Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:4]=2[O:3]1.[CH3:13][N:14]=[C:15]=[O:16]>C1C=CC=CC=1.C(N(CC)CC)C>[CH3:13][NH:14][C:15](=[O:16])[O:11][C:10]1[C:4]2[O:3][C:2]([CH3:12])([CH3:1])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CN=C=O
Reactant: CC1(C)Oc2cccc(O)c2O1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1cccc2c1OC(C)(C)O2
Reaction time: 0.5 h
Yield: 85 %

Procedure:
2,2-Dimethyl-4-hydroxy-1,3-benzodioxole (14 parts) in benzene (25 parts) was treated with methyl isocyanate (6 parts) and a few drops of triethylamine with cooling. After standing for 30 minutes, the crystals of 2,2-dimethyl-1,3-benzodioxol-4-yl N-methylcarbamate which formed were filtered off and washed with benzene then with petroleum (boiling point below 40°C.) to yield the pure compound as a white solid, melting point 129°-130°C. (16 parts, 85% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].Cl[C:14]1[CH:15]=[C:16]2[N:23](C(OC(C)(C)C)=O)[C@@H:22]([CH3:31])[CH2:21][N:17]2[C:18](=[O:20])[N:19]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][O:10][C:14]1[CH:15]=[C:16]2[NH:23][C@@H:22]([CH3:31])[CH2:21][N:17]2[C:18](=[O:20])[N:19]=1
Reactant: OCc1ccc(F)c(F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1Cn2c(cc(OCc3ccc(F)c(F)c3)nc2=O)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3,4-difluorophenyl)methanol (45.4 mg, 0.315 mmol) in tetrahydrofuran (THF) (3 mL) was added dropwise sodium hydride (37.8 mg, 0.945 mmol) at 0° C. After 30 min, (S)-tert-butyl 7-chloro-2-methyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate (90 mg, 0.32 mmol) was added. The reaction mixture was stirred at room temperature for 16 h, then concentrated. Purification via pre-TLC (ethyl acetate) afforded the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:27]C)=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][C:10](=[O:22])[C:9]=2[CH2:23][C:24]([OH:26])=[O:25])[CH:7]=1.Cl.[NH+]1C=CC=CC=1.Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:27])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][C:10](=[O:22])[C:9]=2[CH2:23][C:24]([OH:26])=[O:25])[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1c(CC(=O)O)c(=O)[nH]c2ccc(C(F)(F)F)cc12
Agent: Cl
Agent: c1cc[nH+]cc1
Product: O=C(O)Cc1c(-c2cc(Cl)ccc2O)c2cc(C(F)(F)F)ccc2[nH]c1=O
Temperature: 185 °C
Yield: 86.2 %

