Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.[CH2:18]([NH2:24])[C:19]1[O:23][CH:22]=[CH:21][CH:20]=1.C(O)C>CO>[CH:16]1[C:17]2[N:5]([CH2:4][CH:2]([OH:1])[CH2:3][NH:24][CH2:18][C:19]3[O:23][CH:22]=[CH:21][CH:20]=3)[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: NCc1ccco1
Reactant: c1ccc2c(c1)c1ccccc1n2CC1CO1
Solvent: CCO
Solvent: CO
Product: OC(CNCc1ccco1)Cn1c2ccccc2c2ccccc21
Temperature: 110 °C
Yield: 56.3 %

Procedure:
A suspension of 9-(oxiran-2-ylmethyl)-9H-carbazole (2.97 g, 13.3 mmol) in a solution of furfurylamine (5.3 mL, 60 mmol) and ethanol (11 mL) was heated to 110° C. for 15 minutes in a Biotage Initiator microwave reactor. The resulting solution was diluted with methanol and cooled in an ice bath to precipitate a white solid. The solid was recrystallized by dissolving in a minimal volume of hot methanol and slowly cooled to give the desired product as a fine crystalline white solid (2.4 g, 57%). 1H NMR (CDCl3, 300 MHz) δ 8.10-8.08 (d, 2H, J=8.1 Hz), 7.46-7.44 (m, 3H), 7.32-7.25 (m, 4H), 6.29-6.27 (dd, 1H, J=1.8, 3.3 Hz), 6.11-6.10 (d, 1H, J=3 Hz), 4.39-4.38 (d, 1H, J=2.1 Hz), 4.37 (d, 1H, J=0.9 Hz), 4.21-4.17 (m, 1H), 3.75 (s, 2H), 2.85-2.79 (dd, 1H, J=3.8, 12.3 Hz), 2.69-2.62 (dd, 1H, J=8.4, 12.3 Hz), 2.00 (br s, 2H). ESI m/z: 321.1 (M+H). HPLC analysis: (C18, 10-90% acetonitrile in water+0.1% trifluoroacetic acid over 10 min: retention time, % area at 254 nm): 6.1 min, 99.0%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7](O)[N:6]=[CH:5]2.P(Cl)(Cl)([Cl:16])=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([Cl:16])[N:6]=[CH:5]2
Reactant: Oc1ncc2cc(Br)c(Cl)cc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncc2cc(Br)c(Cl)cc2n1
Temperature: 25 °C
Yield: 48 %

Procedure:
A solution of 6-bromo-7-chloroquinazolin-2-ol (6.0 g, 23 mmol) in phosphorus oxychloride (50 mL) was refluxed for 5 hours. The reaction was cooled to room temperature, and most of phosphorus oxychloride was removed under reduced pressure. The residue was dropwise added to ice water (500 mL), and the resulting precipitate was collected by the filtration to give the title compound as a yellow solid (3 g, 48%).
Reaction SMILES: Br[C:2]1[C:3]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][C:20]([OH:24])=[CH:19]2.C(=O)([O-])[O-].[Cs+].[Cs+].C(CC(=O)C(C)(C)C)(=O)C(C)(C)C>CN1CCCC1=O.[Cu]Cl>[F:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][C:20]([O:24][C:2]1[C:3]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1)=[CH:19]2
Reactant: Oc1cnc2c(F)cccc2c1
Reactant: CC(C)(C#N)c1ncccc1Br
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: CC(C)(C#N)c1ncccc1Oc1cnc2c(F)cccc2c1
Temperature: 130 °C
Reaction time: 23 h
Yield: 29.8 %

Procedure:
1.35 g of 2-(3-bromo-pyridin-2-yl)-2-methyl-propionitrile were dissolved in 6 ml of N-methylpyrrolidone. 0.82 g of 8-fluoro-3-hydroxyquinoline, 1.95 g of cesium carbonate, 0.18 g of dipivaloylmethane and 0.50 g of copper (I) chloride were added thereto followed by stirring for 23 hours at 130° C. Subsequently, the reaction mixture was cooled to room temperature and purified by silica gel column chromatography to obtain 0.46 g of 2-[3-(8-fluoro-quinolin-3-yloxy)-pyridin-2-yl]-2-methylpropionitrile.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13]([OH:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH2:16].C(=O)([O-])[O-].[K+].[K+].O>COCCOCCO.[Cu]>[C:13]([C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([OH:22])=[O:21]
Reactant: Nc1ccccc1C(=O)O
Reactant: CSc1ccc(Cl)c(C(=O)O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCO
Solvent: O
Product: CSc1ccc(Nc2ccccc2C(=O)O)c(C(=O)O)c1
Yield: 30.1 %

