Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][CH3:30])[C:26]([Cl:31])=[CH:25][N:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)Cl>[Cl:31][C:26]1[C:27]([NH:29][CH3:30])=[N:28][C:23]([NH:1][C:2]2[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)=[O:11])=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=2)=[N:24][CH:25]=1
Reactant: CNc1nc(Cl)ncc1Cl
Reactant: COc1cc(C(=O)N2CCOCC2)c(C(F)(F)F)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNc1nc(Nc2cc(C(F)(F)F)c(C(=O)N3CCOCC3)cc2OC)ncc1Cl
Temperature: 100 °C
Yield: 8 %

Procedure:
A mixture of (4-amino-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone (94 mg, 0.31 mmol), 2,5-dichloro-N-methylpyrimidin-4-amine (55 mg, 0.31 mmol) and para-toluene sulfonic acid (59 mg, 0.31 mmol) in dioxane (4 mL) was heated to 100° C. for 36 h. Saturated aqueous sodium bicarbonate solution (10 mL) and DCM (10 mL) were added and the organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-10% EtOAc in iso-hexane) gave (4-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-5-methoxy-2-(trifluoromethyl)phenyl)(morpholino)methanone (11 mg, 8%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=446 at 3.60 min. 1H NMR (400 MHz, CDCl3): δ 8.97 (s, 1H), 8.40 (br s, 1H), 7.90 (s, 1H), 6.76 (s, 1H), 5.59 (q, J=4.9 Hz, 1H), 3.96 (s, 3H), 3.95-3.87 (m, 1H), 3.82-3.69 (m, 3H), 3.62-3.56 (m, 2H), 3.26-3.20 (m, 2H), 3.13 (d, J=4.9 Hz, 3H).
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[CH3:10][O:11][C:12]1[C:13]([CH3:21])=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>C(Cl)Cl.O>[CH3:10][O:11][C:12]1[C:13]([CH3:21])=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH:7][NH:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:16]
Reactant: COc1cccc(C(=O)Cl)c1C
Reactant: CC(C)(C)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cccc(C(=O)NNC(C)(C)C)c1C
Temperature: 25 °C
Yield: 96 %

Procedure:
To a stirred suspension of tert-butylhydrazine hydrochloride (397 g, 3.27 mole) in methylene chloride (2 L) at 0° C., was added sodium hydroxide (50% aqueous, 260 g) diluted with water (400 mL). Following this, 3-methoxy-2-methylbenzoyl chloride (140 g, 0.78 mole) in methylene chloride (1 L) and sodium hydroxide (50% aqueous, 80 g) dilutect with water (400 mL) were added concurrently at -20° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and after additional 30 minutes, the organic layer was washed with water (4×500 mL), dried over magnesium sulfate and stripped to yield N-(3-methoxy-2-methylbenzoyl)-N'-tert-butylhydrazine (177 g). 1H-NMR (CDCl3) δppm 1.19 (s, 9H, t-Bu), 2.29 (s, 3H, CH3), 3.87 (s, 3H, OCH3), 6.90 (d, 1H, C-4 or 6 ), 6.95 (d, 1H, C-4 or C6) 7.19 (dd, 1H, C-5).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([N:11]2[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])=[CH:13][C:12]2=[O:28])[CH:5]=1.[Br:30]NC(=O)CCC(N)=O>C(#N)C>[Br:30][C:13]1[C:12](=[O:28])[N:11]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[Cl:10])[C:3]([O:2][CH3:1])=[O:29])[C:16]([CH3:17])=[CH:15][C:14]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27]
Reactant: COC(=O)c1ccc(Cl)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Reactant: NC(=O)CCC(=O)NBr
Solvent: CC#N
Product: COC(=O)c1ccc(Cl)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Yield: 66 %

Procedure:
methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-chlorobenzoate was prepared by reacting methyl-4-chloro-3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate (2.3 g, 5.47 mmol) with N-bromosuccinamide (0.97 g, 5.47 mmol) in acetonitrile (10 mL) at 0° C., using a similar procedure as described in step 3 of Example 465, to give 1.80 g (66.2%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.06-8.03 (m, 2H), 7.86 (d, J=9.70 Hz, 1H), 7.68 (q, J=7.62, 1H), 7.34 (dt, J=10.07, 2.46 Hz, 1H), 7.17 (dt,J=8.72, 2.90 Hz, 1H), 6.73 (s, 1H), 5.33 (s, 2H), 3.85 (s, 3H), 1.91 (s, 3H). ES-MS m/z 495.9757 (M−H calcd for C21H14BrClF2NO4, requires 495.9795).
Reaction SMILES: [I-:1].[Na+].[CH3:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:26])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22]Cl)=[C:16]([O:24][CH3:25])[CH:15]=2)[CH2:6][CH2:5]1>CC(CC)=O>[CH3:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:26])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][I:1])=[C:16]([O:24][CH3:25])[CH:15]=2)[CH2:6][CH2:5]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCI
Reaction time: 19 h