Procedure:
A neat mixture of crude 4-(5-chloro-2-methoxyphenyl)-1,2-dihydro-2-oxo-6-(trifluoromethyl)-3-quinolineacetic acid prepared in Step C (1.45 g, 3.5 mmol) and pyridinium hydrochloride (5 g, 43.3 mmol) was heated at 185° C. for 3 hours. Reaction mixture was allowed to cool and 1N HCl was added and then extracted with EtOAc to afford the title compound (1.20 g, 86%): mp 158-160° C.;
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[CH3:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][C:26](=[O:32])[NH:27]2>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=[C:25]1[C:24]2[C:28](=[CH:29][CH:30]=[CH:31][C:23]=2[CH3:22])[NH:27][C:26]1=[O:32]
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: Cc1cccc2c1C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCCCC1)CC3)C(=O)N2
Yield: 75.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-methyl-1,3-dihydro-indol-2-one (prepared according to U.S. Pat. No. 6,114,371) as starting materials to give 3-methyl-2-(4-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (41 mg, 75.9%) as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:26])=[C:8]([C:10]2[N:15]=[C:14]3[N:16]([CH3:25])[C:17](=[O:24])[N:18]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]3=[CH:12][CH:11]=2)[CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[CH3:22][C:20]([CH3:21])([CH3:23])[CH2:19][N:18]1[C:13]2[C:14](=[N:15][C:10]([C:8]3[CH:9]=[C:4]([C@@H:1]([OH:3])[CH3:2])[CH:5]=[CH:6][C:7]=3[CH3:26])=[CH:11][CH:12]=2)[N:16]([CH3:25])[C:17]1=[O:24]
Reactant: CC(=O)c1ccc(C)c(-c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc([C@H](C)O)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a microwave vial was added 5-(5-acetyl-2-methylphenyl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (15-7) (15 mg, 0.043 mmol) and sodium borohydride (2.5 mg, 0.064 mmol) under nitrogen. The mixture was dissolve in methanol (0.4 ml), and allowed to stir at room temperature for 1 hour. The reaction was diluted with methanol, and passed through a syringe filter. The solution was purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile) and the desired fractions were collected and concentrated to produce 1-(2,2-dimethylpropyl)-5-{5-[(1S)-1-hydroxyethyl]-2-methylphenyl}-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (25-1). HRMS (M+H)+: observed=354.2178, calculated=354.2176.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:13]([O:15][P:16]([CH2:21][C:22]([OH:24])=O)([O:18][CH2:19][CH3:20])=[O:17])[CH3:14].[Cl:25][C:26]1[CH:27]=[C:28]([NH:40][C:41]2[C:42]3[CH:50]=[C:49]([NH2:51])[N:48]=[CH:47][C:43]=3[N:44]=[CH:45][N:46]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.CC(N(C)C)=O>C1COCC1.O.ClCCl.CO>[Cl:25][C:26]1[CH:27]=[C:28]([NH:40][C:41]2[C:42]3[CH:50]=[C:49]([NH:51][C:22](=[O:24])[CH2:21][P:16](=[O:17])([O:15][CH2:13][CH3:14])[O:18][CH2:19][CH3:20])[N:48]=[CH:47][C:43]=3[N:44]=[CH:45][N:46]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CCOP(=O)(CC(=O)Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cn1)OCC
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 92.7 %

Procedure:
To a stirred mixture of CDI (2.25 g, 13.9 mmol) and dry THF (9 mL), at room temperature and under a nitrogen atmosphere, was added a solution of 2-(diethoxyphosphoryl)acetic acid (2.43 g, 12.4 mmol) in THF (7 mL). After addition the reaction mixture was stirred further at 40° C. (bath) for 15 min (whence evolution of gases ceased). A mixture of compound 221 (1.88 g, 4.96 mmol) in a mixed solvents of dry THF (10 mL) and DMA (16 mL) was added and stirred further at 40° C. The reaction was monitored by TLC (dichloromethane-MeOH=15:1). After stirred for 17 h, it was poured into water (300 mL) and stirred with petroleum ether (300 mL) at room temperature for 30 min. Petroleum ether layer was decanted. It was repeated once more with petroleum ether (300 mL). The solid was collected by suction filtration; washed with water (5×20 mL) and dried to give diethyl 2-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)pyrido[3,4-d]pyrimidin-6-ylamino)-2-oxoethylphosphonate (230) (2.56 g, 93%); mp 113-116° C.; 1H NMR δ [(CD3)2SO]: 10.82 (s, 1H), 10.25 (s, 1H), 8.99 (s, 1H), 8.84 (s, 1H), 8.63-8.56 (m, 214), 7.96 (d, J=2.6 Hz, 1H), 7.88 (td, J=7.7, 1.8 Hz, 1H), 7.70 (dd, J=8.9, 2.6 Hz, 1H), 7.59 (br d, J=7.8 Hz, 1H), 7.41-7.34 (m, 1H), 7.28 (d, J=9.0 Hz, 4.16-4.03 (m, 4H), 3.31 (d, partially obscured by water peak, 211), 1.26 (t, J=7.0 Hz, 6H). Anal. Calcd for C25H26ClN6O5P.1.2H2O: C, 51.90; H, 4.95; N, 14.53%. Found C, 51.85; H, 4.94; N, 14.52%.
Reaction SMILES: C([Si:3]1([C:16]2[CH:21]=CC=CC=2)[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)C.[F:22][C:23]1[CH:24]=[C:25]([Mg]Br)[CH:26]=[CH:27][C:28]=1[F:29]>>[CH2:16]([Si@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]2[CH:10]=[CH:11][C:12]([C:26]3[CH:25]=[CH:24][C:23]([F:22])=[C:28]([F:29])[CH:27]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)[CH3:21]
Reactant: Fc1ccc([Mg]Br)cc1F
Reactant: CC[Si]1(c2ccccc2)CCC(C2CCC(=O)CC2)CC1
Product: CC[Si@H]1CC[C@H](c2ccc(-c3ccc(F)c(F)c3)cc2)CC1

