Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH2:17][OH:18])=[C:12]2[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[O:5].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>ClCCl>[C:35]([O:18][CH2:17][C:13]1[CH:14]=[N:15][C:16]2[C:11]([C:12]=1[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:4](=[O:5])[C:3]1[C:24]([Cl:28])=[CH:25][CH:26]=[CH:27][C:2]=1[Cl:1])(=[O:37])[CH3:36]
Reactant: O=C(Nc1cccc2c(-n3ccnc3)c(CO)cnc12)c1c(Cl)cccc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1-n1ccnc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a suspension of 8-(2,6-dichlorobenzoylamino)-3-hydroxymethyl-4-(imidazol-1-yl)quinoline (250 mg) in dichloromethane (3 ml) were dropwise added pyridine (57.4 mg) and acetic anhydride (0.12 ml) at ambient temperature, and the mixture was stirred for 22 hours at ambient temperature. The mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate. The mixture was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (methanol-dichloromethane) to give 3-acetoxymethyl-8-(2,6-dichlorobenzoylamino)-4-(imidazol-1-yl)quinoline (270 mg).
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[OH:12][CH:13]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl>[OH:30][C:26]1[CH:25]=[C:24]([C:13](=[O:12])[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(O)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)c1cccc(O)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A stirred suspension of PCC (42.3 g, 196 mmol) and Celite (43 g) in DCM (300 mL) was cooled to 0° C. Alcohol 21.18 (35.0 g, 131 mmol) was slowly added to the reaction mixture over a period of 15 min. The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was then filtered through a pad of Celite and the filter bed was washed with DCM. Concentration of the filtrate gave a black tarry mass which was purified by flash chromatography (30-50% ethyl acetate-hexanes gradient) to give tert-butyl 3-(3-hydroxyphenyl)-3-oxopropylcarbamate 21.19 as pale yellow solid. Yield (20.3 g, 58%); 1H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 7.27-7.40 (m, 2H), 7.01 (dd, J=8.0, 1.6 Hz, 1H), 6.80-6.83 (m, 1H), 3.22-3.27 (m, 2H), 3.08 (t, J=6.8 Hz, 2H), 1.36 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Cl-].[CH3:14][O:15][C:16]1[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=1[CH:18]=[N+:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:18]([C:17]1[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=1[O:15][CH3:14])[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: Fc1ccccc1-n1cccc1
Reactant: COc1ccccc1C=[N+]1CCOCC1
Agent: [Cl-]
Product: COc1ccccc1C(c1cccn1-c1ccccc1F)N1CCOCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-(2-fluoro-phenyl)-1H-pyrrole and 4-(2-methoxy-benzylidene)-morpholin-4-ium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [C:1]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C:15](=[O:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1>[CH2:3]([C:2]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]([OH:23])[C:8]2[C:7]([CH:1]=1)=[CH:12][C:11]([O:13][CH3:14])=[CH:10][CH:9]=2)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1cc(OC)ccc1C(=O)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCc1cc2cc(OC)ccc2c(O)c1-c1ccccc1
Temperature: 0 °C
Yield: 67.4 %

Procedure:
A solution of 1-[2-(1-hexyn-1-yl)-4-(methyloxy)phenyl]-2-phenylethanone (80) (0.37 g, 1.21 mmol) in toluene (1.5 mL) was added to a KHMDS solution in toluene (0.5 M, 2.90 mL, 1.45 mmol) at −78° C. under nitrogen. Dry ice bath was removed, the mixture was stirred and allowed to warm up to 0° C., then heated at 80° C. for 1 h. Cooled in an ice bath, the mixture was acidified with 2 N HCl and extracted with ether. The combined ether extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as orange brown oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (15:1) to give 0.25 g (68%) of 81 as a light brown oil. 1H NMR (400 MHz, CDCl3): δ 0.75 (t, J=7.3 Hz, 3H), 1.10-1.25 (m, 2H), 1.35-1.50 (m, 2H), 2.47 (t, J=7.8 Hz, 2H), 3.92 (s, 3H), 5.15 (s, 1H), 7.05-7.10 (m, 2H), 7.22 (s, 1H), 7.34 (d, J=6.9 Hz, 2H), 7.40-7.50 (m, 1H), 7.50-7.56 (m, 2H), 8.08 (d, J=9.8 Hz, 1H). LCMS (ESI): m/z 307 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][C:8](=[O:10])[NH:7][CH2:6]1)(=[O:3])[CH3:2].[CH3:11][Si:12]([CH3:15])([CH3:14])Cl.O1CCCC1>C(N(CC)CC)C>[C:1]([O:4][CH:5]1[CH2:9][C:8](=[O:10])[N:7]([Si:12]([CH3:15])([CH3:14])[CH3:11])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)OC1CNC(=O)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OC1CC(=O)N([Si](C)(C)C)C1
Reaction time: 1 h