Procedure:
A mixture of 2-chloro-5-(methylthio)benzoic acid (10 g), anthranilic acid (7 g), potassium carbonate (14 g) and copper (1 g) in 2-(2-methoxyethoxy)ethanol (100 ml) was heated at 180° for 24 h. Water (400 ml) was then added, and the catalyst was filtered off. The filtrate was acidified with dilute hydrochloric acid. The resulting precipitate was filtered off, washed with water, dried, and crystallised from methanol to give the title compound (4.5 g) as crystals. IR includes peaks at 3300 cm-1 (NH) and 1700 cm-1 (CO2H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>C1COCC1.C(O)C.[Pd]>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(N)cc1
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A solution of 4-(methylsulfonyl)nitrobenzene (6.26 g, 31.1 mmol) in THF (200 mL) and ethanol (100 mL) was placed in a high pressure reaction vessel and to this solution was added 5% Pd/C (1.6 g). The vessel was shaken for 8 h under an atmosphere of hydrogen (60 psi). The solution was then filtered through diatomaceous earth, partially concentrated in vacuo, and diluted with diethyl ether. The resulting precipitate was filtered and dried in vacuo to give 4.84 g (91%) of a tan solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([CH:18]2[CH2:23][NH:22][CH2:21][CH2:20][N:19]2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])=[O:17])[CH2:12][CH2:11]1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([S:40](Cl)(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([CH:18]2[CH2:23][N:22]([S:40]([C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([O:33][CH3:32])[CH:35]=3)(=[O:42])=[O:41])[CH2:21][CH2:20][N:19]2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])=[O:17])[CH2:12][CH2:11]1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNCCN3c3ccc(F)cc3C)CC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(S(=O)(=O)N2CCN(c3ccc(F)cc3C)C(C(=O)N3CCN(c4cc(C)ccc4C)CC3)C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of [4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-[1-(4-fluoro-2-methyl-phenyl)-piperazin-2-yl]-methanone hydrochloride (42 mg) in DMF (1 mL) was added 3-methoxybenzene sulfonyl chloride (21.4 mg) and triethyl amine (40 μL). The reaction mixture was stirred at ambient temperature for 2 h, was diluted with ethyl acetate and washed with a saturated aqueous solution of NaHCO3. The combined organic phases were washed with water and brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by column chromatography (SiO2, n-heptane/ethyl acetate 2:1) to give [4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-[1-(4-fluoro-2-methyl-phenyl)-4-(3-methoxy-benzenesulfonyl)-piperazin-2-yl]-methanone (42 mg) as white solid, MS: 581.3 ([M+H]+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:19][C:20]([F:29])([F:28])C1C=C(C=CC=1)N.N1C=CC=CC=1C=O>>[F:19][C:20]([F:29])([F:28])[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Agent: O=Cc1ccccn1
Product: FC(F)(F)c1cccc(-n2nnc(-c3ccccn3)n2)c1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-trifluoromethylaniline (195 mg, 1.2 mmol) and pyridine-2-carboxaldehyde (128 mg, 1.2 mmol) were employed to obtain 2-[2-(3-trifluoromethylphenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([C:11]([OH:13])=O)([C:8]([OH:10])=[O:9])[CH2:7][CH2:6]1.CCN(CC)CC.[F:21][C:22]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]3[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=3)[CH:30]=2)[CH:25]=[CH:24][C:23]=1[NH2:41]>C1COCC1>[F:21][C:22]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]3[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=3)[CH:30]=2)[CH:25]=[CH:24][C:23]=1[NH:41][C:11]([C:5]1([C:8]([OH:10])=[O:9])[CH2:6][CH2:7]1)=[O:13]
Reactant: O=C(O)C1(C(=O)O)CC1
Reactant: Cn1cc(-c2cc(Oc3ccc(N)c(F)c3)ccn2)cn1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)c(F)c3)ccn2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 23.8 %