Procedure:
The general procedure of Example 12 was repeated using 30.2 g of 4-(4-ethyl-4-phenyl-4-silacyclohexyl)cyclohexanone and 3,4-difluorophenylmagnesium bromide, thereby obtaining the captioned compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])([CH3:3])[CH3:2].[NH2:14]C1C=CC(C#N)=C(C(F)(F)F)C=1.C(N(CC)CC)C>ClCCl>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:14])=[O:8])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccccc1C(=O)Cl
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccccc1C(N)=O

Procedure:
2-Isopropoxy-benzoyl chloride was condensed with 4-Amino-2-trifluromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-4-Cyano-3-trifluoromethyl-phenyl)-2-Isopropoxy-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[CH:7]([OH:9])[CH3:8].[Br:10]N1C(=O)CCC1=O.C1(C(OOC(=O)C2C=CC=CC=2)=O)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7](=[O:9])[CH3:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1scnc1C(C)O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1ncsc1CBr
Temperature: 25 °C
Yield: 39.9 %

Procedure:
To a solution of 1-(5-methyl-1,3-thiazol-4-yl)ethan-1-ol (1.0 g, 7.0 mmol) in anhydrous carbon tetrachloride (50 mL) was added recrystallized 1-bromopyrrolidine-2,5-dione (1.4 g, 7.7 mmol) and benzoyl benzenecarboperoxoate (170 mg, 0.7 mmol). The mixture was stirred at reflux for 5 hours. After cooling to room temperature, the solid material was removed by filtration. The filtrate was recovered and evaporated. The residue was dried in vacuo, affording 1-[5-(bromomethyl)-1,3-thiazol-4-yl]ethan-1-one (615 mg, 40%). The product was used for the next step without further purification.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([NH:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=O)=[CH:8][CH:7]=1)([O-:5])=[O:4].CO>C1COCC1>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:15][CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][CH2:23]2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=C(Cc1ccc([N+](=O)[O-])cc1)NCCN1CCN(c2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1ccc(CCNCCN2CCN(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a stirred solution of NaBH4 (0.449 g, 11.81 mmol) in 50 mL of dry THF at 0° C. under N2 was added dropwise 48% w/w BF3 ether complex (1.47 mL, 11.68 mmol). The cooling bath was removed and the solution was stirred for 1 h at room temperature. Into the above was added dropwise a solution of 2-(4-nitro-phenyl)-N-[2-(4-phenyl-piperazin-1-yl)-ethyl]-acetamide 26a (0.55 g, 1.49 mmol) dissolved in THF (5 mL). The reaction mixture was refluxed for 6 h. After the solution cooled to room temperature, methanol (5 mL) was added slowly. The solvent was removed under reduced pressure and 10% HCl/MeOH (25 mL) was added to the residue and the solution refluxed for 1 h. Solid NaHCO3 was added and methanol was removed in vacuo. The mixture was extracted with EtOAc. The combined organic phase was dried over Na2SO4 and evaporated to give the crude product which was purified by chromatography (EtOAc/MeOH=4/1) to give 27a: 0.385 g (73% yield) as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ 1.62 (1H, bs, NH), 2.50 (2H, t, J=5.6 Hz, CH2—CH2NH), 2.58 (4H, t, J=4.8 Hz, (CH2)2N), 2.76 (2H, t, J=5.6 Hz, CH2Ar), 2.90-2.96 (4H, m, (CH2)2NH), 3.14 (4H, t, J=4.8 Hz, (CH2)2NPh), 6.85 (1H, t, J=7.2, ArH), 6.90 (2H, d, J=9.2, ArH), 7.25 (2H, t, J=9.2, ArH), 7.37 (2H, d, J=8.8, ArH), 8.15 (2H, d, J=8, ArH).
Reaction SMILES: C([C:4]1[O:5][C:6]2[C:12]([Cl:13])=[CH:11][C:10]([F:14])=[C:9]([C:15]3[C:16](=[O:26])[N:17]([CH3:25])[C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[C:7]=2[CH:8]=1)(O)=O>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[Cl:13][C:12]1[C:6]2[O:5][CH:4]=[CH:8][C:7]=2[C:9]([C:15]2[C:16](=[O:26])[N:17]([CH3:25])[C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)=[C:10]([F:14])[CH:11]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3oc(C(=O)O)cc23)c1=O
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3occc23)c1=O
Temperature: 210 °C
Reaction time: 0.25 h
Yield: 70.4 %