Procedure:
10.0 g. of 5-oxo-3-pyrrolidinyl acetate and 8.82 ml. of trimethylchlorosilane are dissolved in 100 ml. of absolute tetrahydrofuran and then 9.65 ml. of triethylamine are added at -5° C. to 0° C. The temperature is held at -5° C. to 0° C. for 1 hour, the mixture is then filtered under an argon atmosphere, the filtrate is evaporated and the residue is distilled in vacuo. There is obtained 5-oxo-1-trimethylsilyl-3-pyrrolidinyl acetate, having a boiling point of 110° C./0.07 mmHg.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][N:35](COCC[Si](C)(C)C)[C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:7][N:6]([C:8]2[C:21]([F:22])=[CH:20][C:11]([C:12]([NH:14][C@@H:15]([CH:17]3[CH2:19][CH2:18]3)[CH3:16])=[O:13])=[C:10]([F:23])[CH:9]=2)[CH2:5]1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([CH2:3][C:4]1([N:24]2[CH:28]=[C:27]([C:29]3[C:30]4[CH:37]=[CH:36][NH:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH:26]=[N:25]2)[CH2:7][N:6]([C:8]2[C:21]([F:22])=[CH:20][C:11]([C:12]([NH:14][C@@H:15]([CH:17]3[CH2:18][CH2:19]3)[CH3:16])=[O:13])=[C:10]([F:23])[CH:9]=2)[CH2:5]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1F)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.3 %

Procedure:
4-{3-(Cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1R)-1-cyclopropylethyl]-2,5-difluorobenzamide (0.48 g) was dissolved in a solution of trifluoroacetic acid (3 mL, 40 mmol) in methylene chloride (3 mL). The solution was stirred at room temperature for 1.5 hours. It was concentrated under reduced pressure. The residue was dissolved in methanol (5 mL). To the solution was added ethylenediamine (3 mL). The mixture was stirred at room temperature for 2 hours. After concentration the crude material was purified by flash chromatography on a silica gel column with methanol in dichloromethylene (0-10%) to afford the desired product (245 mg, 24%). LCMS (M+H)+: m/z=503.2. 1H NMR (400 MHz, DMSO-d6): δ 12.60 (s, 1H), 9.08 (s, 1H), 8.85 (s, 1H), 8.57 (s, 1H), 7.84 (dd, J=8.0, 4.0 Hz, 1H), 7.78 (m, 1H), 7.36 (dd, J=13.0, 7.0 Hz, 1H), 7.23 (m, 1H), 6.64 (dd, J=13.0, 7.0 Hz, 1H), 4.70 (d, J=8.0 Hz, 2H), 4.45 (d, J=8.0 Hz, 2H), 3.78 (s, 2H), 3.43 (m, 1H), 1.09 (d, J=6.5 Hz, 6H), 0.97 (m, 1H), 0.43 (m, 1H), 0.37 (m, 1H), 0.28 (m, 1H), 0.19 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[O:3][C:4](C=O)=[CH:5][CH:6]=1.C1COCC1.Cl.[NH2:15][N:16]1[CH2:20][CH2:19][NH:18][C:17]1=[O:21].[OH-].[Na+]>O>[Br:1][C:2]1[O:3][C:4](=[N:15][N:16]2[CH2:20][CH2:19][NH:18][C:17]2=[O:21])[CH2:5][CH:6]=1
Reactant: NN1CCNC1=O
Reactant: O=Cc1ccc(Br)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1NCCN1N=C1CC=C(Br)O1
Reaction time: 8 h

Procedure:
33.5 pts. by wt. of 2-bromofuran-5-aldehyde, dissolved in 100 pts. by vol. of THF, are added to a solution of 1-amino-2-oxo-imidazolidine hydrochloride in 350 pts. by vol. of water, which has been adjusted to pH 5 with sodium hydroxide solution, and the mixture is stirred overnight. The precipitate is filtered off, washed with water and recrystallised from methanol. 30.0 pts. by wt. of 1-(5-bromofurylideneamino)-2-oxo-imidazolidine of dec. pt. 153°-158° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH3:18])=[C:16](O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:17]=1[CH3:18]
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1c(-c2ccccc2F)nc2ccccc2c1Cl

