29][Si](C)(C)C)[C:25]([CH3:28])([CH3:27])[CH3:26]>ClCCl>[C:25]([N:24]1[CH2:29][C@@H:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[C@@H:10]([C:11]([OH:13])=[O:12])[CH2:23]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C(O)/C=C\c1ccc(F)cc1F
Reactant: COCN(C[Si](C)(C)C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)N1C[C@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (2Z)-3-(2,4-difluorophenyl)acrylic acid, from preparation 35 (400 mg, 2.17 mmol) and trifluoroacetic acid (17 μL, 0.2 mmol) in dichloromethane (1 mL) was added N-(methoxymethyl)-2-methyl-N-[(trimethylsilyl)methyl]propan-2-amine, from preparation 23 (882 mg, 4.35 mmol) over 30 minutes at 0° C. The reaction mixture was warmed to room temperature and stirred for 24 hours. The solvent was removed in vacuo and the white residue formed was triturated with diethyl ether (5 mL) and the solid filtered off to give the desired product, 400 mg (65%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3=[N:19][N:20]=[C:21]([C:22]4[CH:26]=[C:25]([CH3:27])[O:24][N:23]=4)[N:11]3[N:10]=2)=[N:5][C:4]([CH2:28][OH:29])=[N:3]1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3=[N:19][N:20]=[C:21]([C:22]4[CH:26]=[C:25]([CH3:27])[O:24][N:23]=4)[N:11]3[N:10]=2)=[N:5][C:4]([CH:28]=[O:29])=[N:3]1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4nc(CO)nn4C)nn23)no1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4nc(C=O)nn4C)nn23)no1
Reaction time: 24 h
Yield: 32.1 %

Procedure:
A mixture of [1-methyl-5-({[3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazin-6-yl]oxy}methyl]-1H-[1,2,4]triazol-3-yl}methanol (Example 20) (1 g, 2.55 mmol) in chloroform (120 ml) and manganese dioxide (4.4 g, 51 mmol) was heated at reflux for 60 h. More manganese dioxide (2.2 g, 25 mmol) was added and reflux continued for further 24 h. The cooled mixture was filtered through “Hyflo” eluting with chloroform. Solvent was evaporated in vacuo to give the crude carbaldehyde as a yellow solid (320 mg). MS (ES+) 391 (M+1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH3:10])=[CH:5][CH:4]=1.Cl.[Cl:15][C:16]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]=[C:32]([Cl:34])[Cl:33])[CH:26]=[C:25]([Cl:35])[C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][NH2:24].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[Cl:15][C:16]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]=[C:32]([Cl:34])[Cl:33])[CH:26]=[C:25]([Cl:35])[C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][N:24]=[C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1)[CH3:10]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: NOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: CC(=NOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a mixture of 0.15 g of 4′-(trifluoromethyl)acetophenone and 10 ml of pyridine was added 0.30 g of O-(4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyl)hydroxylamine hydrochloride. After stirring at room temperature for 1 hour, the reaction mixture was poured into 5% aqueous citric acid solution, and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.30 g (yield, 75.5%) of 4′-(trifluoromethyl)acetophenone O-(4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyl)oxime, nD21.5 1.5420.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:18])=[CH:4][C:5](F)=[C:6]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O.C1OCCOCCOCCOCCOCCOC1>[Br:1][C:2]1[C:3]([F:18])=[CH:4][C:5]2[O:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH:9]=[N:8][C:6]=2[CH:7]=1
Reactant: Oc1ccccc1C=Nc1cc(Br)c(F)cc1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Fc1cc2c(cc1Br)N=Cc1ccccc1O2
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 115.6 %

