Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[NH2:24][C:25]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[NH2:24][C:25]1[N:26]=[CH:27][C:28]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:29][C:30]=1[C:31]([F:34])([F:32])[F:33]
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(N)c(C(F)(F)F)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 2-amino-3-(trifluoromethyl)pyridine-5-boronic acid pinacol ester (stage 25.1.1, 37 mg, 0.128 mmol) to give the title compound as a pinkish solid. (HPLC: tR 2.40 min (Method A); M+H=454 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.93 (s, 1H), 8.43-8.36 (m, 1H), 8.16-8.11 (m, 1H), 8.09-8.02 (m, 1H), 7.97-7.90 (m, 1H), 7.76-7.70 (m, 1H), 7.45-7.39 (m, 1H), 6.76 (s, br, 2H), 3.88 (s, 3H), 3.56 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:15].N#N.[C:25]([O:33][CH2:34][C:35]1[O:39][N:38]=[C:37]([CH3:40])[C:36]=1B1OC(C)(C)C(C)(C)O1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[C:25]([O:33][CH2:34][C:35]1[O:39][N:38]=[C:37]([CH3:40])[C:36]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:15])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1noc(COC(=O)c2ccccc2)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(c1ccc(Cl)cc1)c1ccccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1noc(COC(=O)c2ccccc2)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 110 °C

Procedure:
To a resealable vial was added Pd(OAc)2 (3.87 mg, 0.017 mmol) and X-phos (16.42 mg, 0.034 mmol) before the vial was sealed and evacuated and purged with N2 (3×). To this vial was added (4-bromo-3-methylisoxazol-5-yl)methyl benzoate (102 mg, 0.344 mmol) in dioxane (1 mL), Et3N (144 μl, 1.033 mmol), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane solution (517 μl, 1M in THF, 0.517 mmol). The reaction was stirred overnight at 80° C., cooled to room temperature and filtered. The filtrate was concentrated to afford crude (3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)methyl benzoate. To a resealable vial was added K2CO3 (47.5 mg, 0.344 mmol), PdCl2(dppf)-CH2Cl2 Adduct (20.06 mg, 0.025 mmol), (2-bromophenyl)(4-chlorophenyl)methanone (72.6 mg, 0.246 mmol). The vial was sealed and evacuated and purged with N2 (3×) before addition of crude (3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)methyl benzoate (118 mg, 0.344 mmol) dissolved in dioxane (2 mL). Water (0.5 mL) was then added to this solution before the vial was heated to 110° C. overnight. The reaction was cooled to room temperature, diluted with EtOAc, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methyl benzoate. LC/MS m/z 432 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[F:18][C:19]1[C:20]([N:28]2[CH2:33][CH2:32][CH:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH2:30][CH2:29]2)=[CH:21][C:22]([O:26][CH3:27])=[C:23]([CH:25]=1)[NH2:24]>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:24][C:23]2[CH:25]=[C:19]([F:18])[C:20]([N:28]3[CH2:29][CH2:30][CH:31]([N:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)[CH2:32][CH2:33]3)=[CH:21][C:22]=2[O:26][CH3:27])=[N:3][CH:4]=1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(F)cc1N
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(F)cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) and 5-Fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 54).
Reaction SMILES: [F:1][C:2]1[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])=[CH:28][CH:27]=[C:26]([F:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15](I)=[CH:14][N:13](S(C3C=CC=CC=3)(=O)=O)[C:10]2=[N:11][CH:12]=1)=[O:5].[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[F:45].C([O-])([O-])=O.[K+].[K+].C(#N)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:38][C:39]1[CH:40]=[C:41]([C:15]2[C:9]3[C:10](=[N:11][CH:12]=[C:7]([NH:6][C:4](=[O:5])[C:3]4[C:26]([F:37])=[CH:27][CH:28]=[C:29]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[C:2]=4[F:1])[CH:8]=3)[NH:13][CH:14]=2)[CH:42]=[CH:43][C:44]=1[F:45]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccccc2)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(-c4ccc(F)c(F)c4)c3c2)c1F
Temperature: 160 °C
Yield: 44.2 %

