Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([C:18]([N:20]([CH3:22])[CH3:21])=O)[C:13](=O)[NH:14]2)=[CH:9][CH:8]=1.Cl>O>[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([CH2:18][N:20]([CH3:22])[CH3:21])[CH2:13][NH:14]2)=[CH:9][CH:8]=1
Reactant: CN(C)C(=O)C1Cc2ccc(Cl)cc2NC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CC1CNc2cc(Cl)ccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
1M Borane/THF complex (80 ml) was added to a THF (180 ml) suspension of 7-chloro-N,N-dimethyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxamide (5.055 g). The reaction mixture was heated under ref lux and left standing for cooling. The reaction mixture was ice-cooled, to which was added water (5 ml) and 6N hydrochloric acid (50 ml). The mixture was stirred at room temperature for one hour, then concentrated. A methanol solution (100 ml) of the residue was heated under reflux for 75 minutes and then concentrated. 3N Aqueous sodium hydroxide solution was added to the residue to make basic, which was extracted with ethyl acetate. The residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/4). The obtained crude crystals were washed with hexane to give the entitled compound (3.991 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[NH:20][C@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C.Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[C@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of methyl (5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinate (D33, 2.5 g, 7.6 mmol), and diisopropylethyl amine (2 ml, 11.4 mmol) in dry DCM (25 ml) at 0° C. was added dropwise benzyl chloroformate (1.3 ml, 9.1 mmol) and the mixture was stirred for 1 h from 0° C. to r.t. The mixture was washed with a 20% solution of citric acid and after with brine. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel using cyclohexane and ethyl acetate (85:15) to afford the title compound (3.4 g, 97%) as a white solid; Rt (HPLC) 6.56 min; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.42-7.60 (m, 3H); 7.29-7.42 (m, 3H); 7.15-7.25 (m, 3H); 7.06-7.15 (m, 1H); 6.86-7.03 (m, 3H); 5.10 and 5.15 (s, s, 2H); 4.84-5.04 (m, 3H); 4.48 and 4.55 (m, m, 1H); 3.69 and 3.84 (s, s, 3H); 2.27-2.39 (m, 1H); 2.16-2.27 (m, 1H); 2.03-2.16 (m, 1H); 1.91-2.03 (m, 1H).
Reaction SMILES: [I:1]I.C([Sn](CCCC)(CCCC)[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][C:13]([C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=1)=[CH:12][C:11]2=[O:27])CCC.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[I:1][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][C:13]([C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=1)=[CH:12][C:11]2=[O:27]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2oc(-c3ccc(N(C)C)cc3)cc(=O)c2c1
Reactant: II
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN(C)c1ccc(-c2cc(=O)c3cc(I)ccc3o2)cc1

Procedure:
A chloroform solution of iodine (1 ml, 1 M) was added to a chloroform solution (5 ml) that contained compound 9 (30 mg, 0.054 mmol) at room temperature. The obtained mixture was reacted at room temperature for 30 minutes, and a saturated sodium bisulfite aqueous solution (5 ml) was then added thereto, so as to terminate the reaction. The chloroform layer was separated, and it was then dried over sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure, and the residue was then subjected to silica gel column chromatography using ethyl acetate/hexane (1/9) as an elution solvent, so as to obtain a product of interest, 6-iodo-4′-dimethylaminoflavone (compound 11). Yield: 10 mg (yield constant: 47.3%) 1H NMR (300 MHz, CDCl3) δ8.54 (s, 1H), 7.92 (d, J=9.0 Hz, 1H), 7.81 (d, J=9.0 Hz, 2H), 7.29 (d, J=9.0 Hz, 1H), 6.71-6.80 (m, 3H), 3.09 (s, 6H). MS m/z 392 (MH+).
Reaction SMILES: F[C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[F:12][CH:13]([F:16])[CH2:14][OH:15]>>[F:12][CH:13]([F:16])[CH2:14][O:15][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: OCC(F)F
Reactant: Cc1cc(C(=O)O)cnc1F
Product: Cc1cc(C(=O)O)cnc1OCC(F)F
Yield: 73 %