Procedure:
Thionyl chloride (1.09 mL, 15.0 mmol) was added slowly over 2 min to a stirring solution of 1,1-cyclopropanedicarboxylic acid (1.95 g, 15.0 mmol) and Et3N (4.29 g, 42.4 mmol) in THF (15 mL) at 0° C. After complete addition, the reaction was further diluted with THF (25 mL) and the reaction was stirred vigorously at 0° C. for 30 min. The hydrochloride salt of Example A1 (4.00 g, 12.5 mmol) was added in three portions and the resulting mixture was allowed to slowly warm to RT over 4 h. The reaction mixture was concentrated to dryness in vacuo and the residue was digested with aqueous MeOH. The remaining solids were collected by filtration. This solid was dissolved in 1 M aq NaOH (30 mL) and methanol. The methanol was removed in vacuo, the remaining aqueous phase was diluted with water to a volume of 150 mL and extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with sat aq NaHCO3. The combined aqueous was acidified to pH 6 with 0.5 M HCl. The resultant fine precipitate was collected by filtration, washed with acetonitrile (20 mL) and dried in vacuo to provide 1-((2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)carbamoyl)cyclopropanecarboxylic acid (1.177 g). The remaining aqueous was concentrated in vacuo to about ⅓ volume and the pH was reduced to pH 5 with 1 M aq HCl. The additional precipitate that formed was collected by filtration, washed with acetonitrile and dried in vacuo to provide an additional crop (1.34 g) of 1-((2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)carbamoyl)cyclopropanecarboxylic acid (2.517 g total, 51% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.51 (br s, 1H), 11.30 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 8.19 (t, J=9.0 Hz, 1H), 7.95 (s, 1H), 7.28 (dd, J=11.6, 2.7 Hz, 1H), 7.22 (d, J=1.6 Hz, 1H), 7.01 (m, 1H), 6.69 (dd, J=5.6, 2.3 Hz, 1H), 3.84 (s, 3H), 1.58-1.51 (m, 4H); MS (ESI) m/z: 397.1 (M+H+).
Reaction SMILES: Cl.[CH2:2]([O:5][N:6]=[C:7]([C:33]1[N:34]=[C:35]([NH:38]C=O)[S:36][CH:37]=1)[C:8]([NH:10][CH:11]1[C:31](=[O:32])[N:13]2[C:14]([C:28]([OH:30])=[O:29])=[C:15]([CH2:18][S:19][C:20]3[N:24]([CH2:25][CH:26]=[CH2:27])[N:23]=[N:22][N:21]=3)[CH2:16][S:17][C@H:12]12)=[O:9])[CH:3]=[CH2:4]>CO>[CH2:2]([O:5][N:6]=[C:7]([C:33]1[N:34]=[C:35]([NH2:38])[S:36][CH:37]=1)[C:8]([NH:10][CH:11]1[C:31](=[O:32])[N:13]2[C:14]([C:28]([OH:30])=[O:29])=[C:15]([CH2:18][S:19][C:20]3[N:24]([CH2:25][CH:26]=[CH2:27])[N:23]=[N:22][N:21]=3)[CH2:16][S:17][C@H:12]12)=[O:9])[CH:3]=[CH2:4]
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC=C)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC=C)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 76.7 %

Procedure:
Conc. hydrochloric acid (0.33 g) was added to a solution of 7-[2-allyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(1.30 g) in methanol (13 ml) and the mixture was stirred for 4.5 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate (25 ml). The aqueous solution was washed with ethyl acetate (25 ml) and adjusted to pH 2.0 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give colorless powder of 7-[2-allyloxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(0.95 g).
Reaction SMILES: CO[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=O.[NH2:12][NH2:13]>>[OH:11][N:9]1[C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:13]=[N:12]1
Reactant: NN
Reactant: COc1cnccc1[N+](=O)[O-]
Product: On1nnc2cnccc21

Procedure:
By reacting either 3-methoxy-4-nitro pyridine or 3-halo-4-nitro pyridine (wherein halo is chloro, bromo or fluoro) with hydrazine in accordance with the procedure of Example 1, the title compound is prepared.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH2:42][C:43](O)=[O:44])=[CH:34]1>>[C:26]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:43](=[O:44])[CH2:42][C:35]4[C:36]5[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:33]([CH3:32])[CH:34]=4)[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Reactant: Cn1cc(CC(=O)O)c2ccccc21
Agent: Cl
Product: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)Cc3cn(C)c4ccccc34)C[C@H]21
Yield: 58 %