Procedure:
2,6-Difluoro-N-(3-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.025 g, 0.038 mmol), 3,4-difluorophenylboronic acid (0.0090 g, 0.057 mmol), K2CO3 (0.026 g, 0.19 mmol), and Pd(PPh3)4 (0.0022 g, 0.0019 mmol) were taken up in 4:1 acetonitrile (“ACN”)/water (1.5 mL) and degassed with argon for 10 minutes. The reaction mixture was heated to 160° C. for 10 minutes under microwave irradiation. The solution was partitioned between water and EtOAc. The organic portion was washed with water (3×), brine, dried over Na2SO4 and concentrated to an oil. DCM was added to the oil, and a solid precipitated out, which was collected by filtration giving N-(3-(3,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (8.5 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ 12.08 (br s, 1H), 10.97 (s, 1H), 9.80 (br s, 1H), 8.66 (br s, 1H), 8.52 (br s, 1H), 7.99 (br s, 1H), 7.69-7.75 (m, 1H), 7.51-7.59 (m, 3H), 7.25-7.30 (m, 1H), 3.11-3.15 (m, 2H), 1.74-1.80 (m, 2H), 0.98-1.02 (m, 3H); m/z (APCI-pos) M+1=505.2.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]2[CH2:13][C:12](=[O:14])[NH:11][C:6]=2[N:7]=[C:8]([SH:10])[N:9]=1.[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.O>CN(C=O)C>[NH2:3][C:4]1[C:5]2[CH2:13][C:12](=[O:14])[NH:11][C:6]=2[N:7]=[C:8]([S:10][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:16]=2[F:15])[N:9]=1
Reactant: Nc1nc(S)nc2c1CC(=O)N2
Reactant: Fc1cccc(CBr)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(SCc2cccc(F)c2F)nc2c1CC(=O)N2
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride (125 mg) in dry DMF (5 ml) was added a solution of the product from example 3, step (a) (0.57 g) in DMF (10 ml). The mixture was allowed to stir for 30 mins. To the solution was added 2,3-difluorobenzyl bromide (0.39 ml) and the mixture stirred for 2 hours. Poured into water and the crude product extracted into ethyl acetate. Chromatography on silica eluting with 10% ethyl acetate/dichloromethane afforded the title compound (0.35 g).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]([C:17](Cl)=[O:18])[C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][C:9]=2[O:20][CH3:21].[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>ClCCl>[CH2:22]([N:24]([CH2:25][CH3:26])[C:17]([CH:12]1[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[O:20][CH3:21])[N:4]([CH2:3][CH2:2][F:1])[C:16]=2[CH2:15][CH2:14][CH2:13]1)=[O:18])[CH3:23]
Reactant: COc1cccc2c1c1c(n2CCF)CCCC1C(=O)Cl
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)C(=O)C1CCCc2c1c1c(OC)cccc1n2CCF
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
9-(2-fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carbonyl chloride (18) (371 mg, 1.2 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0° C. diethylamine (177 mg, 2.4 mmol, 250 μL) was then added and the reaction was stirred overnight at RT. The reaction was quenched with 10% aqueous potassium carbonate (2 mL). The dichloromethane layer was collected through a phase separator then concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A): ethyl acetate (B) (50-100% (B), 50 g, 35.2 CV, 40 mL/min) to afford a pale yellow solid. The solid was next triturated with a minimum amount of diethyl ether to afford 240 mg (58%) of 9-(2-Fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethyl amide (non-radioactive imaging agent 5). The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 13.0, 14.6, 19.9, 21.9, 28.0, 36.3, 40.5, 41.9, 43.1 (d, JCF=23 Hz), 54.7, 82.0 (d, JCF=173 Hz), 99.7, 102.1, 108.3, 117.0, 121.5, 135.3, 137.4, 153.3, and 174.8.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH3:14][O:15][C:16](=[O:19])[CH2:17]Br>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)Cl>[CH3:14][O:15][C:16](=[O:19])[CH2:17][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)CBr
Reactant: c1c[nH]cn1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)Cn1ccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
Under nitrogen, combined 1.0 g of imidazole (14.7 mmol) with 824 mg of potassium hydroxide (14.7 mmol), 2.0 g of potassium carbonate (14.7 mmol) and 82 mg of benzyltriethylammonium chloride (7.34 mmol) in 40 ml of CH2Cl2. Added 695 μl of methylbromoacetate. Reaction is stirred at room temperature for 3 hours. Filtered off solids, rinsed with CH2Cl2, and evaporated the filtrate under reduced pressure to give colorless oil. Product is purified by flash chromatography on a Biotage Flash 40 (Eluent: 95:5 CH2Cl2/CH3OH), yielding 300 mg of a white solid (27%). 1H NMR (400 MHz, CD3OD) δ 3.75 (3H, s), 4.91 (2H, s), 6.96 (1H, s), 7.10 (1H, s), 7.64 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[CH:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1.[I-].[NH2:24][N+:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[K+].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])[CH:13]=[CH:14][CH:15]=3)=[N:24][N:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=23)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1cccc(C=Cc2ccnc(Cl)n2)c1)C(F)(F)F
Reactant: N[n+]1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Yield: 63.5 %