Procedure:
0.29 g (0.74 mmol) of 3-(2-carboxy-7-chloro-5-fluorobenzofuran-4-yl)-1-methyl-6-trifluoromethyl-2-(1H)-pyridone was dissolved in 15 ml of quinoline, and 0.05 g (0.75 mmol) of copper powder was added thereto, followed by stirring at 210° C. for 15 minutes. Then, copper was removed by filtration, and the filtrate was poured into water and acidified by an addition of hydrochloric acid, and then extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.18 g (yield: 70%) of the desired product. Melting point: 178-179° C. 1H-NMR (300 MHz, CDCl3) δ value: 3.74(3H,s), 6.66(1H,d), 6.81(1H,d), 7.20(1H,d), 7.56(1H,d), 7.72(1H,d)ppm.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[CH3:20])[CH2:3]1.OC1C(O)C2C(=CC=CC=2)CC1C1CCN(C)C1>>[OH:1][CH:2]1[CH2:11][C:10]2[CH2:9][CH:8]=[CH:7][CH2:6][C:5]=2[CH:4]([CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[CH3:20])[CH2:3]1
Reactant: CN1CCCCC1CCC1CC(O)Cc2ccccc21
Agent: CN1CCC(C2Cc3ccccc3C(O)C2O)C1
Product: CN1CCCCC1CCC1CC(O)CC2=C1CC=CC2

Procedure:
Following the procedure of Example 6, part D, but substituting the 2-[2-(3-hydroxy-1,2,3,4-tetrahydronaphthalenyl)ethyl]-1-methylpiperidine for the 3-(3,4-dihydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1-methylpyrrolidine, the title E compound is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:7][C@@H:6]([CH2:8][C:9]#[N:10])[CH2:5][C@@H:4]([CH2:11][CH:12]=C)[O:3]1.[O:15]=[O+][O-]>ClCCl>[O:15]=[CH:12][CH2:11][C@H:4]1[O:3][C:2]([CH3:14])([CH3:1])[O:7][C@@H:6]([CH2:8][C:9]#[N:10])[CH2:5]1
Reactant: O=[O+][O-]
Reactant: C=CC[C@@H]1C[C@H](CC#N)OC(C)(C)O1
Solvent: ClCCl
Product: CC1(C)O[C@H](CC=O)C[C@H](CC#N)O1
Temperature: 25 °C

