Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([CH2:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([CH3:17])=[CH:10][C:9]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)[CH3:2].C(O)(=O)C>O>[CH2:19]([O:18][C:9]1[CH:10]=[C:11]([CH3:17])[CH:12]=[C:13]2[C:8]=1[CH:7]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:26])[NH:14]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(=O)Cc1c(OCc2ccccc2)cc(C)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc2c(OCc3ccccc3)cc(C)cc2[nH]1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
The solution of 30.6 g of the thus prepared 2-benzyloxy-4-methyl-6-nitrophenyl pyruvic acid ethyl ester in a composition of 250 ml glacial acetic acid and 15 ml water is brought to boiling. The heating is removed and the solution is mixed with 33.6 g zinc dust in such a manner that the boiling temperature is maintained. 5.6 g zinc dust is additionally added and heated to boiling for 30 minutes. The mixture is aspirated from the excessive zinc dust while still hot. The filter cake is washed well with glacial acetic acid and ethanol. The precipitate resulting during the cooling of the filtrate is aspirated and dried. There is obtained 15.7 g (~59% of theory) 4-benzyloxy-2-ethoxycarbonyl-6-methylindole; m.p. 167°-168° C.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([CH3:13])[CH:7]=1.C([O-])(=O)C.[Na+].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:24][CH:25](C(C)=O)[C:26]([O:28][CH3:29])=[O:27]>O.Cl>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:24][CH:25]([NH:1][NH:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([CH3:13])[CH:7]=2)[C:26]([O:28][CH3:29])=[O:27])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: Cc1ccc(N)cc1C
Reactant: COC(=O)C(Cc1ccc(OC)c(OC)c1)C(C)=O
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)C(Cc1ccc(OC)c(OC)c1)NNc1ccc(C)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
A solution of sodium nitrite (0.414 g) in water (2.0 ml) was dropwise added to a solution of 3,4-xylidine (0.61 g) in concentrated hydrochloric acid (1.5 ml) at a temperature of 0° C., followed by stirring for 30 minutes at 0° C. To the mixture were added sodium acetate (1.23 g) and methyl 2-(3,4-dimethoxybenzyl)acetoacetate (1.33 g). After stirring for an hour at room temperature, the reaction mixture was poured into water and extracted with ethyl ether. The ethereal layer was washed with a saturated sodium hydrogencarbonate aqueous solution and water, dried (MgSO4) and concentrated under reduced pressure. The residue was dissolved in methanol (20 ml), to which 1N-KOH methanolic solution (5 ml) was dropwise added at 0° C. After stirring for an hour at 0° C., the resultant mixture was neutralized with acetic acid and poured into water. The precipitate was collected by filtration and recrystallized from acetone-methanol to give methyl 3-(3,4-dimethoxyphenyl)-2-(3,4 -dimethylphenylhydrazino)propionate (1.25 g, 70%) as pale red prisms.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:27][CH2:26][C:20]2([NH:24][NH:23][C:22](=[O:25])[CH2:21]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CN(C=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:27][CH2:26][C:20]2([N:24]([CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[NH:23][C:22](=[O:25])[CH2:21]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)NN2
Reactant: Fc1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)NN2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 39 %