Procedure:
N-[3-(2-Chloro-pyrimidin-4-ylethenyl)-phenyl]-2,2,2-trifluoro-acetamide (9.14 g, 28.1 mmol), N-aminopyridinium iodide (6.24 g, 28.1 mmol), KOH (1.57 g, 28.9 mmol) and K2CO3 (7.76 g) were stirred in DMSO (175 mL) until all starting material was consumed by LC/MS analysis. Reaction was poured into water to yield a precipitate which was filtered off, washed well with water and dried. Crude product was triturated in EtOAc and filtered to yield 7.45 g of the title compound, Rf=0.2 (2:1 Hexanes/EtOAc).
Reaction SMILES: Br[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3]1>C(OCC)C>[C:4]1(=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:2]=[CH:3]1
Reactant: O=C1CC(Br)c2ccccc21
Solvent: CCOCC
Product: O=C1C=Cc2ccccc21
Reaction time: 2 h

Procedure:
3-Bromoindan-1-one (1.5) was dissolved in diethyl ether (10 ml). The temperature was kept at +2-+4 while TEA (2.7 ml) was added. The resulting mixture was further stirred at +2-+4 for 2 hours. The precipitated salt was filtered off and the filtrate evaporated. The crude inden-1-one was used for further reaction without purification. Yield was 0.9 g.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]([O:12]C(=O)C)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N:6]=1.[OH-].[K+:18]>C1COCC1.CO>[Br:11][C:7]1[N:6]=[C:5]([CH:4]([OH:12])[C:3]([O-:16])=[O:2])[CH:10]=[CH:9][CH:8]=1.[K+:18]
Reactant: COC(=O)C(OC(C)=O)c1cccc(Br)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C([O-])C(O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl(acetyloxy)(6-bromopyridin-2-yl)acetate (1.36 g, 4.70 mmol) in THF (20 mL) and MeOH (10 mL) was added aqueous KOH (1.0 M, 9.88 mL, 9.88 mmol). The solution was stirred at room temperature for 2 hours and then the solvent was evaporated to give the title compound as a colorless solid which was carried on without purification.
Reaction SMILES: [CH2:1]([OH:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].C([O:15]O)(C)(C)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C(OCC)C>C1(C)C=CC=CC=1>[O:15]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9])[CH:2]1[CH2:1][OH:10]
Reactant: CC(C)(C)OO
Reactant: C=CCCCC/C=C/CO
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=CCCCCC1OC1CO
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82 %