Procedure:
The title compound is prepared in 73% yield (1.02 g, an off-white solid) from 6-fluoro-5-methylnicotinic acid (1.00 g, 6.45 mmol) and 2,2-difluoroethanol (1.06 g, 12.9 mmol) by the similar manner in Step-1 of Amine-1.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[CH3:12][CH:13]([C:18]([O:20][CH3:21])=[O:19])[C:14]([O:16][CH3:17])=[O:15]>C1(C)C=CC=CC=1>[CH3:17][O:16][C:14]([C:13]([CH3:12])([CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][N+:1]([O-:3])=[O:2])[C:18]([O:20][CH3:21])=[O:19])=[O:15]
Reactant: COC(=O)C(C)C(=O)OC
Reactant: O=[N+]([O-])/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C(=O)OC)C(C[N+](=O)[O-])c1ccccc1
Temperature: -20 °C
Reaction time: 48 h

Procedure:
[(S,S)-N-(pentamethylbenzenesulfonyl)-1,2-diphenyl-ethylenediamine](hexamethylbenzene)ruthenium (13.7 mg, 0.02 mmol, S/C=50), trans-β-nitrostyrene (149 mg, 1.0 mmol), dimethyl methylmalonate (160 μl, 1.2 mmol) and toluene (1 ml) were added into Schlenk (20 ml) under an argon atmosphere, and stirred at −20° C. for 48 hours. The reaction solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2), showing that the isolation yield of the product was 94%. The optical purity was measured by HPLC (CHIRALPACK AD manufactured by Daicel Co., Ltd., hexane:2-propanol=95:5, flow rate 0.5 m/min, detection by 210 nm), resulting to 97% ee.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[CH:4][C:3]=1[CH:17]([CH:27]([CH3:29])[CH3:28])[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].CI.[CH3:32][Si]([N-][Si](C)(C)C)(C)C.[Na+]>>[F:1][C:2]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:15])([CH3:16])[O:9]2)[CH:5]=[CH:4][C:3]=1[CH:17]([CH:27]([CH3:29])[CH3:28])[CH2:18][N:19]([CH3:32])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)C(CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Agent: [Na+]
Solvent: CI
Product: CC(C)C(CN(C)C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Yield: 96.4 %

Procedure:
Following the procedure described for Example 647, tert-butyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylbutylcarbamate (650 mg, 1.6 mmol) was reacted with methyl iodide (1M solution in toluene, 3.2 mL, 3.2 mmol) and NaHMDS (1 M solution, 4.8 mL, 4.8 mmol) to afford the desired product (650 mg, 94%) as viscous mass. ESI MS m/z 421 [C23H38FBNO4+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]1=[O:14].CCN(C(C)C)C(C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]([CH2:12][O:13][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:8][C:7]1=[O:14]
Reactant: O=C1C=C(CO)CCN1Cc1ccc(F)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCC1=CC(=O)N(Cc2ccc(F)c(Cl)c2)CC1
Reaction time: 1 h

