Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][NH:10][N:9]=[C:8]2[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[S:31])=[CH:25][CH:24]=1.C(Cl)Cl>CCOCC>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:10]2[CH2:11][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][CH:13]=3)=[N:9]2)=[S:31])=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1ccc(C2=NNCC2c2ccccc2)cc1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: FC(F)(F)c1ccc(C2=NN(C(=S)Nc3ccc(Cl)cc3)CC2c2ccccc2)cc1
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A mixture of 0.7 g of the compound from Step B and 0.41 g of 4-chlorophenyl isothiocyanate were combined in a solvent mixture of 2 mL methylene chloride and 5 mL ether. After stirring overnight the precipitated solids were filtered and dried to afford 0.69 g of the title compound as a white solid, mp 208°-210° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1.[OH-].[Na+:37]>O>[CH3:17][C@:5]1([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O-:1])=[C:3]([C:19]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=3[S:21](=[O:35])(=[O:34])[N:20]=2)[C:4]1=[O:18].[Na+:37]
Reactant: CC(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A suspension of the product of Example 40I (2.12 g) in water (10 mL) and treated with 0.997N sodium hydroxide solution (0.969 mL, 0.966 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.412 g, 79%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.46 (m, 1H) 0.69 (m, 6H) 0.80 (m, 1H) 1.29 (m, 1H) 1.38 (m, 3H) 1.72 (m, 1H) 2.14 (m, 1H) 2.90 (m, 3H) 7.34 (m, 6H) 8.05 (m, 1H) 15.42 (m, 1H). MS (ESI−) m/z 516 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C>[Si:19]([O:1][CH2:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[CH:10][CH:11]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: Cc1ccc(CCC(=O)CO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1ccc(CCC(=O)CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To an ice cooled solution of 1-hydroxy-4-(p-tolyl)butan-2-one in DMF (5 ml) was added imidazole (264 mg, 3.88 mmol) followed by tert-butyldimethylsilyl chloride (234 mg, 1.55 mmol). After 30 minutes the ice-bath was removed and then the mixture was stirred overnight at room temperature. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate), and concentrated in vacuo. The residue was purified by silica gel (8 g) column chromatography eluting with hexane/ethyl acetate (50:1) to give 1-(tert-butyldimethylsilyloxy)-4-(4-methylphenyl)butan-2-one (350 mg, 67.9%) as a colorless oil.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CN1C(=O)N(C)CCC1.[H-].[Na+].[Cl:23][C:24]1[CH:25]=[C:26]([C@@H:30]2[C@@H:35]([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)[N:34]([C@@H:43]([CH2:46][CH3:47])[CH:44]=O)[C:33](=[O:48])[C@:32]([CH2:50][CH:51]3[CH2:55][O:54][C:53]([CH3:57])([CH3:56])[O:52]3)([CH3:49])[CH2:31]2)[CH:27]=[CH:28][CH:29]=1>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([C@@H:30]2[C@@H:35]([C:36]3[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=3)[N:34]([C@@H:43]([CH2:46][CH3:47])[CH:44]=[CH:3][C:1]#[N:2])[C:33](=[O:48])[C@:32]([CH2:50][CH:51]3[CH2:55][O:54][C:53]([CH3:57])([CH3:56])[O:52]3)([CH3:49])[CH2:31]2)[CH:27]=[CH:28][CH:29]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC2COC(C)(C)O2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CC[C@@H](C=CC#N)N1C(=O)[C@@](C)(CC2COC(C)(C)O2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a