Procedure:
A solution of (±)-cis-2,2-dimethyl-6-(2-propenyl)-1,3-dioxane-4-acetonitrile, 3 g (15.36 mmol), in 100 mL of dichloromethane is cooled to -78° C. under nitrogen. Ozone (Welsbach generator, flow rate 0.1, voltage=90 V) is then passed through a fritted gas inlet tube into the solution until the blue color of ozone appears. The current is turned off, and oxygen bubbled through until the blue color is discharged. Triphenylphosphine, 4.2 g (16 mmol), is added and the colorless solution allowed to warm to room temperature. Flash chromatography provides, after concentration in vacuo, 2.5 g of pure (±)-cis-6-(2-oxoethyl)-2,2-dimethyl-1,3-dioxane-4-acetonitrile.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][OH:23].[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][O:23][CH2:22][CH2:21][N:20]([CH3:24])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCN(Cc1ccccc1)Cc1ccccc1
Reactant: CN(C)CCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN(C)CCOCCN(Cc1ccccc1)Cc1ccccc1

Procedure:
[2-(2-Dibenzylamino-ethoxy)-ethyl]-dimethyl-amine was prepared following General Procedure S starting from dibenzyl-(2-chloro-ethyl)-amine (640 mg), 2-dimethylamino-ethanol (325 mg), 50% (w/w) KOH solution (3 mL) and tetrabutylammonium bromide (95 mg) in dioxane (3 mL).
Reaction SMILES: C([C:5]1[CH:13]=[C:12]([NH:14][C:15](=[O:37])[CH:16]([N:18]2[CH:23]=[C:22]([C:24]#[N:25])[C:21]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[CH:33]3[CH2:35][CH2:34]3)=[CH:20][C:19]2=[O:36])[CH3:17])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:32][C:30]1[CH:29]=[CH:28][C:27]([CH:33]2[CH2:35][CH2:34]2)=[C:26]([C:21]2[C:22]([C:24]#[N:25])=[CH:23][N:18]([CH:16]([CH3:17])[C:15]([NH:14][C:12]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:13]=3)=[O:37])[C:19](=[O:36])[CH:20]=2)[CH:31]=1
Reactant: CC(C(=O)Nc1ccc(C(=O)O)c(C(C)(C)C)c1)n1cc(C#N)c(-c2cc(Cl)ccc2C2CC2)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(C#N)c(-c2cc(Cl)ccc2C2CC2)cc1=O

Procedure:
66 mg (0.13 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyclopropylphenyl)-5-cyano-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoic acid (racemate) (Example 18.3A) were hydrolysed with TFA according to General Method 2. Yield: 39 mg (68% of theory)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C@@H:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:5]([C:32]2[CH:33]=[CH:34][C:35](F)=[C:36]([CH:40]=2)C(N)=O)=[CH:4][CH:3]=1.NC1N=C(C(NC(=O)CC2C3C(=CC=C(F)C=3)NC=2)CC2C=C(F)C=C(F)C=2)C(Br)=CC=1.[S:74](C1C=C(B(O)O)C=CC=1)(=[O:77])(=[O:76])[NH2:75]>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]([NH:18][C:19](=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[NH:23][CH:22]=2)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:5]([C:32]2[CH:33]=[CH:34][CH:35]=[C:36]([S:74](=[O:77])(=[O:76])[NH2:75])[CH:40]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: NC(=O)c1cc(-c2ccc(N)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)ccc1F
Agent: Nc1ccc(Br)c(C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)n1
Product: Nc1ccc(-c2cccc(S(N)(=O)=O)c2)c(C(Cc2cc(F)cc(F)c2)NC(=O)Cc2c[nH]c3ccc(F)cc23)n1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 1H of Example 1 utilizing 1G and (3-sulfamoylphenyl)boronic acid. 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 8.03 (d, J=7.7 Hz, 1H), 7.96 (s, 2H), 7.91 (m, 1H), 7.57 (m, 3H), 7.24 (m, 1H), 6.92 (d, J=9.3 Hz, 2H), 6.70 (d, J=8.7 Hz, 1H), 6.54 (s, 1H), 6.20 (d, J=5.7 Hz, 2H), 5.54 (s, 2H), 5.33 (d, J=9.0 Hz, 1H), 3.63 (s, 2H), 2.99-2.85 (m, 2H). MS (m/z) 580.0 [M+H]+.
Reaction SMILES: [OH-].[Na+:2].C(O)C.[F:6][C:7]([F:18])([C:13]([O:15]CC)=[O:14])[C:8]([O:10]CC)=[O:9]>O>[F:6][C:7]([F:18])([C:13]([O-:15])=[O:14])[C:8]([O-:10])=[O:9].[Na+:2].[Na+:2]
Reactant: CCOC(=O)C(F)(F)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C([O-])C(F)(F)C(=O)[O-]
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
Sodium hydroxide (0.90 g, 0.022 mol) was dissolved in 5 mL water followed by dilution with 25 mL ethanol and the solution was heated to 60° C. Diethyl difluoromalonate (2 g, 0.01 mol) was then added to the stirred reaction mixture. A white precipitate formed immediately. The mixture was stirred for another 45 min while maintaining the temperature at 60° C. The fine white precipitate was collected and dried at 45° C. for 18 h. Yield 1.84 g (99%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[F:19][C@H:20]1[CH2:24][NH:23][C@H:22]([C:25]([NH2:27])=[O:26])[CH2:21]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:23]3[CH2:24][C@H:20]([F:19])[CH2:21][C@H:22]3[C:25]([NH2:27])=[O:26])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: NC(=O)[C@@H]1C[C@@H](F)CN1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: NC(=O)[C@@H]1C[C@@H](F)CN1C(=O)c1ccc(C2CC2)c(OCC2CC2)n1
Yield: 72.6 %