Procedure:
19.5 g of sodium iodide was added to a solution of 4.57 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138) in 300 ml of methylethylketone. The solution was stirred for 19 hours, while it was refluxed. After reaction, the reaction solution was washed three times with 200 ml of an aqueous sodium thiosulfate solution and once with an aqueous sodium chloride solution, and was dried over magnesium sulfate. Then, the solvent was removed in vacuo. The product obtained was recrystallized from methylene chloride/ether, yielding 4.86 g of N-(trans-4-methylcyclohexyl)-4-(2-iodoethoxy)-3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: C([O:8][N:9]1[CH:12]([CH2:13][O:14]CC2C=CC=CC=2)[CH:11]([N:22]2[CH:30]=[N:29][C:28]3[C:23]2=[N:24][CH:25]=[N:26][C:27]=3[NH:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:10]1=[O:40])C1C=CC=CC=1.[H][H]>CO.[Ni]>[OH:8][N:9]1[CH:12]([CH2:13][OH:14])[CH:11]([N:22]2[CH:30]=[N:29][C:28]3[C:23]2=[N:24][CH:25]=[N:26][C:27]=3[NH:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:10]1=[O:40]
Reactant: [H][H]
Reactant: O=C(Nc1ncnc2c1ncn2C1C(=O)N(OCc2ccccc2)C1COCc1ccccc1)c1ccccc1
Agent: [Ni]
Solvent: CO
Product: O=C(Nc1ncnc2c1ncn2C1C(=O)N(O)C1CO)c1ccccc1

Procedure:
1-N-Benzyloxy-3-(N-benzoyladenin-9-yl)-4-benzyloxymethyl-2-azetidinone (10 mmole) is taken up in methanol (50 ml) and hydrogenated using Raney nickel(5 g) and hydrogen at a pressure of 40 psi for 6 hours. The reaction mixture is filtered, the catalyst washed with methanol (20 ml) and the combined methanol fractions are concentrated to give the title compound asa solid.
Reaction SMILES: C[O:2][C:3](=[O:41])[C@H:4]([CH3:40])[NH:5][C:6](=[O:39])[C@@H:7]([CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)[NH:8][C:9](=[O:28])[C@H:10]([CH2:22][C:23]1[N:27]=[CH:26][NH:25][CH:24]=1)[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].CO.[OH-].[Na+]>CO.O>[CH2:15]([O:14][C:12]([NH:11][C@H:10]([C:9]([NH:8][C@@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:41])=[O:2])[CH3:40])=[O:39])[CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=[O:28])[CH2:22][C:23]1[N:27]=[CH:26][NH:25][CH:24]=1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H](NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 48 h

Procedure:
Under an argon atmosphere, the viscous oil containing tripeptide 20 (ca. 0.253 mol), was hydrolyzed in a solution of MeOH (1500 mL), H20 (500 mL) and NaOH (0.08 g/mL, 11.11 g, 0.278 mol). The reaction was allowed to react at room temperature (ca. 25° C.) while being monitored by HPLC. After two days, HPLC analysis indicated that hydrolysis was complete. The solution was concentrated to a residue in vacuo. Water (500 mL) was then added to the residue. The pH of the resulting solution was ca. 10. This aqueous solution was then extracted with EtOAc (2×500 mL). After this extraction the pH of the aqueous layer was ca. 9. All insoluble material in the aqueous layer was collected by vacuum filtration. The pH of the filtrate was then adjusted to ca. 5 with 2N HCl. This resulted in the precipitation of an oil which was isolated from the aqueous layer by decantation. The oil was taken up in a methanol-water solution and concentrated to a residue in vacuo (109.42 g, 0.200 mol, ca. 79% overall yield from dipeptide 26). This isolated material was consistent with 27 by 1H NMR FDMS=547, M+1.
Reaction SMILES: [CH2:1]([N:8]1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=3)[C:33]2=[O:48])[S:27][C:28]=1[C:29]([OH:31])=O.C(N)C1C=CC=CC=1>>[CH2:1]([NH:8][C:29]([C:28]1[S:27][C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:40][CH:39]=3)[C:33]2=[O:48])=[N:25][C:24]=1[CH3:23])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Solvent: NCc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 44 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a white powder in 44% yield: mp 127-128° C.; 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J=8.1 Hz, 2H), 7.41-7.26 (m, 7H), 5.90 (t, J=5.7 Hz, 1H), 4.55 (d, J=5.7 Hz, 2H), 4.51 (s, 2H), 4.09 (t, J=8.1 Hz, 2H), 3.46 (t, J=8.1 Hz, 2H), 2.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.2, 157.2, 155.4, 152.8, 139.6, 137.9, 130.2, 128.8, 128.5, 127.8, 127.6, 125.8, 122.1, 117.5, 47.6, 44.0, 42.1, 41.9, 17.1; MS (ES+) m/z 475.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C([O:12][B:13](OC(C)C)[O:14]C(C)C)(C)C>C1COCC1>[Cl:8][C:4]1[N:3]=[C:2]([B:13]([OH:14])[OH:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Clc1cccc(Br)n1
Solvent: C1CCOC1
Product: OB(O)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73.4 %

