Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[C:22](B(O)O)[C:21]([F:27])=[CH:20][N:19]=1.C(Cl)Cl>COCCOC.C([O-])([O-])=O.[Na+].[Na+].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]>[Cl:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)[N:7]=2)[C:21]([F:27])=[CH:20][N:19]=1
Reactant: Fc1cccc(CNc2cccc(Br)n2)c1
Reactant: OB(O)c1cc(Cl)ncc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: Fc1cccc(CNc2cccc(-c3cc(Cl)ncc3F)n2)c1
Temperature: 110 °C
Yield: 11.2 %

Procedure:
To a solution of 6-bromo-N-(3-fluorobenzyl)pyridin-2-amine (636 mg, 2.262 mmol) and 2-chloro-5-fluoropyridin-4-yl-boronic acid (555 mg, 3.17 mmol) in DME (4 ml) and 2M Na2CO3 aq (2 ml) was added PdCl2(dppf). CH2Cl2 adduct (92 mg, 0.113 mmol). This was then heated at 110° C. for 16 hours. The reaction mixture was allowed to cool and then the DME was evaporated under reduced pressure. The resulting residue was partitioned between EtOAc and water. The organics were combined, then washed with H2O (×3), saturated aq. brine (×3), then dried (Na2SO4), filtered and evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel; 20% EtOAc/hexane) to give 2′-chloro-5′-fluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine (84 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[C:18]([S:24][CH2:25][CH3:26])[CH:17]=1.S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>O.CC(N(C)C)=O>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:8][CH:7]=3)[N:1]=2)=[C:18]([S:24][CH2:25][CH3:26])[CH:17]=1
Reactant: CCSc1cc(Cl)ccc1C=O
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1N
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCSc1cc(Cl)ccc1-c1nc2cc(C(F)(F)F)ccc2c(=O)[nH]1
Temperature: 150 °C
Reaction time: 15 h
Yield: 80.7 %

Procedure:
A mixture of 1.0 g of 2-amino-4-trifluromethylbenzamide, 944 mg of 4-chloro-2-ethylsulfanylbenzaldehyde, 765 mg of sodium bisulfite and 4 ml of DMA was stirred at 150° C. for 15 hours. A saturated aqueous sodium bicarbonate solution and water were added to the cooled reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 1.46 g of 2-(4-chloro-2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-quinazolin-4-one.
Reaction SMILES: [N:1]([O-])=O.[Na+].[N+:5]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([NH2:18])=[CH:10][CH:9]=1)([O-:7])=[O:6].[ClH:19]>O.CC(O)=O>[ClH:19].[NH:18]([C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=1)[NH2:1]
Reactant: Nc1ccc([N+](=O)[O-])c2ccccc12
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NNc1ccc([N+](=O)[O-])c2ccccc12
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.9 g of sodium nitrite in 10 ml of water is added to a suspension, cooled to -5° C., of 5.2 g of 4-nitro-1-naphthylamine in 150 ml of concentrated HCl, 100 ml of 1N HCl and 150 ml of AcOH. The mixture is left stirring for 1 hour 15 minutes at a temperature of between -5° C. and 0° C. It is cooled to -15° C., and a solution of 12.5 g of stannous chloride dihydrate in 30 ml of concentrated HCl is added very slowly. The temperature is allowed to rise to RT and the reaction mixture is kept stirring for 2 hours 30 minutes. It is filtered, the solid is then taken up with water and the mixture is filtered again. 5.9 g of the expected product are obtained.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(Br)cc1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Br)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-bromophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.19 (2H, s), 5.72 (1H, s), 7.30-7.32 (2H, m), 7.41 (1H, d, J=0.8 Hz, J=5.2 Hz), 7.52-7.54 (2H, m), 7.56 (1H, d, J=0.8 Hz), 8.03 (1H, s), 8.69 (1H, d, J=4.0 Hz). [M+H] Calc'd for C16H11BrN4O, 355; Found, 355.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])[NH:7][C:8]2=[O:11])=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:15]=1[Cl:25].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.N1C(C)=CC=CC=1C>ClCCl>[Cl:25][C:15]1[CH:16]=[C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:19][C:14]=1[O:13][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][S:33]([C:30]1[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=1)(=[O:35])=[O:34])[C:8](=[O:11])[NH:7][C:6]2=[O:12]
Reactant: COC(=O)Cc1ccc(Oc2cc3c(cc2N)C(=O)NC3=O)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(Oc2cc3c(cc2NS(=O)(=O)c2ccc(Cl)cc2)C(=O)NC3=O)c(Cl)c1