Procedure:
Prepared according to procedure S using 2-(2-fluorophenyl)-3-methylquinolin-4-ol (0.13 g, 0.51 mmol) in POCl3 (1 mL, 10 mmol). The resulting precipitate was collected by filtration to have 4-chloro-2-(2-fluorophenyl)-3-methylquinoline. Mass Spectrum (ESI) m/e=272 (M+1).
Reaction SMILES: [C:1]1([C:7]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:24]1([CH2:29][CH2:30]O)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[C:1]1([C:7]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:30][CH2:29][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:21][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCN1CCCC1
Reactant: Oc1ccc(C2=C(c3ccccc3)Sc3ccccc3O2)cc1
Product: c1ccc(C2=C(c3ccc(OCCN4CCCC4)cc3)Oc3ccccc3S2)cc1

Procedure:
The entitled compound was obtained according to the method of Example 3 but using 4-(3-phenyl-1,4-benzoxathiin-2-yl)phenol synthesized in Reference Example 1-1 and 2-pyrrolidin-1-ylethanol as the starting material.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][CH:14]=1>>[O:12]=[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:19]([C:16]3[CH:17]=[CH:18][C:13]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:14][CH:15]=3)=[O:20])=[CH:3][CH:4]=2)[NH:9]1
Reactant: Nc1ccc2ccc(=O)[nH]c2c1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Product: O=C(Nc1ccc2ccc(=O)[nH]c2c1)c1ccc(-c2ccccc2)cc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-amino-1H-quinolin-2-one (D89) (30 mg, 0.19 mmol) and 4-biphenylcarboxylic acid (44 mg, 0.22 mmol) as an off-white solid. 1H NMR (400 MHz, DMSO) δ (ppm): 11.80 (br, 1H), 10.58 (br, 1H), 8.09 (d, 2H), 8.04 (d, 1H), 7.85 (m, 3H), 7.77 (d, 2H), 7.62 (d, 1H), 7.52 (m, 3H), 7.44 (t, 1H), 6.39 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][Cl:19]>CN(C=O)C>[Cl:19][CH2:18][CH2:17][CH2:16][N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:12]
Reactant: O=C1CCc2cc(F)ccc2N1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2cc(F)ccc2N1CCCCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
A reaction flask was charged with 6-fluoro-3,4-dihydro-1H-quinolin-2-one (0.180 g, 1.09 mmol) in dry DMF (2 mL) under Argon. NaH (60% in oil, 0.048 g, 1.20 mmol) was added and the mixture was stirred at rt for 0.5 h. Then 1-bromo-3-chloropropane (0.180 g, 1.14 mmol) was added followed by stirring at rt for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; DCM) to give the title compound (92LH79) (0.193 g, 73%). 1H NMR (CDCl3) δ 7.02-6.88 (m, 3H), 4.09-4.05 (m, 2H), 3.61 (t, J=6.3 Hz, CH2), 2.87 (t, J=6.7 Hz, CH2), 2.65-2.61 (m, 2H), 2.16-2.09 (m, 2H); 13C NMR (CDCl3) δ 169.8, 158.4 (J=242.9 Hz), 135.7 (J=2.7 Hz), 128.5 (J=7.7 Hz), 115.7 (J=8.1 Hz), 115.1 (J=22.7), 113.8 (J=22.3 Hz), 42.6, 40.3, 31.5, 30.1, 25.5.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([OH:32])([CH2:23][NH:24]CC1C=CC=CC=1)[C:19]([F:22])([F:21])[F:20])=[O:15]>C(O)C.[Pd]>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:23][NH2:24])([OH:32])[C:19]([F:22])([F:21])[F:20])=[O:15]
Reactant: Nc1c(C(=O)NCC(O)(CNCc2ccccc2)C(F)(F)F)cnn1-c1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: NCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Yield: 89.4 %

Procedure:
5-amino-1-(4-fluorophenyl)-N-(3,3,3-trifluoro-2-hydroxy-2-{[(phenylmethyl)amino]methyl}propyl)-1H-pyrazole-4-carboxamide (20.47 g) was dissolved in ethanol (100 ml) and hydrogenated over 10% palladium on carbon (2 g). A small portion was filtered using celite to give an orange yellow solution and LC/MS analysis indicated complete reaction. Therefore the remainder of the suspension was then filtered and the orange yellow solution concentrated in vacuo to give a pale yellow solid. This was dried on the vacuum line overnight to give the title compound (14.64 g) as a white solid.
Reaction SMILES: CCOCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]([OH:30])/[CH:12]=[CH:13]/[C@@H:14]1[C@@H:18]([CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C@@H:17]([OH:28])[CH2:16][C@H:15]1[OH:29].[H][H]>[Pd].C(OCC)(=O)C>[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][C@H:11]([OH:30])/[CH:12]=[CH:13]/[C@@H:14]1[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C@@H:17]([OH:28])[CH2:16][C@H:15]1[OH:29]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)O)[C@@H](O)C[C@H]1O