Procedure:
A solution of n-Buli (2.5 M, 24.91 mL, 62.3 mmol) in freshly distilled THF (100 mL) was cooled to −78° C., followed by the addition of a solution of 2-bromo-6-chloropyridine (10.0 g, 51.96 mmol) in 10 mL THF. The resulting dark colored mixture was stirred at this temperature for 45 min. A solution of triisopropylborate (11.72 g, 62.3 mmol) was added and the mixture was stirred at −78° C. for 2 h, and warmed to RT and stirred for an additional 1 h. The mixture was quenched by slow addition of 3% aq NaOH solution (400 mL). The resulting aqueous layer was collected and acidified down to pH 5-6 by dropwise addition of 3N HCl (180 mL), keeping the internal temperature below 5° C. The mixture was extracted with EtOAc and the combined organic layers were dried, filtered and concentrated. The residue was recrystallized from Et2O to give 6-chloropyridin-2-ylboronic acid (6 g, 73.6%) as a white solid. MS (ESI, pos. ion) m/z: 158 (M+1); 1H NMR (DMSO-d6, 300 MHz): δ ppm 8.51 (brs, 1H), 7.84 (m, 2H), 7.51-7.48 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:16])[C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18]>>[CH3:16][C:4]1[C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=[C:2]([C:18]#[C:17][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:3]=1
Reactant: Cc1cc(Br)cnc1NCCN1CCCC1
Reactant: C#C[Si](C)(C)C
Product: Cc1cc(C#C[Si](C)(C)C)cnc1NCCN1CCCC1
Temperature: 50 °C

Procedure:
Prepared analogously to Example 15c from 500 mg (1.76 mmol) (5-bromo-3-methyl-pyridin-2-yl)-(2-pyrrolidin-1-yl-ethyl)-amine and 0.29 mL (2.11 mmol) ethynyl-trimethyl-silane, while the reaction mixture is heated to 50° C. for 12 h.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14](=[O:23])[CH2:15][C@@H:16]([CH2:20][CH2:21][CH3:22])[C:17](O)=[O:18])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:24]([O:28][C:29](=[O:37])[CH2:30][CH:31]([NH2:36])[CH:32]([OH:35])[CH2:33][F:34])([CH3:27])([CH3:26])[CH3:25].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1>[C:24]([O:28][C:29](=[O:37])[CH2:30][CH:31]([NH:36][C:17](=[O:18])[CH:16]([CH2:15][C:14]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:23])[CH2:20][CH2:21][CH3:22])[CH:32]([OH:35])[CH2:33][F:34])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)CC(N)C(O)CF
Reactant: CCC[C@H](CC(=O)n1c2ccccc2c2ccccc21)C(=O)O
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCCC(CC(=O)n1c2ccccc2c2ccccc21)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Temperature: 25 °C
Yield: 53 %