Procedure:
4-Fluorobenzylbromide (0.37 mL, 2.97 mmol) was added dropwise to a solution of 84AF15 (289 mg, 1.13 mmol) in dry DMF (50 mL) at rt. The mixture was stirred at rt for 6 days under argon atmosphere. The solvent was removed by evaporation under reduced pressure and the residue partitioned between chloroform and water. The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane, afforded the desired compound (160 mg, 39%).
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[N:13]([O-])=[O:14].[Na+]>C(O)(=O)C>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([O:11][CH3:12])[C:10]([N:13]=[O:14])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: COc1cc2cccc(Br)n2n1
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1nn2c(Br)cccc2c1N=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After dissolving 7-bromo-2-methoxypyrazolo[1,5-a]pyridine (400 mg) in acetic acid (4 mL), an aqueous solution (2 mL) containing sodium nitrite (134 mg) was added and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration and washed with water. After dissolving the obtained crude 7-bromo-2-methoxy-3-nitrosopyrazolo[1,5-a]pyridine, without further purification, in 1,2-dimethoxyethane (40 mL) and water (20 mL), 4,6-dimethyl-2-methoxyphenylboric acid (475 mg), tetrakis(triphenylphosphine)palladium (0) complex (203 mg) and barium hydroxide octahydrate (829 mg) were added and the mixture was heated and stirred at 80° C. for 1 hour. Water was added to the reaction mixture, extraction was performed with ethyl acetate, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and the title compound (200 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][N:24]([CH3:36])[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>>[CH3:36][N:24]([CH3:23])[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([NH:33][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[N:12]=[C:11]([CH3:13])[O:10][N:9]=4)=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])=[CH:34][CH:35]=1
Reactant: CN(C)CCCOc1ccc(N)cc1
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)Nc4ccc(OCCCN(C)C)cc4)cc3)c(C)c2)no1

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP 0533268 A1) and 4-(3-dimethylaminopropoxy) aniline (D29) using a similar procedure to Example 20 (38%), as an off-white solid mp 162°-165° C.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[C:30]2[N:29]=[CH:28][CH:27]=[N:26][C:25]=2[C:24]([C:31](O)=[O:32])=[CH:23][CH:22]=1.FC1C=CC=CC=1B(O)O>C(Cl)Cl.CO>[CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:31]([C:24]2[C:25]3[N:26]=[CH:27][CH:28]=[N:29][C:30]=3[C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[F:14])=[CH:22][CH:23]=2)=[O:32])=[CH:8][CH:7]=1
Reactant: CN(C)CCOc1ccc(N)cc1
Reactant: O=C(O)c1ccc(-c2ccccc2F)c2nccnc12
Agent: OB(O)c1ccccc1F
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCOc1ccc(NC(=O)c2ccc(-c3ccccc3F)c3nccnc23)cc1
Reaction time: 8 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture overnight and using 4-(2-dimethylamino-ethoxy)-phenylamine (Step 5.1) and 8-(2-fluoro-phenyl)-quinoxaline-5-carboxylic acid. The latter compound was prepared as described in Steps 1.2-1.7 but using 2-fluorophenylboronic acid in Step 1.4. Title compound: ESI-MS: 431.0 [M+H]+; tR=3.93 min (System 1); TLC: Rf=0.29 (DCM/MeOH/NH3aq, 96:3:1).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([Cl:9])[CH:3]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12](B(O)O)[CH:11]=1>>[Cl:9][C:4]1[CH:3]=[C:2]([C:12]2[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:5]=1[NH2:6]
Reactant: Nc1ccc(Br)cc1Cl
Reactant: OB(O)c1cccnc1
Product: Nc1ccc(-c2cccnc2)cc1Cl
Yield: 94 %

Procedure:
Prepared according to Method C (Preparation 85) using 4-bromo-2-chloroaniline and pyridin-3-ylboronic acid. Purified using Biotage silica gel column chromatography eluting with DCM/EtOH 99/1 to 97/3 and filtered on SCX-2 column to afford the title product as a yellow oil (93 mg, 94%). 1H NMR (500 MHz, CDCl3): δ 3.96 (br s, 2H), 6.87 (d, J=8.2 Hz, 1H), 7.32 (dd, J=8.2, 2.2 Hz, 1H), 7.35 (ddd, J=7.9, 4.8, 1.0 Hz, 1H), 7.51 (d, J=2.2 Hz, 1H), 7.80 (ddd, J=7.9, 2.3, 1.6 Hz, 1H), 8.54 (dd, J=4.8, 1.6 Hz, 1H), 8.79 (dd, J=2.3, 1.0 Hz, 1H).
Reaction SMILES: CC1N=C(C2C=CC=CC=2C([NH:11][C@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)=O)ON=1.[F:32][C:33]1[CH:34]=[CH:35][C:36]([C:42]2[N:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=[C:37]([CH:41]=1)[C:38]([OH:40])=O.Cl.FC(F)(F)C1C=CC(N[C@H]2CCC[C@@H]2N)=NC=1>>[F:32][C:33]1[CH:34]=[CH:35][C:36]([C:42]2[N:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=[C:37]([CH:41]=1)[C:38]([NH:11][C@H:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][N:19]=1)=[O:40]
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Reactant: Cc1noc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2ccc(C(F)(F)F)cn2)n1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1cc(F)ccc1-c1ncccn1