Procedure:
2.72 g (19.4 mM) (E)-nona-2,8-diene-1-ol (11) is added into the reaction mixture after another 5 minutes. Then, after yet another 5 minutes, 6.9 ml of a 3.39 molar solution in toluene (23.4 mM) of tertiary butyl hydroperoxide is added. The reaction mixture is allowed to react for 3 days at -25° C. Subsequently, the reaction vessel is put into an ice bath and 10 ml (1 ml per mM tetraisopropyl titantate added) saturated aqueous sodium sulfate solution and another 100 ml diethyl ether are added to the reaction mixture. The reaction solution is vigorously agitated for approximately 1 hour until the solution has warmed up to room temperature. The gelatinous orange-colored precipitation is separated out by means of a glass filter, washed twice with 100 ml quantities of ether and dried by suction. The solvent is evaporated from the combined filtrates and the residue is mixed with 100 ml ether and 2 ml dimethyl sulfide in order to destroy excess tertiary butyl hydroperoxide. The solution is agitated for one hour. Then, 50 ml 1 molar sodium hydroxide is added and the mixture is agitated another 3-4 hours. The ether phase is separated out, washed with 2×40 ml water, dried over magnesium sulfate and, after evaporation of the solvent in a vacuum, 2.48 g (15.9 mM) 2S, 3S-2-epoxy-1-hydroxynon-8-ene (III) is obtained by bulb tube distillation at 110° C./0.5 mm pressure. This corresponds to a yield of 82%.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14](=[O:17])[CH2:15][Cl:16])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+].[C:22](O)(=[O:24])[CH3:23]>O1CCCC1>[C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[CH:14]([O:17][C:22](=[O:24])[CH3:23])[CH2:15][Cl:16])(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1sccc1C(=O)CCl
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OC(CCl)c1ccsc1S(=O)(=O)NC(C)(C)C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
1.5 g (0.005 mole) of N-t-butyl-3-(chloroacetyl)-2-thiophenesulfonamide synthesized in Example 6 was dissolved in the combined solution of 1 ml of acetic acid and 10 ml of tetrahydrofuran and then 0.31 g (0.005 mole) of sodium cyanoborohydride was added slowly thereto. The reaction solution was stirred at normal temperature for 30 minutes and then subjected to a vacuum evaporator to remove the solvent. To the residue was added 10 ml of water and then the resulting solution was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and filtered. To the filtrate were added acetic anhydride, pyridine and N,N-dimethylaminopyridine and the mixture was stirred at normal temperature for 24 hours and then washed with 5% aqueous hydrochloric acid solution. The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and the residue was subjected to column chromatography on silica gel to obtain 5 g (Yield: 84%) of the title compound. 1H NMR(CDCl3, δ): 1.3(s, 9H), 2.15(s, 3H), 3.57-3.9(m, 2H), 5.23(s, 1H), 6.5(m, 1H), 7.13(d, 1H), 7.5 (d, 1H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:20](=[O:24])[CH:21](O)O)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C@H:34]([NH2:36])[CH3:35])=[CH:29][CH:28]=1>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:20](=[O:24])[CH:21]=[N:36][C@H:34]([CH3:35])[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C[C@@H](C)N)cc1
Reactant: O=C(c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12)C(O)O
Solvent: CS(C)=O
Product: COc1ccc(C[C@@H](C)N=CC(=O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
One g of 8-benzyloxy-5-(dihydroxyacetyl)carbostiril 1/3 hydrate and 520 mg of (R)-N-(2-(p-methoxyphenyl)-1-methylethyl)amine are dissolved in 10 ml of dimethylsulfoxide, and the solution is stirred at room temperature for one hour. After the reaction is completed, the mixture is treated in the same manner as described in Example 10-(1). 1.06 g of 8-benzyloxy-5-{1-oxo-2-[N-((1R)-2-(p-methoxyphenyl)-1-methylethyl)imino]ethyl}carbostyril are obtained as pale yellow scales. Yield: 75%
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CO>[CH2:18]([NH:2][C@@H:3]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:4]([OH:6])=[O:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C[C@H](N)C(=O)O
Reactant: ClCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C[C@H](NCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To a solution of 10 g (S)-2-amino-4-methoxy-4-oxobutanoic acid hydrochloride in 400 ml methanol was added 15 g sodium carbonate, and the mixture was stirred at 25° C. Twenty (20) g benzyl chloride was then added dropwise at this temperature. After completion of the reaction, the mixture was maintained at this temperature for 12 h. The reaction solution was neutralized with a diluted aqueous hydrochloride acid solution to produce a neutralized solution. Methanol was evaporated, and the residue was partitioned and extracted with ethyl acetate. The organic layer was concentrated and then washed with water 2˜3 times to afford 16 g crude (S)-2-(benzylamino)-4-methoxy-4-oxobutanoic acid, with a yield of 91.3%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC#N>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:5]=[O:6]
Reactant: ClCc1ccccc1
Reactant: O=Cc1ccc(O)c(F)c1
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccc2)c(F)c1
Temperature: 40 °C
Yield: 74.5 %