Procedure:
A stirred mixture of (2R)-2-(2-carbazol-9-yl-2-oxo-ethyl)-pentanoic acid (2.94 g, 9.50 mmol), 3-amino-5-fluoro-4-hydroxy-pentanoic acid tert-butyl ester (2.07 g, 9.99 mmol), HOBT (1.41 g, 10.43 mmol), DMAP (1.34 g, 10.97 mmol) and anhydrous THF (40 ml) was cooled to 0° C. before EDC (2.00 g, 10.43 mmol) was added. The mixture was allowed to warm to room temperature during 16 h then concentrated under reduced pressure. The residue purified by flash chromatography (33% EtOAc in 40/60 hexanes) to give the sub-title compound (2.51 g, 53%) as a foam: 1H NMR (400 MHz, CDCl3) δ 0.90-1.03 (3H, m), 1.20-1.90 (13H, m), 2.50-3.00 (3H, m), 3.12-3.26 (1H, m), 3.59-3.80 (2H, m), 4.00-4.68 (3H, m), 6.53-6.89 (1H, m), 7.30-7.52 (4H, m), 7.95-8.05 (2H, m), 8.15-8.26 (2H, m); 19F NMR (376 MHz, CDCl3) −229.10, −229.34, −230.95, −231.09.
Reaction SMILES: [Na+].[S:2]1[C:6]2[CH:7]=[C:8]([S:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.N1C=CC=CC=1.Br[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[CH2:25]([O:24][C:22](=[O:23])[C:21]([S:11]([C:8]1[CH:9]=[CH:10][C:5]2[N:4]=[CH:3][S:2][C:6]=2[CH:7]=1)(=[O:13])=[O:12])([CH3:28])[CH3:27])[CH3:26]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=S([O-])c1ccc2ncsc2c1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)S(=O)(=O)c1ccc2ncsc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
The crude 1,3-benzothiazol-6-sulfinic acid sodium salt (1.1 g, 4.97 mmol) is suspended in DMF (15 mL). Pyridine (0.33 mL) and ethyl α-bromoisobutyrate (0.61 mL) are added. The reaction is stirred at 50° C. under nitrogen for 2 h. The reaction mixture is cooled to room temperature and the solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate (20 mL) and washed with 2M aqueous HCl solution (20 mL). The acidic aqueous layer is back-extracted with ethyl acetate (2×20 mL). The combined organic extracts are washed with brine (20 mL) and dried over Na2SO4. Filtration, concentration under reduced pressure, followed by column chromatography of the residue (silica, eluent DCM, 30-40% ethyl acetate) afforded 0.85 g of 2-(benzothiazole-6-sulfonyl)-2-methyl-propionic acid ethyl ester. Yield: 66%, ES-MS: m/z 314 [M+H]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.19 (3 H, t, J=7.16 Hz), 1.67 (6 H, s), 4.15 (2 H, q, J=7.13 Hz), 7.99 (1 H, dd, J=8.68, 1.79 Hz), 8.28 (1H, d, J=8.68 Hz), 8.54 (1 H, d, J=1.48 Hz), 9.26 (1 H, s);
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].C(Cl)(=O)C([Cl:15])=O>CN(C)C=O.ClCCl>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:15])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(CBr)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(CBr)c1
Reaction time: 48 h

Procedure:
A solution of 12 g of m-bromomethylbenzoic acid 10.62 g of oxalyl chloride, 100 ml of dichloromethane and 5 drops of dimethylformamide was allowed to stand 48 hours and then evaporated. Hexane and ether were added, the mixture evaporated and the residue distilled on a Kugelroher, giving 12.5 g of m-bromomethylbenzoyl chloride as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:19])[CH2:15][C:16]([NH2:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.B#B.Cl.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:19])[CH2:15][CH2:16][NH2:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(CC(N)=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: B#B
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(CCN)c1ccc(-c2ccc(Cl)cc2)cc1
Reaction time: 2 h

Procedure:
A solution of 27.5 g of 3-(4'-chloro-4-biphenylyl)butyramide [m.p. 185°-187°; obtainable from p-chlorobiphenyl via 4-acetyl-4'-chlorobiphenyl (m.p. 100°-103°), 3-(4'-chloro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester (m.p. 71°-74°) and 3-(4'-chloro-4-biphenylyl)-butyric acid (m.p. 154°-156°)] in 300 ml of THF is added dropwise, while stirring, to a solution of 4.6 g of diborane in 50 ml of THF, and the mixture is boiled for two hours, cooled and treated with 25% hydrochloric acid. It is then poured into water and worked up with sodium hydroxide solution and ethyl acetate to give 3-(4'-chloro-4-biphenylyl)-butylamine. Hydrochloride, m.p. 256°-259°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([OH:26])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:48]3[CH2:53][CH2:52][NH:51][C:50](=[O:54])[CH2:49]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:16]=[C:15]([C:24]([N:48]3[CH2:53][CH2:52][NH:51][C:50](=[O:54])[CH2:49]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:11])([F:10])[F:12])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3cccnc3)n2)CCN1