solution of diethyl cyanomethylphosphonate (126 μL, 0.799 mmol) and DMPU (481 μL, 3.99 mmol) in THF (1.33 mL) was added 60% sodium hydride in mineral oil (24.0 mg, 0.599 mmol) at 0° C. The mixture was stirred for 30 min, and then treated with a solution of (2S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)butanal prepared above in Step D (207 mg, 0.399 mmol) in THF (1.33 mL). After being stirred for 4 h, the reaction was quenched (water), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (24 g SiO2, 30 to 40% EtOAc/Hex, gradient elution) provided the title compound as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([NH:8][NH2:9])[CH:7]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O.O>ClCCl>[CH2:17]([O:16][C:11](=[O:15])[C:12](=[N:9][NH:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[F:10])[CH3:14])[CH3:18]
Reactant: NNc1cc(Cl)ccc1F
Reactant: CCOC(=O)C(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(C)=NNc1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
(5-Chloro-2-fluoro-phenyl)-hydrazine (22.5 g, 140 mmol) was dissolved in dichloromethane (80 mL). Ethyl pyruvate (16.3 mL, 140 mmol) was added slowly to this solution at room temperature. The mixture was stirred for another 1 h at room temperature, added to water and extraxcted with dichloromethane. Organic phases were pooled, washed subsequently with hydrochloric acid (1 N) and brine and dried with MgSO4. Solvents were removed in vacuo and the residue was triturated with n-hexane to yield the title product as beige solid (22.8 g, 62.9%), ISP-MS: m/e=259.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.O1CCCC1.C([Li])CCC.[C:19](=[O:21])=[O:20].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:5]([F:8])=[CH:4][N:3]=1)[C:19]([OH:21])=[O:20]
Reactant: O=C=O
Reactant: Fc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)ncc1F
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-5-fluoropyridine (5.0 g) in tetrahydrofuran (100 mL) was 2.6 mol/L n-butyllithium tetrahydrofuran solution (12 mL) in a dropwise manner at −70° C., and this mixture was stirred at same temperature for 2 hours. To this reaction mixture was added excessive amounts of dry-ice at −70° C., and this mixture was stirred at room temperature for 12 hours. This mixture was poured into water, and this mixture was extracted with diethyl ether. To this obtained aqueous layer was added 1 mol/L hydrochloric acid (2 mL), and this mixture was extracted with ethyl acetate. This organic layer was concentrated to give the title compound (5.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1.O>[CH2:24]([O:23][C:21](=[O:22])[C:20](=[CH:10][C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][C:3]2[C:2]([Cl:1])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:18])=[CH:7][CH:8]=1)[C:19]([O:27][CH2:28][CH3:29])=[O:26])[CH3:25]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)OCC
Yield: 98.6 %