Procedure:
To a stirring solution of 3-fluoro-4-hydroxybenzaldehyde (508 mg, 3.63 mmol) and CsCO3 (1.25 g, 3.84 mmol) in dry MeCN (5.6 mL) under nitrogen at ambient temperature was added benzyl chloride (0.45 mL, 3.91 mmol) and the mixture heated at 40° C. for 27 h. The mixture was then allowed to cool to rt, was quenched by the addition of aqueous NaOH (2N, 30 mL) and the product extracted with EtOAc (2×50 mL). The combined organic layer was then washed with brine (80 mL) and reduced under vacuum. The residue was then purified by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc (gradient 50:1 to 0:1) to afford the title compound as a colourless solid (623 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[C:8]([F:15])[CH:7]=1.S(Cl)([Cl:18])=O>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:18])=[O:11])=[C:8]([F:15])[CH:7]=1
Reactant: O=C(O)c1ccc(OCCCCl)cc1F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(OCCCCl)cc1F

Procedure:
4-(3-chloropropoxy)-2-fluorobenzoic acid i78 (0.68 g, 2.92 mmol, 1 eq) is refluxed in thionyl chloride (4.27 ml, 57.46 mmol, 20 eq) for 3 hours. The mixture is then concentrated under reduced pressure to give 0.73 g of crude 4-(3-chloropropoxy)-2-fluorobenzoyl chloride i80, which is used in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][OH:9])[N:3]=1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Br:1][C:2]1[N:3]=[C:4]([CH2:8][O:9][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cccc(Br)n1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Brc1cccc(COC2CCCCO2)n1
Reaction time: 24 h
Yield: 83.8 %

Procedure:
2-Bromopyridine-6-methanol (prepared as described in Tetrahedron Lett., 1996, 50, 2537) (5 g, 26.5 mmol) was added to a solution of dihydropyran (2.65 ml, 29.2 mmol), and p-toluenesulfonic acid (506 mg, 2.7 mmol) in dichloromethane (150 ml) at room temperature under nitrogen. After 24 h, the mixture was washed with sodium carbonate solution (×1) and water (×1), dried (MgSO4), evaporated in vacuo and the residue flash chromatographed on silica gel, eluting with 10% ethyl acetate/hexane to give the title-compound (6.04 g, 84%), 1H NMR (250 MHz, CDCl3) δ 1.5-1.9 (6H, m, 3 of CH2), 3.56 (1H, m, CH2O), 3.88 (1H, m, CH2O), 4.62 (1H, d, J=14.2 Hz, CH2O), 4.76 (1H, t, J=3.4 Hz, CHO), 4.93 (1H, d, J=14.6 Hz, CH2O), 7.37 (1H, d, J=7.6 Hz, Ar—H), 7.46 (1H, d, J=6.6 Hz, Ar—H), 7.56 (1H, t, J=7.6 Hz, Ar—H); MS (ES30) m/e 272 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[O:11])=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([CH2:8][CH2:9][C:10](=[O:11])[N:12]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[CH:3]=1
Reactant: O=C(CCc1cnc(Cl)cc1-c1ccccc1Cl)Nc1ccccc1Cl
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCc2c(-c3ccccc3Cl)cc(Cl)nc2N1c1ccccc1Cl
Yield: 115.6 %

Procedure:
3-[6-Chloro-4-(2-chlorophenyl)-3-pyridinyl]-N-(2-chlorophenyl)propanamide (1.51 g, 3.43 mmol) was dissolved in DMF (40 ml), potassium carbonate (0.95 g, 6.87 mmol) and copper(I) iodide (1.3 g, 6.83 mmol) added and the mixture heated at reflux for 1 h. Most of the DMF was removed in vacuo, the residue was treated with water (10 ml) and brine (10 ml), and extracted with dichloromethane (2×15 ml) and ethyl acetate (15 ml). The extracts were passed through a hydrophobic frit and evaporated in vacuo to give the title compound as an off-white solid (1.6 g)