Procedure:
To a solution of 2-[[(5-bromo-2,4-difluorophenyl)imino]methyl]phenol (14.5 g, 46.5 mmol) in DMSO (0.43 L), K2CO3 (12.8 g, 71.8 mmol) and 18-Crown-6 (145 mg, 0.55 mmol) were added. The resulting mixture was stirred at 140° C. for 2.5 h and then allowed to cool to ambient temperature. Water (0.6 L) was added and the product was collected by filtration, washed with water and dried under reduced pressure to yield the title compound (15.7 g, 100%) which was used without further purification. 1H-NMR (400 MHz, CDCl3) 6.93-6.96 (d, J=8.2, 1H), 7.10-7.14 (d, J=8.2, 1H), 7.23-7.28 (m, 1H), 7.34-7.37 (m, 1H), 7.46-7.51 (m, 1H), 7.55-7.57 (d, J=7.8, 1H), 8.47 (s, 1H). (m/z)=292+294 (M+H)−.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH:6]1([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:34]([O:36][CH3:37])=[O:35])=[CH:17][C:18]=3[N:19]3[C:25]=2[C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[NH:22][CH:21]([C:30]([O:32][CH3:33])=[O:31])[CH2:20]3)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>CCOC(C)=O>[Cl:1][CH2:2][C:3]([N:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[C:25]2=[C:12]([CH:6]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)[C:13]3[CH:14]=[CH:15][C:16]([C:34]([O:36][CH3:37])=[O:35])=[CH:17][C:18]=3[N:19]2[CH2:20][CH:21]1[C:30]([O:32][CH3:33])=[O:31])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)OC)Nc1ccccc1-3
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)OC)N(C(=O)CCl)c1ccccc1-3
Temperature: 40 °C

Procedure:
Chloroacetyl chloride (5 eq) was added to a sealed tube containing dimethyl 13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-6,10-dicarboxylate (1 eq.). The mixture was heated at 40° C. overnight. The mixture was allowed to cool to RT before being diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound (quant.). MS (ES+) m/z 509 (M+H)+.
Reaction SMILES: CO[C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[CH:21]([CH2:22][C:23](=[O:29])[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:30])=[N:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[CH:21]([CH2:22][C:23](=[O:29])[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=[O:30])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)CCC(C)C)nc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)CCC(=O)CC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 50 °C

Procedure:
A solution of 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone (16.2 g) in phosphoryl chloride (160 cc) is heated to 100° C. for 6 hours. The mixture is then cooled to a temperature in the region of 50° C. and concentrated to dryness under reduced pressure (2.7 kPa). The residue is treated with ice (150 g) and water (150 g). The mixture is then alkalinized with aqueous ammonia solution (d=0.92) to a pH in the region of 12, and extracted with ethyl acetate (3×300 cc). The organic phases are combined, washed with water (4×100 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by chromatography on silica (300 g) contained in a column 4 cm in diameter (eluent: dichloromethane). Elution is first performed with 400 cc of solvent: the corresponding eluate is discarded; elution is then performed with 1800 cc of solvent and the corresponding eluate is concentrated to dryness under reduced pressure (2.7 kPa). After the residue obtained is recrystallized in acetonitrile, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone (6.4 g), m.p. 180° C., is obtained.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][O:21][C:22](=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:16][C@@H:11]([O:12][CH:13]=[CH:14][CH3:15])[C@@H:10]1[NH:39][C:40](=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:57][CH2:58][C:59](Cl)=[O:60].Cl>O.C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([O:8][C@H:9]1[C@H:18]([O:19][C:59](=[O:60])[CH2:58][Cl:57])[C@@H:17]([CH2:20][O:21][C:22](=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:16][C@@H:11]([O:12][CH:13]=[CH:14][CH3:15])[C@@H:10]1[NH:39][C:40](=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=CO[C@@H]1O[C@H](COC(=O)CCCCCCCCCCCCCCC)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1NC(=O)CCCCCCCCCCCCCCC
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC=CO[C@@H]1O[C@H](COC(=O)CCCCCCCCCCCCCCC)[C@@H](OC(=O)CCl)[C@H](OCc2ccccc2)[C@H]1NC(=O)CCCCCCCCCCCCCCC
Temperature: 0 °C

Procedure:
To 0.4 g. of Compound 7 in 15 ml. of CH2Cl2 was added 0.4 ml. of pyridine. The reaction mixture was cooled to about 0° C. and 0.4 ml. chloroacetyl chloride in 5 ml. of CH2Cl2 was added dropwise with stirring. After stirring at room temperature for 30 minutes, thin layer chromatography showed the reaction was complete. Next water was added, then 5% HCl followed by a wash with water and NaHCO3. The dried chloroform layer was evaporated and the residue taken up in hot methanol and the solid material filtered off. Thin layer chromatography showed the solid material to be Compound 8 of high purity.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:18]1([CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:25][CH2:26][NH2:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.CCOC(C)=O>[C:28]1([CH:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:25][CH2:26][NH:27][CH2:2][CH2:3][CH2:4][C:5]2[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=2)[O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)COc1cccc(CCCI)c1
Reactant: NCCC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc(CCCNCCC(c2ccccc2)c2ccccc2)c1
Reaction time: 8 h
Yield: 40.3 %