Procedure:
Prepared according to the procedure for 2-(3-methyl-1,2,4-oxadiazol-5-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 8) from 5-fluoro-2-(pyrimidin-2-yl)benzoic acid (CAS number 1293284-57-7; 61 mg, 0.28 mmol) and (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 72 mg, 0.26 mmol) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.[N:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[CH2:50][CH2:51]O>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:51][CH2:50][C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][N:44]=4)=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: OCCc1ccccn1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCc3ccccn3)cc21
Reaction time: 168 h
Yield: 45 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 61 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 2-(pyridin-2-yl)ethanol instead of 4-(2-hydroxyethyl)morpholine, being stirred for 7 d, and being purified by silica gel column chromatography (CH2Cl2/EtOAc=1:4) to obtain the title compound (45%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:23](OC(ON=C(C#N)C(OCC)=O)=O)[CH:24]([CH3:26])[CH3:25]>O1CCCC1>[CH2:23]([O:14][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH:24]([CH3:26])[CH3:25]
Reactant: CCOC(=O)C(C#N)=NOC(=O)OCC(C)C
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 142.7 %

Procedure:
To a solution of N-benzyloxycarbonylglycine (1.05 g) and triethylamine (0.7 ml) in dry tetrahydrofuran (15 ml), ethyl 2-isobutoxycarbonyloxyimino-2-cyanoacetate (2.42 g) is added, and the resulting mixture is stirred at room temperature for 2 hours. The reaction mixture is treated as in Example A to give N-benzyloxycarbonylglycine isobutyl ester (1.9 g) as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([CH2:14][CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[N:3]=1.[NH2:20][NH2:21]>O1CCOCC1>[NH:20]([C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([CH2:14][CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[N:3]=1)[NH2:21]
Reactant: CC(C)(O)CCc1nc(Cl)cc(N2CCOCC2)n1
Reactant: NN
Solvent: C1COCCO1
Product: CC(C)(O)CCc1nc(NN)cc(N2CCOCC2)n1
Yield: 80 %

Procedure:
4-(4-chloro-6-morpholin-4-yl-pyrimidin-2-yl)-2-methyl-butan-2-ol (3.3 g, 11.5 mmol) was dissolved in dioxane (30 mL). To the reaction mixture was added anhydrous hydrazine (7.5 mL, 220 mmol). The reaction was then heated at reflux for five hours. The solvent was removed under reduced pressure, and the crude solid was dissolved in a mixture of dichloromethane (800 mL) and 10% potassium carbonate (40 mL). The organic layer was isolated, dried with sodium sulfate, and evaporated to give 4-(4-hydrazino-6-morpholin-4-yl-pyrimidin-2-yl)-2-methyl-butan-2-ol (2.61 g, 9.2 mmol).
Reaction SMILES: C([O:8][C:9](=[O:34])[CH2:10][N:11]1[C:16]([CH3:17])=[C:15]([Cl:18])[N:14]=[C:13]([NH:19][CH2:20][C@@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:12]1=[O:33])C1C=CC=CC=1>[OH-].[Pd+2].[OH-]>[C:29]([O:28][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:21]1[CH2:20][NH:19][C:13]1[C:12](=[O:33])[N:11]([CH2:10][C:9]([OH:34])=[O:8])[C:16]([CH3:17])=[C:15]([Cl:18])[N:14]=1)=[O:27])([CH3:30])([CH3:31])[CH3:32]
Reactant: Cc1c(Cl)nc(NC[C@@H]2CCCN2C(=O)OC(C)(C)C)c(=O)n1CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Product: Cc1c(Cl)nc(NC[C@@H]2CCCN2C(=O)OC(C)(C)C)c(=O)n1CC(=O)O