Procedure:
75 mg (0.16 mmol) of the compound of Example 39A is reacted analogously to the synthesis of the compound of Example 4 with 17 mg (0.17 mmol) of 2-oxopiperazine. 21 mg (25% of theory) of the title compound is obtained as a fine precipitate as well as 37 mg (46% of theory) of the title compound after the filtrate is purified by means of preparative HPLC (mobile solvent: acetonitrile/water gradient).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:17]=[CH:16][C:7]([C:8]([O:10][CH2:11][C:12]([NH2:15])([CH3:14])[CH3:13])=[O:9])=[CH:6][CH:5]=1.C([O-])([O-])=O.[Na+].[Na+].[C:24](Cl)(Cl)=[S:25]>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][C:12]([N:15]=[C:24]=[S:25])([CH3:14])[CH3:13])=[O:9])=[CH:16][CH:17]=1
Reactant: S=C(Cl)Cl
Reactant: COc1ccc(C(=O)OCC(C)(C)N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(=O)OCC(C)(C)N=C=S)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
A biphasic mixture of 2-amino-2-methylpropyl 4-methoxybenzoate hydrochloride (0.24 g, 0.92 mmol), DCM (9.2 mL) and saturated aqueous Na2CO3 (18.5 mL) was cooled to 0° C. Thiophosgene (0.35 mL, 4.62 mmol) was added and the mixture was stirred for 15 min. The organic layer was separated, dried with Na2SO4, filtered and concentrated to give the title compound (0.24 g, 99%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.17-7.92 (m, 2 H), 7.06-6.81 (m, 2 H), 4.27 (s, 2 H), 3.89 (s, 3 H), 1.50 (s, 6 H).
Reaction SMILES: C([BH3-])#N.[Na+].[F:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2>C(O)(=O)C>[F:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH2:11][CH2:10][CH2:9]2
Reactant: Fc1ccc2ncccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1ccc2c(c1)CCCN2
Reaction time: 12 h
Yield: 71 %

Procedure:
Sodium cyanoborohydride (6.45 g, 103 mmol) was added gradually to the solution of 6-fluoro quinoline (5 g, 34 mmol) in glacial acetic acid (100 ml) at ambient temperature. After stirring for 12 h the reaction mixture was quenched in water and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water, brine and dried over sodium sulfate, filtered and evaporated in vacuo, the residue was purified by a silica gel column with 1% to 5% ethyl acetate in petroleum ether to afford 6-fluoro-1,2,3,4-tetrahydroquinoline as a light yellow liquid (3.65 g, 71.6%).
Reaction SMILES: [CH2:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])[CH2:2][CH3:3].CC(C)([O-])C.[K+].Br[C:19]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]>N1C=CC=CC=1.[Cu]I>[CH3:24][O:23][C:21](=[O:22])[C:20]1[CH:19]=[CH:28][C:27]([F:29])=[CH:26][C:25]=1[O:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:4]=1[CH2:1][CH2:2][CH3:3]
Reactant: COC(=O)c1ccc(F)cc1Br
Reactant: CCCc1c(O)cccc1O
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CCCc1c(O)cccc1Oc1cc(F)ccc1C(=O)OC
Temperature: 25 °C
Yield: 14.6 %

Procedure:
To a solution of 2-propylresorcinol (10.0 g, 65.7 mmol) in pyridine (120 mL) was added potassium tert-butoxide (7.00 g, 62.5 mmol) at room temperature with stirring. To this was added a mixture of methyl 2-bromo-4-fluorobenzoate (7.60 g, 32.6 mmol) and copper(I) iodide (12.5 g, 65.7 mmol) in pyridine (120 mL). The resulting mixture was gently refluxed for 4 hours. The reaction was cooled to room temperature and stirred for 18 hours. The mixture was concentrated in vacuo and the resulting material dissolved in ethyl ether. The solution was washed once with 5N aqueous hydrochloric acid. The aqueous layer was extracted once with fresh ethyl ether and the combined organic layers were washed twice with 5N aqueous ammonium hydroxide. The organic layer was washed once with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography of the resulting residue provided 1.45 g (15%) of the desired intermediate product as a light tan solid: mp 92-94° C.; NMR (CDCl3) 7.95 (m, 1H), 7.04 (t, J=9.5 Hz, 1H), 6.79 (t, J=9 Hz, 1H), 6.65 (d, J=9.5 Hz, 1H), 6.50 (m, 2H), 5.25 (bs, 1H, —OH), 3.88 (s, 3H), 2.60 (t, J=8.7 Hz, 2H), 1.55 (hextet, J=7.8 Hz, 2H), 0.92 (t, J=7.8 Hz, 3H); MS-FD m/e 305 (p+1, 40), 304 (p, 100); IR.