Procedure:
By working in accordance with Example 4, starting from 0.75 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride and 0.32 g of (1-methyl-3-indolyl)acetic acid, 0.56 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(1-methyl-3-indolyl)acetyl)perhydroisoindol-4-ol is obtained in the form of a beige foam.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20]>>[CH3:8][C@H:4]1[NH:3][C@@H:2]([CH3:1])[CH2:7][N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([F:20])([F:21])[F:22])[CH2:5]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2C(F)(F)F)C[C@H](C)N1

Procedure:
The title compound is obtained in a similar manner as described in Example 18b starting with cis-2,6-dimethylpiperazine (Aldrich, Buchs, Switzerland) and 2-fluoro-5-nitrobenzotrifluoride (Aldrich, Buchs, Switzerland). Title compound: ES-MS: 304 (M+H)+; analytical HPLC: tret=2.89 minutes (Grad 1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([Cl:9])[CH:3]=1.N1C=CC=CC=1.[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:19](=[O:20])[CH2:18][CH2:17][Cl:16])=[C:4]([Cl:9])[CH:3]=1
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccc(Br)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCCl)Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
To a solution of 4-bromo-2-chloro-phenylamine (32 g, 0.15 mol) and pyridine (13.45 g, 0.17 mol) in DCM (200 mL) was added 3-chloropropionyl chloride (21.65 g, 0.17 mol) dropwise at 15° C. After stirring at room temperature for 1 hour, the mixture was washed with water and then hydrochloric acid (2 N, aqueous). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford title compound (10.9 g, yield: 90%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][O:6][C:5](=[O:8])[CH:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH2:21]([N:1]([CH2:2][CH:3]1[CH2:7][O:6][C:5](=[O:8])[CH:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCC1COC(=O)C1c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1OCC(CN(Cc2ccccc2)Cc2ccccc2)C1c1ccccc1
Yield: 46 %

Procedure:
(3RS, 4RS) 4-Aminomethyl-3-phenyl-dihydrofuran-2-one (2.15 g, 0.011 mol) was added to potassium carbonate (15.5 g), benzyl bromide (6.69 ml) and dimethylformamide (10 ml) and stirred for 3 hours at 50° C. dimethylformamide was removed in vacuo and the reaction was dispersed between ethyl acetate (40 ml) and water (60 ml), the aqueous phase was washed with ethyl acetate (2×30 ml) and the organic layers were combined and washed with brine solution (100 ml) and dried over MgSO4. The solvent was removed in vacuo and purified by flash column chromatography on silica gel and eluting in increasing concentrations of ethyl aceate in hexane (5-50%) to give the title compound (1.15 g, 46%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:7]([CH2:8][NH2:9])[CH2:6][CH:5]([O:10][CH3:11])[O:4]1.[C:12](Cl)(=[O:14])[CH3:13]>>[C:12]([NH:9][CH2:8][CH:7]1[CH2:6][CH:5]([O:10][CH3:11])[O:4][CH:3]1[O:2][CH3:1])(=[O:14])[CH3:13]
Reactant: COC1CC(CN)C(OC)O1
Reactant: CC(=O)Cl
Product: COC1CC(CNC(C)=O)C(OC)O1

Procedure:
4.0 g of 2,5-dimethoxy-3-aminomethyltetrahydrofuran and 1.75 ml of acetyl chloride were reacted as in Example 89a. 3.7 g of impure product were obtained and were immediately reacted further.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][C:11]([OH:13])=O)=[O:5])C.[CH2:17]([NH2:19])[NH2:18]>>[CH2:17]([NH:19][C:11](=[O:13])[CH2:10][O:9][C:8]1[CH:7]=[C:6]([CH:16]=[CH:15][CH:14]=1)[C:4]([OH:3])=[O:5])[NH:18][C:11](=[O:13])[CH2:10][O:9][C:8]1[CH:7]=[C:6]([CH:16]=[CH:15][CH:14]=1)[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cccc(OCC(=O)O)c1
Reactant: NCN
Product: O=C(COc1cccc(C(=O)O)c1)NCNC(=O)COc1cccc(C(=O)O)c1