Procedure:
To a solution of 4-(2,6-dichlorobenzyloxy)benzaldehyde (5.62 g, 20 mmol) and diethyl malonate (3.52 g, 22 mmol) in benzene (75 mL), were added piperidine (90 μL) and glacial acetic acid (0.25 mL). After refluxing for 24 h with azeotropic water removal, the cooled reaction was concentrated in vacuo then partitioned between ether and water. The organic extract was washed successively with 1N hydrochloric acid, saturated sodium bicarbonate solution, water, brine and dried (MgSO4). Removal of volitiles in vacuo afforded the crude title compound (8.35 g, 97%) which was used in the next step without farther purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:10]1[N:11]([CH3:19])[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C(Cl)Cl>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]3[N:11]([CH3:19])[N:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:14]=3)[CH:5]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COc1ccc(N)cc1-c1cc(C(F)(F)F)nn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1cc(C(F)(F)F)nn1C
Yield: 87.5 %

Procedure:
4-Methoxy-3-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-phenylamine (0.02 g, 0.08 mmol) was treated with 4-chlorophenyl isocyanate (0.01 g, 10.45 μL, 0.093 mmol, 1.2 equiv.) in CH2Cl2 (3.0 mL), in a similar manner as described in Example 1.102. The product was further purified via reverse phase C-18 HPLC to afford Compound 42 (0.03 g, 0.07 mmol, 88% yield) as a white solid: LCMS m/z (%)=425 (M+H37Cl, 100), 427 (M+H35Cl, 34). 1H NMR (400 MHz, MeOH-d4) δ: 7.50 (dd, J=10.0, 2.0 Hz, 1H), 7.42 (dd, J=8.0 Hz, 3H), 7.27 (dd, J=6.0, 2.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 1H), 3.84 (s, 3H), 3.76 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:20]([O:24][C:25](=[O:36])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]O)=[CH:29][CH:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:13][CH2:14][C:15]([F:16])([F:18])[F:17])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:34][CH2:33][C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:36])=[CH:32][CH:31]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCO)cc1
Reactant: COC(=O)C(Cc1ccc(O)cc1)OCC(F)(F)F
Product: COC(=O)C(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)OCC(F)(F)F

Procedure:
3-[4-(2-{4-tert-Butoxycarbonylaminophenyl}ethoxy)phenyl]-2-(2,2,2-trifluoroethoxy)propanoic acid methyl ester was synthesized using the same method as in Example 62 (a) from 3-(4-hydroxyphenyl)-2-(2,2,2-trifluoroethoxy)propanoic acid methyl ester and 4-(2-hydroxyethyl)phenylcarbamic acid tert-butyl ester(described in Example 38b.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13]OCC)=[O:10])=[CH:5][CH:4]=1.CCOCCO[C:25](/[CH:27]=[CH:28]/[C:29]1C=CC(OC)=CC=1)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:8][C:9]([O:11][CH:12]2[CH2:13][CH2:29][CH2:28][CH2:27][CH2:25]2)=[O:10])=[CH:17][CH:18]=1
Reactant: CCOCCOC(=O)/C=C/c1ccc(OC)cc1
Reactant: CCOCCOC(=O)C=Cc1ccc(OC)cc1
Product: COc1ccc(C=CC(=O)OC2CCCCC2)cc1

Procedure:
2-ethoxyethyl p-methoxycinnamate or "Cinoxate" according to the common international name, sold under the trade name Giv-Tan F;
Reaction SMILES: [C:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[S:6][C:7]=1I)#[N:2].[F:22][C:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.CCOC(C)=O.C([O-])(O)=O.[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[S:6][C:7]=1[C:27]1[CH:26]=[CH:25][N:24]=[C:23]([F:22])[CH:28]=1)#[N:2]
Reactant: CCOC(=O)c1sc(I)c(C#N)c1-c1ccc(Cl)cc1Cl
Reactant: OB(O)c1ccnc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(-c2ccnc(F)c2)c(C#N)c1-c1ccc(Cl)cc1Cl
Temperature: 140 °C

Procedure:
A mixture of ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-iodothiophene-2-carboxylate (1.81 g, 0.00400 mol), 2-Fluoro-4-pyridinylboronic acid (1.13 g, 0.00801 mol), Tetrakis(triphenylphosphine)palladium(0) (0.231 g, 0.0002 mol) and sodium carbonate (1.27 g, 0.0120 mol) in 1,2-Dimethoxyethane (20 mL) and Water (10 mL) was heated under microwave irradiation at 140° C. for 15 min. The reaction mixture was diluted with EtOAc and sat. NaHCO3. The layers were separated and the aqueous layer was extracted 2× with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to in vacuo to a brown oil. The residue was loaded onto a 24 g Analogix silica gel column and eluted with hexane (3 min) to 50% EtOAc in hexanes (25 min gradient). The appropriate fractions were concentrated to a white solid (1.25 g, 74%). LCMS: (FA) ES+, 421, 423. 1H NMR (400 MHz, d6-DMSO) 8.42 (d, J=5.28 Hz, 1H), 7.65 (td, J=5.27, 1.51, 1.51 Hz, 1H), 7.57 (d, J=2.00 Hz, 1H), 7.45-7.34 (m, 1H), 7.29 (d, J=8.26 Hz, 1H), 4.34-4.17 (m, 1H), 1.21 (t, J=7.14, 7.14 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13]>>[CH2:17]([O:16][C:10](=[O:15])[C:11](=[C:6]([NH2:7])[C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:12](=[O:13])[CH3:14])[CH3:18]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)C(C(C)=O)=C(N)c1ccc(Cl)cc1