Procedure:
The title compound was prepared by a similar method to preparation 44 from tert-butyl (2S)-2-[({4-[2-(benzyloxy)-2-oxoethyl]-6-chloro-5-methyl-3-oxo-3,4-dihydro-2-pyrazinyl}amino)methyl]-1-pyrrolidinecarboxylate [see preparation 64] and palladium hydroxide. The title compound was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (90:10:0.5) changing to (80:20:3), to afford the product as a colourless oil, (44%).
Reaction SMILES: ClC(Cl)(Cl)C(O)=O.C[O:9][CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[O:20][CH3:21]>ClCCl.O>[CH3:21][O:20][C:13]1[C:14]([O:18][CH3:19])=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH:10]=[O:9]
Reactant: COC=Cc1cccc(OC)c1OC
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1cccc(CC=O)c1OC
Reaction time: 2 h
Yield: 104.1 %

Procedure:
Trichloroacetic acid (817 mg, 5.00 mmol) was added to a solution (10 mL) of 2-(2,3-dimethoxyphenyl)ethenyl methyl ether (808 mg, 4.16 mmol) in dichloromethane at room temperature and stirred for 2 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The extract solution was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 2-(2,3-dimethoxyphenyl)acetaldehyde (780 mg, 100%) as a yellow oil.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]([NH:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:8])(=O)C.[OH-].[Na+]>>[SH:4][CH2:5][CH:6]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]([NH:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:8]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)NN1CCCC1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NN1CCCC1)C(CS)Cc1ccccc1
Yield: 85.8 %

Procedure:
Using the procedure of Example 6, 0.77 g of the product of Example 9 and 26 ml of 0.1N sodium hydroxide were reacted to obtain after chromatography on silica (eluent:methylene chloride - methanol, 100-3), 0.57 g of the expected product melting at 93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[OH-].[Li+]>CO>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[C:19]([F:20])([F:21])[F:22]
Reactant: COC(=O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 50 °C
Yield: 54.5 %

Procedure:
Methyl 4-[4-chloro-3-(trifluoromethyl)phenoxy]benzoate (Preparation 1, 2.7 g, 8.34 mmol) was dissolved in methanol (50 mL) followed by addition of a 1M aqueous solution of lithium hydroxide (50 mL, 50 mmol) whereupon a precipitate was observed. The reaction mixture was heated to 50° C. to aid dissolution and the reaction mixture then stirred at 50° C. 18 hours. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in a 1M aqueous solution of sodium carbonate (−100 mL) and extracted with ethyl acetate (30 mL). The organic phase was concentrated in vacuo to give a yellow solid. The solid was partitioned between tert-butylmethyl ether and a 1M aqueous solution of sodium carbonate. The organic phase was washed sequentially with a 2M aqueous solution of hydrogen chloride and brine, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to afford the title compound as an off-white solid (1.44 g, 55%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([Cl:12])(=[O:11])=[O:10])[CH3:2].O(Cl)[Cl:14]>C(Cl)(Cl)(Cl)Cl>[Cl:14][CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([Cl:12])(=[O:11])=[O:10])[CH3:2]
Reactant: CCc1ccccc1S(=O)(=O)Cl
Reactant: ClOCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Cl)c1ccccc1S(=O)(=O)Cl
Yield: 83.9 %