Procedure:
By following the processes described in stages A to C of Example R13, Example R37 is prepared by dimerization of [3-(ethoxycarbonyl)phenoxy]acetic acid with methylenediamine. A white powder is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH:3]=1.CCCCCC.S(Cl)([Cl:34])(=O)=O>>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[C:3]=1[Cl:34]
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)cc(N)c2F)c1F
Reactant: O=S(=O)(Cl)Cl
Solvent: CCCCCC
Product: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)c(Cl)c(N)c2F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Propan-2-yl 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate (3.065 g, 8.59 mmol) was dissolved in sulfuryl chloride (150 mL). The solution was stirred under nitrogen at room temperature for 8 h. During this time, a white precipitate formed. Hexane (100 mL) was added, and the mixture was stored overnight at −20° C. The product was filtered, washed with hexane and then slurried in EtOAc (100 mL). The organic suspension was neutralized with satd aq NaHCO3 solution, which caused all solids to dissolve. The organic layer was separated and washed with 10% aq NaHSO3 solution and brine, dried (MgSO4), and concentrated under reduced pressure to give a white solid (1.962 g, 58%): mp 109-111° C.; 1H NMR (400 MHz, CDCl3) δ 7.25 (m, 2H), 5.32 (septet, J=6.3 Hz, 1H, CHMe2), 5.07 (br s, 2H), 3.97 (d, JF-H=1.0 Hz, 3H, OMe), 1.40 (d, J=6.3 Hz, 6H, CHMe2); 19F NMR (376 MHz, CDCl3) δ −128.16 (dd, JF-F=33.3 Hz, JF-H=2.5 Hz, phenyl F), −138.35 (d, JF-F=33.4 Hz, pyridine F5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[C:12](=[O:14])[CH2:11][CH2:10]2
Reactant: COc1ccc(CCC(=O)O)cc1Cl
Solvent: O
Product: COc1cc2c(cc1Cl)CCC2=O
Yield: 66 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)propanoic acid (10 g, 46.7 mmol, commercially available) in PPA (100 mL) was stirred for 2 h at 70 C. Water was added to the mixture and extracted with EA twice. The organic phase were combined and dried over anhydrous Na2SO4, concentrated, purified by FC to afford 6 g of the title compound (y=66%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:16](=[O:17])[CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41]Cl.C([O-])(O)=O.[Na+].N12CCN(CC1)CC2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14](=[O:23])[N:15]([CH2:18][C:19]([F:21])([F:22])[F:20])[C:16](=[O:17])[C:10]2([CH2:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)N(CC(F)(F)F)C(=O)C2C1
Agent: C1CN2CCN1CC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2C(=O)N(CC(F)(F)F)C(=O)C2(Cc2ccccn2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In flame-dried glassware, 1,3-dioxo-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (prepared as described in Step 4, 10.11 g, 30 mmol) was dissolved in 150 mL of DMF/30 mL of THF and cooled to −78° C. Potassium bis(trimethylsilyl)amide (KHMDS, 0.5 M solution, 90 mL, 45 mmol) was added dropwise and allowed to stir for 1 h at −78° C. In separate glassware, 2-picolyl chloride HCl (14.76 g, 90 mmol) was reacted with saturated aqueous NaHCO3 (150 mL), extracted with CH2Cl2 (3×150 mL), dried with MgSO4, evaporated and added 50 mL of dry THF with some molecular sieves. The resulting solution of 2-picolyl chloride free base was added to the reaction mixture at −78° C. via syringe and allowed to warm to room temperature overnight. The toluene and THF were evaporated and resulting DMF solution was partitioned with 150 mL of H2O/150 mL of IPE. 1,4-Diazabicyclo[2,2,2]octane (7.3 g, 65 mmol) and K2CO3 (12 g, 90 mmol) were added to the solution and the solution was stirred for one hour to remove excess 2-picolyl chloride. The organic solvents were separated and were removed by evaporation to give 11.45 g (89%) of essentially pure title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][N:6]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=2)[CH:10]=[CH:9][C:8]=1[CH3:20])[CH3:2].C([O-])(=O)C.[Na+]>C(O)C.O1CCCC1.[C].[Pd]>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:27])[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]=2)[CH:10]=[CH:9][C:8]=1[CH3:20])[CH3:26]
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(-c2cc(Cl)ncn2)ccc1C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CN(CC(=O)OCC)c1cc(-c2ccncn2)ccc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.2 %

Procedure:
The compound (696 mg, 1.78 mmol) obtained in step B was dissolved in a ethanol (25 ml)-tetrahydrofuran (2 ml) mixed solvent. Then, sodium acetate (164 mg, 2.00 mmol) and 10% palladium carbon (containing water) (0.68 g) were added, and the mixture was stirred at room temperature for 5 hr under a hydrogen atmosphere. The insoluble material was filtered off through celite, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (466 mg, yield 73%) as a colorless oil.