Procedure:
A solution of 1-(3-chloro-4-fluorobenzyl)-4-hydroxymethyl-5,6-dihydropyridin-2(1H)-one (3.1 g, 11 mmol) from the previous step and DIEA (2.8 mL, 16 mmol) in CH2Cl2 (50 mL) was cooled to 0° C. with stirring. Methanesulfonyl chloride (1.4 g, 12 mmol) was added and the mixture was stirred at 0° C. for 30 min and then at ambient temperature for 1 hour. The reaction mixture was diluted with CH2Cl2 (75 mL) and extracted with water (2×30 mL). The CH2Cl2 layer was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give the title compound as a gum. 1H NMR (400 MHz, CDCl3) δ 7.31 (dd, J=6.9, 2.9 Hz, 1H), 7.1-7.2 (m, 2H), 4.64 (d, J=15 Hz, 1H), 4.44 (d, J=15 Hz, 1H), 4.13 (ABX, J=6, 15 Hz, 2H), 3.28 (m, 2H), 3.04 (s, 3H), 2.64 (m, 1H), 2.34 (m, 1H), 2.23 (dd, J=6, 16 Hz, 1H), 2.02 (m, 1H), 1.61 (m, 1H); HPLC RT=2.99 min (Method A); ES MS M+1=350.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[CH:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:26])[CH3:25])[CH2:20][CH2:19]1)=[O:4].[OH-].[Na+].Cl>C1COCC1>[C:24]([N:21]1[CH2:22][CH2:23][CH:18]([C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:8]=3[S:9][C:5]=2[C:3]([OH:4])=[O:2])[CH2:19][CH2:20]1)(=[O:26])[CH3:25]
Reactant: COC(=O)c1sc2c(C(F)(F)F)cccc2c1C1CCN(C(C)=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)N1CCC(c2c(C(=O)O)sc3c(C(F)(F)F)cccc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.9 %

Procedure:
To a solution of 3-(1-acetyl-piperidin-4-yl)-7-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid methyl ester (4.10 g, 10.6 mmol) in THF (25 mL) was added 0.5 N aqueous sodium hydroxide (23.4 mL, 11.7 mmol) and the reaction stirred at room temperature. After 18 h, the reaction was acidified with 1 N HCl (200 mL) and the mixture extracted with DCM (2×100 mL). The organics were washed with water (100 mL), dried over magnesium sulfate, filtered, and concentrated to give 4.13 g of the desired product as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([O:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=2)[CH:3]=1.[BH4-].[Na+].B(F)(F)F.CCOCC>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([O:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=2)[CH:3]=1
Reactant: COc1cc(OC)cc(Oc2cc(Br)ccc2C(=O)O)c1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(OC)cc(Oc2cc(Br)ccc2CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a solution of 75.4 g (F.W. 353.168, 213 mmol) of 4-bromo-2-(3,5-dimethoxyphenoxy)benzoic acid (22) in 300 mL of tetrahydrofuran was added 8.9 g (F.W. 37.83, 235 mmol) of sodium borohydride portionwise at room temperature and then, 31 mL (F.W. 141.93, d=1.154, 252 mmol) of boron trifluoride diethyl etherate was added thereto dropwise. The resulting solution was stirred at room temperature for one hour. To this reaction solution was added 200 mL of ice water slowly. The resulting solution was extracted with ethyl acetate and the extract was washed with a saturated sodium chloride aqueous solution three times. After drying with anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The residue was recrystallized from benzene-diisopropyl ether to obtain 46.6 g (64%) of alcohol (23). (TLC; ethyl acetate:hexane=1:4).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[C:8]([Cl:13])=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:5].S(=O)(=O)(O)O>O.C(O)(=O)C>[Cl:13][C:8]1[C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=2[F:1])=[C:12]([C:4](=[O:5])[CH2:3][CH2:2][CH3:17])[CH:11]=[CH:10][N:9]=1
Reactant: O=C(Nc1cccnc1Cl)c1ccccc1F
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCCC(=O)c1ccnc(Cl)c1NC(=O)c1ccccc1F
Yield: 25 %