Procedure:
To a solution of ethyl [3-(3-iodopropyl)phenoxy]acetate (2.5 g) in DMF (50 mL) was added (3,3-diphenylpropyl)amine (1.7 g) at ambient temperature. The reaction mixture was stirred for 8 hours at the same temperature. The resulting mixture was diluted with EtOAc and washed successively with saturated NaHCO3 aqueous solution, water and brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:MeOH=100:0-95:5) to give ethyl (3-{3-[(3,3-diphenylpropyl)amino]propyl}phenoxy)acetate (1.25 g).
Reaction SMILES: FC(F)(F)[C@](O)(C)C(O)=O.[F:11][C:12]([F:19])([F:18])[C@:13]([OH:17])([CH3:16])[C:14]#[N:15].FC(F)(F)C(C)=O.[C-]#N.[Na+].Cl>>[F:11][C:12]([F:19])([F:18])[C:13]([OH:17])([CH3:16])[C:14]#[N:15]
Reactant: C[C@](O)(C#N)C(F)(F)F
Agent: CC(=O)C(F)(F)F
Agent: C[C@](O)(C(=O)O)C(F)(F)F
Agent: Cl
Product: CC(O)(C#N)C(F)(F)F

Procedure:
In a particular aspect of the invention, (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid is prepared by reaction of (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile with acid. (S)-3,3,3-Trifluoro-2-hydroxy-2-methylpropanenitrile can be prepared by reacting 1,1,1-trifluoroacetone with sodium cyanide in the presence of hydrochloric acid to form racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile. The racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile is then reacted with an acid chloride such as butyryl chloride to form the ester. The racemic ester is reacted with a lipase enzyme such as crude porcine pancreatic lipase that selectively cleaves the ester group from the (R) enantiomer leaving the ester of the (S) enantiomer. The ester group of the (S) enantiomer is then removed using standard procedures to provide (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanenitrile, which is in turn treated with acid such as sulfuric acid or hydrochloric acid to form (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:11]([CH2:15][CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:22]([NH2:24])[CH3:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:11]([CH2:15][CH3:16])[C:12]([NH:24][CH2:22][CH3:23])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCC(C(=O)O)N(CC(F)(F)F)c1ccc(C#N)c(Cl)c1
Reactant: CCN
Product: CCNC(=O)C(CC)N(CC(F)(F)F)c1ccc(C#N)c(Cl)c1

Procedure:
Synthesized in a manner similar to example 3 using 2-[(3-chloro-4-cyanophenyl)(2,2,2-trifluoroethyl)amino]butanoic acid and ethylamine: MS (ES) m/z 348 (M+1).
Reaction SMILES: Cl[C:2]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[CH:20]([C:23]1[N:24]=[C:25]([NH2:28])[S:26][CH:27]=1)([CH3:22])[CH3:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH:20]([C:23]1[N:24]=[C:25]([NH:28][C:2]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=2)[S:26][CH:27]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1csc(N)n1
Reactant: CCOC(=O)c1cnc(Cl)cc1Oc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cnc(Nc2nc(C(C)C)cs2)cc1Oc1ccccc1
Yield: 82.5 %

Procedure:
Using the method of Example 3, Step B, ethyl 6-chloro-4-phenoxynicotinate (4.296 g, 15.47 mmol), 4-isopropylthiazol-2-amine (2 g, 14.06 mmol), potassium phosphate (3.283 g, 15.47 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.3219 g, 0.3516 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.2238 g, 0.3867 mmol) were reacted in water (15 mL) and toluene (40 mL) to afford the desired product (4.447 g, 74.22% yield) as a yellow solid. 1H NMR (DMSO), 11.36 (s, 1H), 8.72 (s, 1H), 7.49 (m, 2H), 7.30 (m, 1H), 7.17 (m, 1H), 7.15 (m, 1H), 6.59 (m, 2H), 4.24 (q, 2H), 2.81 (m, 1H), 1.25 (t 3H), 1.15 (d, 6H); Mass spectrum (apci) m/z=384 (100) (M+H).