Procedure:
The title compound was synthesized in analogy to Example 1 from 4-chlorobenzonitrile and ethyl acetoacetate: MS (m/z) 268.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([F:9])=[C:4](Cl)[N:3]=1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[NH:12][NH2:13].C(N(C(C)C)CC)(C)C.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:13][NH:12][C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]([F:9])=[C:6]([Cl:8])[N:7]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: Fc1c(Cl)nc(Cl)nc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNc1nc(Cl)nc(Cl)c1F
Reaction time: 1.5 h
Yield: 101.4 %

Procedure:
2,4,6-Trichloro-5-fluoropyrimidine (20.92 g, 104.1 mmol) was dissolved in THF (300 mL) at room temperature and stirred. To this stirring solution was added t-butyl carbazate (13.74 g, 104.1 mmol), followed by diisopropylethylamine (19.0 mL, 109.3 mmol). The reaction mixture turned light yellow, and after several minutes a precipitate formed. The reaction appeared complete after 1.5 h, as monitored by TLC (10% EtOAc/Hex). The reaction mixture was concentrated in vacuo to remove most of the THF, and the residue was dissolved in CH2Cl2 (˜400 mL). The solution was washed with ˜400 mL of sat. aq. NH4Cl. The organics were dried and concentrated to give a pale yellow solid (31.37 g). LCMS: (M+H+2Na-Boc)+: 241.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16](=[O:17])[C:15]([F:22])([F:21])[F:14])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Br)cn1)C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
2,5-Dibromopyridine (7.11 g, 30 mmol) was dissolved in dry toluene (200 mL) and cooled to −78° C. n-BuLi (14.4 mL, 2.5 M in THF, 36 mmol) was added dropwise. The mixture was stirred at −78° C. for 2 hours and ethyl trifluoroacetate (6.39 g, 45 mmol) was added. The resulting mixture was allowed to warm to room temperature slowly and stirred at room temperature for 30 min. The reaction was quenched with NH4Cl (aq.) and extracted with EtOAc. The organics were dried and concentrated and the resulting residue was purified by column chromatography (silica gel, 0-30% EtOAc/Hexane) to give the product 1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethanone (5.87 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[NH:38][CH:37]=[CH:36]2.[CH3:44][N:45]1[CH:49]2[CH2:50][CH:51](O)[CH2:52][CH:46]1[CH2:47][CH2:48]2>C(N(CC)CC)C.ClCCl>[CH3:44][N:45]1[CH:49]2[CH2:48][CH2:47][CH:46]1[CH2:52][CH:51]([O:32][C:33]1[CH:34]=[C:35]3[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[NH:38][CH:37]=[CH:36]3)[CH2:50]2
Reactant: CN1C2CCC1CC(O)C2
Reactant: O=c1[nH]ccc2cc(O)ccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C2CCC1CC(Oc1ccc3c(=O)[nH]ccc3c1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
8 mL of dry dichloromethane were added to 814 mg (1.73 mmol) of polystyrene bound triphenyl phosphine. At 0° C. 234 μL (1.48 mmol) of diethyl azodicarboxylate were added. 200 mg (1.24 mmol) of 6-hydroxy-2H-isoquinolinone (66), 210 mg (1.49 mmol) of tropine and 261 μL of triethylamine were added and the reaction mixture was allowed to warm to room temperature and stirred overnight. Another 279 mg of PS-triphenyl phosphine, 43 mg of tropine, 26 μL of diethyl azodicarboxylate and 2 mL of dry dichloeomethane were added and stirring was continued overnight. The solids were filtered off and washed with THF. The mixture was evaporated and purified by flash chromatography to give 158 mg of 6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-2H-isoquinolin-1-one (53). Rt=0.79 min (Method B). Detected mass: 279.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([CH2:24][OH:25])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.O.Cl>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([CH:24]=[O:25])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CS(=O)(=O)c1ccc(Cn2c(CO)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Cn2c(C=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a solution of 6-bromo-3-hydroxymethyl-2-(4-methanesulfonylbenzyl)-4-phenyl-2H-isoquinolin-1-one (1.0 g) in DMSO (10 ml) was added triethylamine (4.4 ml), and pyridine sulfur trioxide complex (2.6 g) was added at room temperature, and the mixture was stirred for 1 hr. and the reaction mixture was added to water. 10% Hydrochloric acid was added to acidify the aqueous layer and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from diisopropyl ether to give the title compound (940 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.Cl.[NH2:12][C@@H:13]([C:15]([NH2:17])=[O:16])[CH3:14].CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C@H:13]([CH3:14])[C:15]([NH2:17])=[O:16])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: C[C@@H](N)C(N)=O
Reactant: N#Cc1ncc(Cl)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Yield: 100.2 %