Procedure:
A solution of 2-ethylbenzenesulfonyl chloride (obtained by chlorosulfonation of ethylbenzene) (7.78 g) in carbon tetrachloride (5.0 ml) was contacted with a solution of dichlorine monoxide (82 mmol) in carbon tetrachloride (100 ml) and the mixture was heated in a closed system at 50°-60° for 16 hrs. The mixture was dried (MgSO4) and volatiles were removed under vacuum. The residue was kugelrohr distilled to give 7.63 g of colorless oil, bp 75°-80° (0.15 mm). 1H nmr δCDCl3TMS 8.20-7.35 (m). 6.13 (q, J=7 Hz), 1.90 (d, J=7 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[OH:32]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=2[Cl:24])=[N:3][CH:4]=1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc(Cl)cc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 2,4-dichlorophenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.6 Hz), 8.09–7.99 (4H, m), 7.52 (1H, d, J=2.3 Hz), 7.44 (2H, d, J=8.2 Hz), 7.36 (1H, dd, J=8.7, 2.4 Hz), 7.26 (1H, d, J=8.7 Hz), 5.44–5.34 (1H, m), 3.89 (3H, s), 1.61 (3H, d, J=6.9 Hz).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[N:15][CH:14]=1)[CH3:10]>C(#N)C>[CH2:9]([O:11][C:12](=[O:20])[C:13]1[CH:18]=[C:17]([Cl:1])[C:16]([NH2:19])=[N:15][CH:14]=1)[CH3:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1ccc(N)nc1
Solvent: CC#N
Product: CCOC(=O)c1cnc(N)c(Cl)c1
Yield: 79.5 %

Procedure:
N-Chlorosuccinimide (21.7 g, 0.162 mol) was added to a suspension of 6-amino-nicotinic acid ethyl ester (18.0 g, 0.108 mol) in acetonitrile (270 ml) and the mixture was refluxed for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with water and dried. Flash chromatography (2.5% MeOH in CH2Cl2) gave pure 6-amino-5-chloro-nicotinic acid ethyl ester (17.23 g, 79%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:15](OCC)(OCC)(OCC)[CH3:16].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:15]([CH3:16])[N:9]([CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1NC1CCCC1
Reactant: CCOC(C)(OCC)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nc2ccc(Br)cc2n1C1CCCC1

Procedure:
Heat a mixture of 4-bromo-N2-cyclopentyl-benzene-1,2-diamine (10.6 g), triethyl orthoacetate (9.5 ml) and acetic acid (6.3 mL) at 100° C. for 2.5 h. Dilute with DCM and pour onto an aqueous saturated solution of sodium bicarbonate. Dry over sodium sulfate and remove the solvent under vacuum. Purify by silica gel column chromatography, eluting with DCM/ethanol-10% NH3 (0-3%) to afford 10.67 g of the title compound. MS (ES+): m/z=280 (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=1[O:15][CH3:16])(=O)=O.[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[CH:20]=[CH2:21].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:13]([C:10]1[CH:11]=[CH:12][C:7](/[CH:21]=[CH:20]/[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:8]([O:15][CH3:16])[CH:9]=1)#[N:14]
Reactant: COc1cc(C#N)ccc1OS(=O)(=O)C(F)(F)F
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C#N)ccc1/C=C/C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 24 h

Procedure:
4 g (5.7 mmol) of bis(triphenylphosphine)palladium(II) chloride are added to a degassed solution of 37.13 g (132 mmol) of 4-cyano-2-methoxyphenyl trifluoromethanesulfonate, 35 ml (245 mmol) of tert-butyl acrylate and 90 ml (645 mmol) of triethylamine in DMF (250 ml). The solution is stirred at 100° C. under a protective gas atmosphere for 24 h. Ice-water (1000 ml) is then added, and the suspension is extracted with ethyl acetate (3×100 ml). The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 10:1). 24.6 g (72% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:12]1[C:17]([NH2:20])=[N:18][OH:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]([C:25]#[C:26][C:27]([O:29][CH3:30])=[O:28])=[O:24]>C(Cl)(Cl)Cl>[CH3:21][O:22][C:23](=[O:24])[C:25]([O:19][N:18]=[C:17]([NH2:20])[C@@H:12]1[CH2:13][C@H:14]([F:16])[CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[CH:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: NC(=NO)[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1
Reactant: COC(=O)C#CC(=O)OC
Solvent: ClC(Cl)Cl
Product: COC(=O)C=C(ON=C(N)[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1)C(=O)OC

Procedure:
Benzyl-(2S,4S)-2-[amino(hydroxyimino)methyl]-4-fluoropyrrolidine-1-carboxylate in chloroform was treated with dimethylacetylene dicarboxylate for 3 hours at 60° C. The chloroform was then concentrated to give the title compound as a 8:2 mixture of isomers.