Procedure:
Refer to Chart 36. The mixed formula-CC bis(THP ether) of the PGF2α compounds (Example 36, 1.5 g.) in 60 ml. of ethyl acetate are reduced at C5 -C6 by hydrogenation at about 25° C. in the presence of 200 mg. of 5% palladium-on-carbon with slightly over the theory for one equivalent of hydrogen. The solids are filtered off and the filtrate concentrated to yield the corresponding formula-CCXII bis(THP ether) of the PGF1α compounds having Rf 0.28 (TLC on silica gel in acetone-Skellysolve B (1:2)).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[O:6][CH:7]=1.[O:13]=[CH:14][C:15]1[CH:23]=[CH:22][C:20]([OH:21])=[C:17]([O:18][CH3:19])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:5]1[O:6][CH:7]=[C:3]([CH2:2][O:21][C:20]2[CH:22]=[CH:23][C:15]([CH:14]=[O:13])=[CH:16][C:17]=2[O:18][CH3:19])[N:4]=1
Reactant: ClCc1coc(-c2ccco2)n1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCc1coc(-c2ccco2)n1
Temperature: 80 °C
Reaction time: 15 h
Yield: 91.4 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-1,3-oxazole (10.0 g), vanillin (8.29 g), potassium carbonate (7.53 g) and N,N-dimethylformamide (100 mL) was stirred at 80° C. for 15 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 4-{[2-(2-furyl)-1,3-oxazol-4-yl]methoxy}-3-methoxybenzaldehyde as brown crystals (14.90 g, yield 91%). Recrystallization from hexane-ethyl acetate gave pale-yellow prism crystals. melting point: 138-139° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](O)=[N:8][CH:7]=[C:6]2[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[C:6]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)ncc(N3CCOCC3)c2c1
Product: COc1ccc2c(Cl)ncc(N3CCOCC3)c2c1
Yield: 18 %

Procedure:
A solution of 6-methoxy-4-morpholinoisoquinolin-1-ol (0.33 g, 1.268 mmol) in POCl3 (5 ml) was refluxed for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The combine organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get desired compound (0.065 g, 18%) as oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.18-8.16 (d, J=8 Hz 1H), 7.94 (s, 1H), 7.45-7.40 (m, 2H), 3.98 (s, 3H), 3.88-3.86 (m, 4H), 3.09-3.07 (m, 4H); MS: MS m/z 279.1 (M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][C:10]1[C:14](B2OC(C)(C)C(C)(C)O2)=[C:13]([CH3:24])[O:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Br:8][C:6]1[CH:7]=[C:2]([C:14]2[C:10]([CH3:9])=[N:11][O:12][C:13]=2[CH3:24])[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1cncc(Br)c1
Temperature: 95 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
To a solution of 3,5-dibromopyridine (0.20 g, 0.85 mmol) in 1,4-dioxane (8 mL) and H2O (0.55 mL) under nitrogen was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.13 g, 0.93 mmol), and potassium carbonate (0.35 g, 2.5 mmol). The reaction mixture was degassed with nitrogen for 15 min. (1,1′-Bis(diphenylphosphino)ferrocene)palladium (II) chloride dichloromethane complex (62 mg, 0.08 mmol) was added and the reaction mixture was again degassed for 10 min with nitrogen. The reaction mixture was stirred at 95° C. for 16 h, then allowed to cool to room temperature and quenched by the addition of water. The reaction mixture was transferred to a separation funnel and the aqueous layer extracted with ethyl acetate. The combined organic portions were washed with water and saturated NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to provide 4-(5-bromopyridin-3-yl)-3,5-dimethylisoxazole (0.15 g, 71%) as a white solid. LCMS Method T: retention time 1.52 min, [M+1]=253.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]([NH2:24])=[S:23])=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].Br[CH2:31][C:32](=O)[CH2:33][CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]2[S:23][CH:31]=[C:32]([CH2:33][CH2:34][N:35]3[C:39](=[O:40])[C:38]4=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]4[C:36]3=[O:45])[N:24]=2)=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: O=C(CBr)CCN1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)C1=C(COCC(N)=S)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CCO
Product: CCOC(=O)C1=C(COCc2nc(CCN3C(=O)c4ccccc4C3=O)cs2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl

Procedure:
A mixture of 2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}thioacetamide (2.19 g) and 1-bromo-4-phthalimido-2-butanone (1.48 g) in ethanol (50 ml) was heated under reflux for 4 hours and then evaporated. The residue was triturated with ether/hexane and the resulting solid collected, recrystallised from methanol and dried to give 2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}-4-(2-phthalimidoethyl)thiazole as a hemihydrate (1.73 g), m.p. 156°-157° C. Found: C,59.71; H,5.06; N,6.31. C32H29ClN3O7S.0.5H2O: requires C,59.58; H,4.80; N,6.51%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[O:13][CH2:14][O:15][CH3:16])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:21]([NH:25][OH:26])([CH3:24])([CH3:23])[CH3:22]>C1C=CC=CC=1>[CH3:16][O:15][CH2:14][O:13][C:12]1[C:11]([C:17]([CH3:18])([CH3:20])[CH3:19])=[CH:10][C:7]([CH:8]=[N+:25]([C:21]([CH3:24])([CH3:23])[CH3:22])[O-:26])=[CH:6][C:5]=1[C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: COCOc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Reactant: CC(C)(C)NO
Solvent: c1ccccc1
Product: COCOc1c(C(C)(C)C)cc(C=[N+]([O-])C(C)(C)C)cc1C(C)(C)C
Yield: 69 %

Procedure:
To a solution of 3,5-di-tert-butyl-4-methoxymethoxybenzaldehyde (11.42 g, 40 mmol) in benzene (200 mL) was added tert-butylhydroxylamine (4.0 g, 50 mmol). The resulting solution was refluxed for 72 h until no more aldehyde was detected by TLC (Rf=0.56 for product and 0.78 for starting material in 1:1 hexanes/EtOAc). The solvent was removed in vacuo and the residue was suspended in hexane/EtOAc. The suspension was filtered, washed with hexanes and dried to afford the title compound (69% yield) as a white solid, m.p. 202.2-205.9° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:34])=[C:4]([CH:29]=[CH:30][C:31]=1[C:32]#[N:33])[C:5]([NH:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:27])([C:23]([F:26])([F:25])[F:24])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[Cl:28])=[O:6].[H-].[Na+].C(C1C=CC(C(NC2C(Br)=CC(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)=CC=2Br)=O)=CC=1N[C:70](=[O:80])[C:71]1[CH:76]=[CH:75][C:74]([C:77]#[N:78])=[CH:73][C:72]=1[CH3:79])#N.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[C:32]([C:31]1[CH:30]=[CH:29][C:4]([C:5]([NH:7][C:8]2[C:9]([Cl:28])=[CH:10][C:11]([C:15]([F:27])([C:23]([F:24])([F:25])[F:26])[C:16]([F:21])([F:22])[C:17]([F:18])([F:19])[F:20])=[CH:12][C:13]=2[Cl:14])=[O:6])=[C:3]([F:34])[C:2]=1[NH:1][C:70](=[O:80])[C:71]1[CH:76]=[CH:75][C:74]([C:77]#[N:78])=[CH:73][C:72]=1[CH3:79])#[N:33]
Reactant: Cc1cc(C#N)ccc1C(=O)Nc1cc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc2Br)ccc1C#N
Reactant: N#Cc1ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc2Cl)c(F)c1N
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C#N)ccc1C(=O)Nc1c(C#N)ccc(C(=O)Nc2c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc2Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To a suspension of 3-amino-4-cyano-N-[2,6-dichloro-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)phenyl]-2-fluorobenzamide (Example 1.7) (0.054 g, 0.10 mmol) in N,N-dimethylacetamide (“DMA”) (1 ml) was added sodium hydride (55% w/v) (0.018 g, 0.40 mmol). The reaction mixture was stirred for 30 minutes at ambient temperature and then 4-cyano-2-methylbenzoyl chloride (see first part of Example 2.1) (0.10 mmol) was added. The reaction mixture was stirred at ambient temperature for 16 hours. Satruated aqueous sodium hydrogen carbonate (30 ml) was added and the organic phase extracted twice with ethyl acetate (2×20 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent:cyclohexane/ethyl acetate 7:3) to give Compound No. A18 of Table A (0.010 g, 15% yield).