Procedure:
Compound 30.2 (25 mg, 0.07 mmol) and 4-chlorobenzenesulfonyl chloride (30 mg, 0.14 mmol) were stirred in dichloromethane (0.5 mL) with 2,6-lutidine (0.25 mL, 0.21 mmol) at 25° C. for 14 h. The reaction mixture was loaded directly on a silica gel column and purified using 20% EtOAc/hexane as the eluent to give methyl 2-(3-chloro-4-(6-(4-chlorophenylsulfonamido)-1,3-dioxoisoindolin-5-yloxy)phenyl)acetate, and a compound with LC-MS matching a bis-sulfonamide. Both acetates were hydrolyzed in MeOH/THF/water (0.3 mL each) with LiOH.H2O (6 mg, 0.14 mmol) at 25° C. for 2 h to give the same desired product (30). The reaction mixtures were acidified to pH ˜3 and extracted with dichloromethane to give compound 30 as a pale-yellow solid. MS ESI (pos.) m/e calcd for (M+H3O)+ 539.0. found 539.0. 1H NMR (500 MHz) (DMSO-d6) δ 12.46 (br. s, 1H); 10.42 (s, 1H); 7.79 (d, J=8.3 Hz, 2H); 7.64 (d, J=8.5 Hz, 2H); 7.50 (d, J=1.9 Hz, 1H); 7.24 (dd, J=11.9, 8.3 Hz, 1H); 7.18 (s, 1H); 7.08 (s, 1H); 6.98 (s, 1H); 6.81 (d, J=8.2 Hz, 1H); 3.64 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:17])=[CH:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CCOCC>[CH3:17][C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH:12]([NH:14][C:25](=[O:26])[O:27][CH2:28][CH3:29])[CH3:13])=[CH:15][CH:16]=1
Reactant: CC(C)=CCOc1ccc(OCC(C)N)cc1
Reactant: CCOC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)NC(C)COc1ccc(OCC=C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the above amine (0.86 g, 3.7 mmol) and pyridine (0.64 g, 8.0 mmol ) in 8 ml of ether at 5° is added dropwise over 10 min. ethyl chloroformate (0.43 g, 4.0 mmol) in 2 ml of ether. The mixture is stirred at 5° for 1 hour and is then allowed to warm to RT. Excess ethyl chloroformate is quenched with water and the reaction mixture is poured into water and ether and the aqueous phase is extracted with ether (3X). The combined organic layers are washed with 2N ammonium sulfate, with 10% sodium carbonate, then with water until neural and with brine. The organic layer is dried, filtered, the solvent removed and the product purified by prep. TLC to give ethyl N-{2-[4-(3-methyl-2-butenoxy)phenoxy]-1-methylethyl}carbamate m/s (M+) 307.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH:16]=[CH:15][S:14]2)=[CH:9][CH:8]=1.O>CN(C=O)C>[N:1]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17](=[O:18])[CH:16]=[CH:15][S:14]2)=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: O=c1ccsn1-c1ccc(CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(-n2sccc2=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.7 %

Procedure:
Sodium azide (6.0 mg, 0.0923 mmol) was added to a solution of 2-(4-bromomethylphenyl)isothiazol-3-one 31 (18.2 mg, 0.0674 mmol) in DMF (1 mL) and stirred for 20 h at room temperature. Water (10 mL) was added and the mixture was extracted with diethyl ether. The combined organic layer was dried (MgSO4), filtered and evaporated. The residue was purified on flash silica gel column chromatography (hexane:ethyl acetate=4:1 to 1:1), afforded the desired compound 32 (11.7 mg, 75%). 1H-NMR (CDCl3, 300 MHz) δ 4.38 (s, 2H), 6.34 (d, J=6.3 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 8.17 (d, J=6.3 Hz, 1H). HRMS: Found 233.0496. Calcd for C10H9N4OS (M+H)+233.0497.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)([CH2:11][OH:12])[CH2:9]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.CN(C([S-])=S)C.CN(C([S-])=S)C.[Zn+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]3[CH:14]=[N:15][C:16]([N:19]4[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:23][CH2:24]4)=[N:17][CH:18]=3)[CH2:9][O:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(CO)(CO)c3ccc(F)cc3)cn2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CN(C)C(=S)[S-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C3(c4ccc(F)cc4)COC3)cn2)CC1
Temperature: 40 °C
Yield: 5.6 %