Procedure:
Using the procedure described in Examples 1 and 2, but replacing 2-phenyloxazolo[4,5-b]pyridine by 3-(2-fluorobenzoylamino)-2-chloropyridine and using 1.5 ml of concentrated sulfuric acid in 7.5 ml of water and 25 ml of acetic acid, and after the separation of 2-chloro-3-(2-fluorobenzoylamino)-6-butyrylpyridine, the expected product is obtained.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]5)[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: O=S1(=O)CCN(C2CNC2)CC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCS(=O)(=O)CC4)C3)n(C)c2n1
Reaction time: 18 h
Yield: 72.6 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (1.2 g, 3.07 mmol), 4-azetidin-3-ylthiomorpholine-1,1-dioxide (640 mg, 3.37 mmol) and 4 Å powdered molecular sieves (2.5 g) in DCE (65 mL) was stirred at room temperature for 6.5 h before the addition of sodium triacetoxyborohydride (1.3 g, 6.13 mmol). The reaction mixture was stirred for 18 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%). A mixture of the resulting yellow powder and 3-mercaptopropyl ethyl sulphide silica (250 mg) was stirred in a mixture of EtOH and DCM at 50° C. for 3 h. The mixture was filtered and concentrated in vacuo. The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with EtOH and the product eluted with 2M NH3/EtOH. The resulting oil was triturated with Et2O and dried in vacuo at 60° C. affording 354 as a pale yellow solid (1.26 g, 73%). LCMS (Method I): RT 2.43 min [M+H]+ 566.3. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.97 (m, 1 H); 7.77-7.73 (m, 1 H); 7.29-7.22 (m, 2 H); 4.34 (m, 4 H); 3.89-3.80 (m, 9 H); 3.59 (m, 2 H); 3.39-3.23 (m, 3 H); 3.12-3.04 (m, 6 H); 2.85 (m, 4 H) and 1.44 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:10][C@H:11]([C:15]([NH2:17])=[O:16])[CH2:12][CH2:13][CH3:14].CCN(CC)CC>>[CH:1](=[N:17][C:15](=[O:16])[C@H:11]([CH2:12][CH2:13][CH3:14])[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CCC[C@H](N)C(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCC[C@H](N)C(=O)N=Cc1ccccc1
Temperature: 23 °C
Reaction time: 1.17 h
Yield: 95.9 %

Procedure:
Fresh benzaldehyde (4.02 g, 37.9 mmol) was added to a slurry of 4.0 g L-norvalinamide-HCl (XII) (26.2 mmol) in 70 mL 1-PrOH, followed by 4.08 mL Et3N (29.3 mmol). The mixture, which became clear after stirring at 23° C. for 70 minutes, was then evaporated to 15 mL, and 175 mL Et2O added. After filtration, the precipitated salts were washed with additional Et2O, solvent evaporated from the combined filtrate, and residual benzaldehyde removed under high vacuum to give 5.13 g N-benzylidene-L-norvalinamide (XIII) as a light yellow solid (UV λmax =249 nm in MeOH). The purity of this material was determined by normal phase HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[C:14](I)[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[O:19])=[N:6][CH:7]=1.[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[C:14]([C:37]3[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=3)[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[O:19])=[N:6][CH:7]=1
Reactant: CC(C)N1CCC(C(=O)Nc2ccc(I)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CC(C)N1CCC(C(=O)Nc2ccc(-c3ccncc3)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 8 h
Yield: 10 %

Procedure:
To a stirring solution of N-(5-chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide (0.52 g, 0.98 mmol), dichlorobis(triphenylphosphine)-palladium(II) (34 mg, 0.05 mmol), and lithium chloride (0.15 g, 3.56 mmol) in 1,4-dioxane (5 mL) was added 4-(tributylstannyl)pyridine (1.16 g, 3.14 mmol) and dioxane (5 mL). The reaction mixture was heated to reflux, stirred overnight, and then filtered through diatomaceous earth. The filtrate was partitioned between 3:1 chloroform:-isopropanol and saturated aqueous sodium bicarbonate, and the layers separated. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography over silica gel, eluting with a step gradient of 10-25% 2 M ammonia/methanol solution in dichloromethane. The chromatography product was recrystallized from methanol and ethyl acetate to give 47 mg (10%) of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:20])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCCCC2)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Cl)cc(N(C)C2CCCCC2)c1C
Temperature: 80 °C
Yield: 55.2 %