Procedure:
A solution of 3,5-dichloropyrazine-2-carbonitrile (150 mg, 0.862 mmol), D-alaninamide hydrochloride (107 mg, 0.858 mmol) and DIEA (0.400 mL, 2.30 mmol) in NMP (4 mL) was stirred at room temperature for 20 h. Water and EtOAc were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)propanamide as an oil (194 mg).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:17]=1[C:18]([NH2:20])=[O:19]>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:17]=1[C:18]([NH:20][C:11]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=1)=[O:12])=[O:19]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: NC(=O)c1cc(F)ccc1Cl
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1cc(F)ccc1Cl)Nc1ccc(OC(F)(F)F)cc1
Yield: 82.3 %

Procedure:
A solution of 4.06 g (0.02 mol) of 4-trifluoromethoxy-phenyl isocyanate in 10 ml of dry toluene is added to 3.48 g (0.02 mol) of 2-chloro-5-fluorobenzamide in 100 ml of dry toluene, at 100° C., in the absence of moisture. The mixture is boiled under reflux for 10 hours. After it has been cooled, the precipitated product is filtered off under suction and rinsed with methanol. 6.2 g (82.5% of theory) of 1-(2-chloro-5-fluoro-benzoyl)-3-(4-trifluoromethoxyphenyl)-urea of melting point 199° C. are obtained. The compound is identical to the compound prepared by process variant (a).
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=O.C(OC)(=O)[CH2:17][CH2:18][C:19]([O:21]C)=[O:20]>CCOCC>[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:11]
Reactant: COC(=O)CCC(=O)OC
Reactant: COC(=O)c1cccc(Cl)c1
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: O=C(O)CCC(=O)c1cccc(Cl)c1

Procedure:
Sodium (11 g, spheres) was added to 200 ml ethanol with stirring. When the gas evolution ceased, methyl 3-chlorobenzoate (10 g, 0.057 mole) and dimethyl succinate (9.0 g, 0.615 mole) were added rapidly and the mixture was stirred for 5 minutes at room temperature. The mixture was slowly concentrated on a rotary evaporator to yield a greenish paste which was slurried in 100 ml ether and an additional 2 ml of dimethyl succinate was added. The reaction was evaporated to a paste, quenched with water and extracted with ether. The ether extracts were washed with water and brine, dried and evaporated in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:15][C:14]1[CH:16]=[CH:17][C:18]([C:20]([F:21])([F:22])[F:23])=[CH:19][C:13]=1[Cl:12])=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Product: O=C(Nc1ccc(C(F)(F)F)cc1Cl)c1cc(Br)ccc1O
Yield: 34.9 %

Procedure:
Using 5-bromosalicylic acid and 2-chloro-4-(trifluoromethyl)aniline as the raw materials, the same operation as the Example 1(1) gave the title compound.