Procedure:
A mixture of tert-butyl 4-(5-(2-(4-fluorophenyl)-1,3-dihydroxypropan-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate (650 mg, 1.5 mmol), triphenylphosphine (470 mg, 1.8 mmol), diisopropyl azodicarboxylate (360 mg, 1.8 mmol) and ziram (500 mg, 1.8 mmol) in THF (50 mL) was heated at 40° C. overnight under N2 and concentrated. The residue was diluted with EtOAc (40 mL), washed with water (50 mL*2) and brine, dried over Na2SO4 and concentrated. The residue was purified by Prep-HPLC to give the desired product (35 mg, yield 6%) as a white solid. MS (ES+) C22H27FN4O3 requires: 414. found 359 [M+H−56]+; purity: 93% (UV214).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:21]1([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([S:36]([C:39]3[CH:47]=[CH:46][C:42](C(O)=O)=[CH:41][CH:40]=3)(=[O:38])=[O:37])[CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1CC(CO)C1.C(N(CC)CC)C.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C1COCC1.ClCCl>[OH:14][CH2:12][CH:10]1[CH2:9][N:8]([C:6]([C:42]2[CH:41]=[CH:40][C:39]([S:36]([N:29]3[C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:28]3)(=[O:38])=[O:37])=[CH:47][CH:46]=2)=[O:7])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: OCC1CNC1
Agent: [Al+3]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1)N1CC(CO)C1
Reaction time: 18 h
Yield: 35.3 %

Procedure:
Dissolve azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (300 mg, 1.50 mmol.) in THF (5.0 mL) and treat with lithium aluminum hydride (1.0M in ether, 3.0 mL, 3.0 mmol). Stir for 18 hours, quench with 3.0 mL of 1.0M NaOH, dilute with ether, filter through celite and evaporate. Treat the resulting 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester with 10 mL of trifluoroacetic acid for 20 minutes an evaporate. Use this material without further purification. Combine 4-(3-Phenyl-indole-1-sulfonyl)-benzoic acid (100 mg, 0.26 mmol) and the resulting azetidin-3-yl-methanol in dichloromethane (1.0 mL) and triethylamine (0.100 mL, 0.717 mmol, excess) and add benzotriazol-1-yloxytris(dimethylamino)phosphonium hexfluorophosphate (BOP Reagent) (150 mg, 0.33 mmol, excess) at room temperature. Stir for 30 minutes, evaporate and load entire reaction directly onto pre-packed silica gel column and purify by flash column chromatography (EtOAc/Hexanes) to give 41 mg of (3-Hydroxymethyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone as a white solid (35%). LRMS: MH+ 447.2.
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:21]([OH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1I>[Cu]I.C1(C)C=CC=CC=1>[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:28][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Brc1ccccc1I
Reactant: OCc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Brc1ccccc1OCc1ccccc1
Temperature: 110 °C
Reaction time: 36 h
Yield: 71.1 %

Procedure:
A test tube was charged with CuI (20 mg, 0.10 mmol, 0.10 equiv), 1,10-phenanthroline (36 mg, 0.20 mmol, 0.20 equiv), Cs2CO3 (456 mg, 1.4 mmol, 1.4 equiv), benzyl alcohol (207 μL, 2.0 mmol, 2.0 equiv), 2-bromo-iodobenzene (128 μL, 1.0 mmol, 1.0 equiv) and toluene (0.5 mL). The test tube was sealed and the reaction mixture was stirred at 110° C. for 36 h. The resulting suspension was cooled to room temperature and filtered through a 1×1 cm pad of silica gel, eluting with dichloromethane. The filtrate was concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (2×20 cm; pentane:dichloromethane 2:1) provided 187 mg (71% yield) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([N+:17]([O-])=O)=[CH:12][CH:13]=2)[CH2:8]1)=[O:5])[CH3:2]>C(O)C.[H][H].[C].[Pd]>[NH2:17][C:11]1[CH:10]=[C:9]2[C:14]([CH2:15][CH2:16][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:8]2)=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: CCOC(=O)CN1CCc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN1CCc2ccc(N)cc2C1
Yield: 90.2 %