Procedure:
To a stirred solution of methyl 5-chloro-3-(cyclohexylamino)-2-methylbenzoate (1.4 g, 0.0049 mole) in acetonitrile (10 mL), cesium carbonate (3.2 g, 0.0099 mole) and methyl iodide (3.5 g, 0.0024 mole) were added; resulting reaction mass was heated at 80° C. for 13 h. On completion, reaction mass was cooled to room temperature and filtered, residue was washed with ethyl acetate and filtrate was concentrated and then purified by column chromatography to afford desired compound (800 mg, 55%).
Reaction SMILES: CC([CH:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[N:20]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[C:23]([C:33]([F:36])([F:35])[F:34])[CH:22]=4)[O:18][N:17]=3)=[CH:15][C:10]=2[CH2:9][CH2:8][N:7](C([O-])=O)[CH2:6]1)(C)C.[ClH:40]>O1CCOCC1>[ClH:40].[F:36][C:33]([F:34])([F:35])[C:23]1[CH:22]=[C:21]([C:19]2[O:18][N:17]=[C:16]([C:14]3[CH:13]=[CH:12][C:11]4[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][C:10]=4[CH:15]=3)[N:20]=2)[CH:26]=[CH:25][C:24]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)C1CN(C(=O)[O-])CCc2cc(-c3noc(-c4ccc(-c5ccccc5)c(C(F)(F)F)c4)n3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)c1cc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)ccc1-c1ccccc1
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl-7-{5-[2-(trifluoromethyl)-4-biphenylyl]-1,2,4-oxadiazol-3-yl}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 45) (440 mg, 0.82 mmol) was dissolved in 4M HCl in dioxane (3 ml) and the solution stirred for 2 h. The title compound was filtered off as a white solid (376 mg, 0.82 mmol). δH (d6DMSO, 400 MHz): 9.27 (2H, brs), 8.53 (1H, d), 8.51 (1H, dd), 8.01 (1H, d), 7.97 (1H, dd), 7.74 (1H, d), 7.54-7.50 (3H, m), 7.47 (1H, d), 7.43-7.39 (2H, m), 3.28-3.20 (8H, m). MS (ES): C25H20F3N3O requires 435; found 436 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][N:12]=2)[CH:4]=1)[CH3:2].[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([NH:24][C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[N:12][CH:13]=1)=[O:19])[CH2:21][CH2:22][CH3:23]
Reactant: CCc1cc(-c2ccc(C(=O)O)cn2)c(C)[nH]c1=O
Reactant: CCCCN
Product: CCCCNC(=O)c1ccc(-c2cc(CC)c(=O)[nH]c2C)nc1

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-5-carboxylic acid and n-butyl amine to afford the title compound. MS: m/e=314 (M+H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[N:7][C:6]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:2]C.[CH3:19][O:20]C(C1C=NC(Cl)=C(Br)N=1)=O.N1CCCC1.[OH-].[K+]>COCCO>[CH3:19][O:20][CH2:2][CH2:1][O:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[N:7][C:6]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1cnc(Cl)c(Br)n1
Reactant: CCCOc1nc(C(=O)O)cnc1N1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCNC1
Solvent: COCCO
Product: COCCOc1nc(C(=O)O)cnc1N1CCCC1
Yield: 17 %

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid (example 10, step c), the title compound was synthesized from 6-bromo-5-chloro-pyrazine-2-carboxylic acid methyl ester, 2-methoxy-ethanol (commercially available), pyrrolidine (commercially available) and subsequent saponification with KOH in 17% yield. m/z (ES+): 268.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of commercially available 4-chloro-3-(trifluoromethyl)aniline (15.0 g, 76.7 mmol) in anhydrous THF (200 mL) cooled to 0-5° C. was added triethylamine (11.7 mL, 84.4 mmol) followed by pivaloyl chloride (10.4 mL, 84.4 mmol) over 30 min. The ice bath was removed and the mixture stirred at rt for 1 h. The mixture was diluted with ether and filtered. The filtrate was washed with water (2×) and brine, dried over MgSO4, filtered and concentrated. The residue was triturated with hexanes and the solid was filtered and dried in vacuo to afford compound 841A (20.4 g, 95%). MS (ES): m/z=280 [M+1]+.