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 50 mg, 214 μmol) was reacted with (2S,4R)-4-fluoropyrrolidine-2-carboxamide hydrochloride (CAN 796884-06-5, 39.8 mg, 236 μmol) to obtain the title compound (54 mg, 73%) as white solid; LC-MS (UV peak area, ESI) 100%, 348.1727 [MH+].
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C@@:10]23[CH2:28][C@H:27]2[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22][N:21]([CH:29]2[CH2:31][CH2:30]2)[CH2:20][C@H:19]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:18](=[O:40])[N:17]2[C@@H:13]([CH2:14][C@@H:15]([O:41][Si](C(C)(C)C)(C)C)[CH2:16]2)[C:12](=[O:49])[NH:11]3)=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH:1]1([S:4]([NH:7][C:8]([C@@:10]23[CH2:28][C@H:27]2[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22][N:21]([CH:29]2[CH2:30][CH2:31]2)[CH2:20][C@H:19]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])[C:18](=[O:40])[N:17]2[C@@H:13]([CH2:14][C@@H:15]([OH:41])[CH2:16]2)[C:12](=[O:49])[NH:11]3)=[O:9])(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(C2CC2)CCCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1CN(C2CC2)CCC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1CN(C2CC2)CCC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CN(C2CC2)CCCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](O)CN2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of compound (1S,4R,6S,14S,18R)-[7-cis-4-Cyclopropanesulfonylaminocarbonyl-12-cyclopropyl-18-(tert-butyldimethylsilyloxy)-2,15-dioxo-3,12,16-triaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]carbamic acid, tert-butyl ester (250 mg, 0.35 mmol.) in 15 mL of THF was added tetrabutylammonium fluoride (129 mg, 0.46 mmol.). The mixture was stirred at rt for 18 h. THF was removed by rotary evaporation, and the residue was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and concentrated in vacuo to give the crude product. Purification by triturating with hexane provided 200 mg (94%) of (1S,4R,6S,14S,18R)-[7-cis-4-Cyclopropanesulfonylaminocarbonyl-12-cyclopropyl-18-hydroxy-2,15-dioxo-3,12,16-triaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]carbamic acid, tert-butyl ester as a white solid: LC-MS (retention time: 2.32 min), MS m/z 610 (M++1). (Phenomenex 10 μm C18 HPLC column: 3.0×50 mm length. Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B. Gradient time: 3 min. Hold time: 1 min. Flow rate: 4 mL/min. Detector Wavelength: 220 nM. Solvent A: 10% MeOH/90% H2O/0.1% TFA. Solvent B: 10% H2O/90% MeOH/0.1% TFA.) (Retention time: 2.32 min), MS m/z 610 (M++1).