Procedure:
1.1 g of 2-(ethoxycarbonylmethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline was dissolved in 20 ml of ethanol, and a catalytic amount of 10% palladium-carbon was added to the solution. The solution was stirred overnight in hydrogen atmosphere. The catalyst was separated by filtration and the solvent was distilled off under reduced pressure to obtain 0.88 g of 7-amino-2-(ethoxycarbonylmethyl)-1,2,3,4-tetrahydroisoquinoline, which was an oily product. This product with no further purification was dissolved in 10 ml of N,N-dimethylformamide (DMF), and 1.3 g of 1-(benzyloxy-carbonyl)-4-(carboxymethoxy)piperidine and 1.1 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide which have been separately synthesized were added to the solution. After adding water, the solution was extracted with ethyl acetate, washed with saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride in this order, and dried with anhydrous sodium sulfate. After separating the desiccant by filtration, the product was purified by silica gel column chromatography to obtain 1.7 g of 7-[1-(benzyloxycarbonyl)piperidine-4-yloxyacetylamino]-2-(ethoxycarbonylmethyl)-1,2,3,4-tetrahydroisoquinoline. (Yield: 90%, oily product).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:40])[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33]4[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][N:34]=4)[N:27]=3)=[CH:24][N:25]=2)[CH2:17][CH2:16]1)(C)(C)C.[ClH:41].C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:41].[ClH:41].[CH3:39][C:37]1[CH:36]=[CH:35][N:34]=[C:33]([NH:32][C:28]2[N:27]=[C:26]([C:23]3[S:22][C:21]([N:18]4[CH2:17][CH2:16][CH:15]([CH2:14][C:13]([OH:40])=[O:12])[CH2:20][CH2:19]4)=[N:25][CH:24]=3)[CH:31]=[CH:30][CH:29]=2)[CH:38]=1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(N4CCC(CC(=O)OC(C)(C)C)CC4)s3)n2)c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1ccnc(Nc2cccc(-c3cnc(N4CCC(CC(=O)O)CC4)s3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (20 ml) was added to a solution of (1-{5-[6-(4-methylpyridin-2-ylamino)pyridin-2-yl]thiazol-2-yl}piperidin-4-yl)acetic acid tert-butyl ester (4.30 g, 9.23 mmol) obtained in Step 3 in chloroform (20 ml) and the solution was stirred overnight at room temperature. Subsequently 4N hydrochloric acid-ethyl acetate solution (20 ml) was added to the concentrate obtained by concentrating the reaction solution in vacuo, and the precipitated solid was collected by filtration, washed with ethyl acetate (20 ml) and the title compound (4.46 g, 100%) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](O)=[O:8].[BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+].O>S(Cl)(Cl)=O.C(OCC)(=O)C>[Br:1][C:2]1[C:3]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[CH2:7][OH:8]
Reactant: Cc1cccc2sc(C(=O)O)c(Br)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cccc2sc(CO)c(Br)c12
Reaction time: 1 h

Procedure:
A solution of 3-bromo-4-methyl-benzo[b]thiophene-2-carboxylic acid (23c) (420 mg, 1.55 mmol) in thionyl chloride (10 mL) was refluxed for 1 hour. Thionyl chloride was then evaporated under reduced pressure and the residue was diluted with dimethoxyethane (20 mL). Sodium tetraborohydride (70 mg, 1.85 mmol) was then added to the solution. After 1 hour, the mixture was hydrolyzed with water (5 mL) and diluted with ethyl acetate (20 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated to dryness to afford the desired alcohol (23d) as a white solid without further purification (400 mg, 1.55 mmol, 100%).
Reaction SMILES: C([Li])CCC.CSCS(C)=O.[F:12][C:13]1[CH:20]=[C:19](F)[C:18]([F:22])=[CH:17][C:14]=1[C:15]#[N:16].S(=O)(=O)(O)O.C1C[O:31][CH2:30]C1>O>[F:12][C:13]1[CH:20]=[C:19]([CH:30]=[O:31])[C:18]([F:22])=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1cc(F)c(F)cc1F
Reactant: C1CCOC1
Agent: CSCS(C)=O
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: O
Product: N#Cc1cc(F)c(C=O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
n-Butyllithium solution (1.6 M in hexanes, 8.75 mL, 14 mmol) was added dropwise to a solution of methyl methylthiomethyl sulfoxide (1.58 g, 12.7 mmol) in THF (25 mL) at −78° C. After 30 minutes at −78° C., 2,4,5-trifluorobenzonitrile (commercial, 1 g, 6.35 mmol) was added dropwise. The solution was then allowed to warm to room temperature, and stirred for 18 hours under a nitrogen atmosphere. The deep red reaction mixture was poured into water (75 mL), and extracted with EtOAc (2×75 mL). The combined organics were dried over magnesium sulphate and evaporated to yield a brown oil. The oil was redissolved in THF (15 mL) and concentrated sulphuric acid (4.1 mL, 77.2 mmol) and water (4 mL) were added. After stirring for 5 hours the reaction was quenched with saturated aqueous sodium bicarbonate (30 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over magnesium sulphate, and evaporated to yield a brown oil, which was purified by silica gel chromatography eluting with 50% heptane in DCM to afford the title compound as a yellow oil (280 mg, 26%).
Reaction SMILES: [F:1][CH:2]([C:7]1[CH:16]=[CH:15][C:10]2[C:11](=[O:14])[O:12][CH2:13][C:9]=2[CH:8]=1)[CH:3]([OH:6])CO.C(Cl)(Cl)(Cl)Cl.O.CC(O)(C)C>C(Cl)(Cl)(Cl)Cl.CC(O)(C)C.O>[F:1][CH:2]([C:7]1[CH:16]=[CH:15][C:10]2[C:11](=[O:14])[O:12][CH2:13][C:9]=2[CH:8]=1)[CH:3]=[O:6]
Reactant: O=C1OCc2cc(C(F)C(O)CO)ccc21
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)(C)O
Solvent: O
Product: O=CC(F)c1ccc2c(c1)COC2=O
Reaction time: 1.5 h

Procedure:
NaIO4 (71 mg, 0.33 mmol) was added to a stirring solution of 5-(1-Fluoro-2,3-dihydroxypropyl)-2-benzofuran-1(3H)-one (30 mg, 0.13 mmol) in 5:2:2 CCl4-H2O-t-BuOH (5 mL) (the starting material was dissolved in CCl4-t-BuOH, and H2O was added last). After stirring 1.5 hours, the suspension was diluted with H2O (3 mL) and extracted with CH2Cl2 (50 mL). The combined organic extracts were washed with 10% aqueous NaHSO3 (8 mL) and water (8 mL), dried over Na2SO4 and evaporated. The residue was purified by prep-TLC to give the title product
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[C:25]1([CH3:33])[CH:30]=[CH:29][CH:28]=[C:27]([Mg]Br)[CH:26]=1>O1CCCC1>[Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([C:5]([C:27]2[CH:26]=[C:25]([CH3:33])[CH:30]=[CH:29][CH:28]=2)=[O:7])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1cccc(Cl)c1[N+](=O)[O-]
Reactant: Cc1cccc([Mg]Br)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)c2cccc(Cl)c2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 200 mL round-bottomed flask was charged with 3-chloro-2-nitrobenzoic acid (2.5 g, 12.40 mmol) and tetrahydrofuran (50 mL). Oxalyl chloride (1.194 mL, 13.64 mmol) was added slowly followed by DMF (0.096 mL, 1.240 mmol). The reaction mixture was stirred at room temperature for 2 hrs. After cooling to 0° C., a 1M solution of m-tolylmagnesium bromide (24.81 mL, 24.81 mmol) was added. After 1 hr, another portion of m-tolylmagnesium bromide (24.81 mL, 24.81 mmol) was added. After a further hour, the reaction mixture was partitioned between ethyl acetate (200 mL) and 1N HCl (150 mL). The aqueous layer was back extracted with ethyl acetate (2×100 mL). The combined organic phases were dried with Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography (Teledyne ISCO CombiFlash Rf, 0% to 100% solvent A/B=ethyl acetate/heptane, REDISEP® SiO2 120 g). Concentration of the appropriate fractions provided Intermediate A-10A (0.700 g, 21%). 1H NMR (400 MHz, DMSO-d6) δ 8.04 (dd, J=8.1, 1.1 Hz, 1H), 7.82 (t, J=7.9 Hz, 1H), 7.71 (dd, J=7.7, 1.1 Hz, 1H), 7.66-7.54 (m, 3H), 7.52-7.46 (m, 1H), 2.40 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[C:29]1([CH:35]([CH3:38])[CH2:36][OH:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH3:26][C:23]1[C:22]([CH2:27][O:37][CH2:36][CH:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:38])=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:6]4([C:4]([OH:3])=[O:5])[CH2:7][CH2:8]4)=[CH:10][CH:11]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CC(CO)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1COCC(C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 48, Step 2, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-phenyl-propan-1-ol.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[C:13]([OH:14])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1>C(O)(=O)C>[Br:1][C:6]1[CH:5]=[C:4]([F:3])[C:13]([OH:14])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2
Reactant: Oc1c(F)ccc2cccnc12
Reactant: BrBr
Solvent: CC(=O)O
Product: Oc1c(F)cc(Br)c2cccnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.6 %

Procedure:
An rt solution of bromine (2.34 g, 14.7 mmol) in acetic acid (10 mL) was slowly added to a solution of 7-fluoro-8-quinolinol (2.0 g, 12.2 mmol) in acetic acid (30 mL). The brown reaction mixture was stirred at rt for 16 h, after which the mixture was quenched with saturated sodium bisulfite solution. The resulting mixture was extracted with methyl t-butyl ether 3 times. The combined organic phases were washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo to dryness to give 3.0 g (97.0%) 5-bromo-7-fluoro-8-quinolinol as a green solid.