Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[S:12]([NH:15][CH3:16])(=[O:14])=[O:13].Cl.[CH3:18][NH:19][CH3:20].C(N(CC)CC)C.Cl>C(Cl)Cl.O>[CH3:18][N:19]([CH3:20])[C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([S:12]([NH:15][CH3:16])(=[O:14])=[O:13])=[C:2]([F:1])[CH:7]=1
Reactant: CNC
Reactant: CNS(=O)(=O)c1cc([N+](=O)[O-])c(F)cc1F
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)c1cc([N+](=O)[O-])c(N(C)C)cc1F
Reaction time: 1 h
Yield: 45.7 %

Procedure:
A solution of 2,4-difluoro-N-methyl-5-nitrobenzenesulfonamide (8.0 g, 31.6 mmol) in CH2Cl2 (200 mL) at −20° C. was treated with dimethylamine hydrochloride (2.56 g, 31.6 mmol). The resulting mixture was treated dropwise with triethylamine and stirred for 1 hour before being treated with 15% aqueous HCl to adjust the pH to 3, diluted with water, and extracted with EtOAc. The organic extract was dried (sodium sulfate), concentrated, and subjected to flash chromatography (20-50% EtOAc-petroleum ether) to give 4-(dimethylamino)-2-fluoro-N-methyl-5-nitrobenzenesulfonamide (4.0 g, 46%) as a yellow solid. MS (m/z) 278.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])[C:26]([CH2:37]Cl)=[CH:25]2>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]([CH2:37][C:26]3[C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])=[N:28][C:29]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:19])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: ClCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Reactant: Nc1ncnc2[nH]ccc(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(=O)ccn2Cc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (0.05 g, 0.308 mmol), Cs2CO3 (0.1515 g, 0.46 mmol, 1.5 eq), and KI (0.0051 g, 0.0309 mmol, 0.1 eq) in DMF (1 mL) was added 8-chloro-3-(chloromethyl)-2-(2-chlorophenyl)quinoline (0.1 g, 0.309 mmol, 1.0 eq) and the mixture was stirred at 140° C. for 1 h. The mixture was concentrated under reduced pressure. The crude product was purified by column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 14 min and then 100% isocratic of EtOAc for 14 min as eluent to provide 4-amino-8-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one [PI3Kδ IC50=33 nM] as white solid. 1H NMR (DMSO-d6) δ ppm 9.52 (1 H, d, J=4.7 Hz), 8.25 (1 H, s), 8.11 (1 H, d, J=4.7 Hz), 8.09 (1 H, s), 8.04 (1 H, dd, J=8.4, 1.4 Hz), 7.97 (1 H, dd, J=7.6, 1.4 Hz), 7.81 (1 H, d, J=7.8 Hz), 7.63 (1 H, d, J=7.8 Hz), 7.57-7.61 (1 H, m), 7.42-7.53 (3 H, m), 6.14 (1 H, d, J=7.8 Hz), 5.40 (2 H, s). Mass Spectrum (ESI) m/e=448.0 and 450.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[NH:38]1[CH2:43][CH2:42][CH:41]([C:44]([NH2:46])=[O:45])[CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:38]3[CH2:43][CH2:42][CH:41]([C:44]([NH2:46])=[O:45])[CH2:40][CH2:39]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NC(=O)C1CCNCC1
Product: CCOc1cc(C(F)(F)F)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperidine-4-carboxylic acid amide (isonipecotamide, Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C33H34N4O3F3Cl2 [(M+H)+] 661.1955, observed 662.1955.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18].[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:31]=1)[C:26](O)=[O:27]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:26](=[O:27])[C:25]1[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[N:31]=[C:23]([C:22]([F:37])([F:21])[F:36])[CH:24]=1
Reactant: CS(=O)(=O)CCNc1cnccc1-c1ccccc1F
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: CS(=O)(=O)CCN(C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1)c1cnccc1-c1ccccc1F

Procedure:
The title compound was prepared in analogy to example 90, from [4-(2-fluoro-phenyl)-pyridin-3-yl]-(2-methanesulfonyl-ethyl)-amine and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 15 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Off-white solid (38%). MS (ESI): m/z=536.09 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:10][N:9]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([CH2:18][OH:19])=[CH:13][N:12]=2)[CH2:8][CH2:7][NH:6]1)=[O:4].Cl[C:21]1[NH:25][C:24]2[CH:26]=[C:27]([C:39]([F:42])([F:41])[F:40])[CH:28]=[C:29]([C:30]3[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=3)[C:23]=2[N:22]=1>CCO>[CH3:1][NH:2][C:3]([CH:5]1[CH2:10][N:9]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([CH2:18][OH:19])=[CH:13][N:12]=2)[CH2:8][CH2:7][N:6]1[C:21]1[NH:22][C:23]2[C:29]([C:30]3[CH:31]=[C:32]([F:38])[C:33]([F:37])=[C:34]([F:36])[CH:35]=3)=[CH:28][C:27]([C:39]([F:42])([F:40])[F:41])=[CH:26][C:24]=2[N:25]=1)=[O:4]
Reactant: CNC(=O)C1CN(c2ncc(CO)cc2Cl)CCN1
Reactant: Fc1cc(-c2cc(C(F)(F)F)cc3[nH]c(Cl)nc23)cc(F)c1F
Solvent: CCO
Product: CNC(=O)C1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1

Procedure:
A mixture of 4-(3-chloro-5-hydroxymethyl-pyridin-2-yl)-piperazine-2-carboxylic acid methylamide from step (d) above (114 mg, 0.4 mmol) and 2-chloro-6-trifluoromethyl-4-(3,4,5-trifluoro-phenyl)-1H-benzoimidazole (140 mg, 0.4 mmol, Example 51b) in EtOH (1 mL) reacted under the conditions of Example 3c to give the title compound as a white solid. MS ESI, pos. ion) m/e: 599 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[CH2:23]1[C:27]2([CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)[CH2:26][CH:25]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[NH:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.CN(C)C=O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:24]2[CH:25]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:26][C:27]3([CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]3)[CH2:23]2)=[CH:21][CH:22]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1
Reactant: CCOC(=O)C1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1
Reactant: O=Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.8 %

Procedure:
Under an argon atmosphere, 4-{[bis(1H-imidazol-2-ylmethyl)amino]methyl}benzaldehyde (International Publication WO 2007/058322 pamphlet, Example 28; 21.0 g) and 8-tert-butyl 3-ethyl 2,8-diazaspiro[4.5]decane-3,8-dicarboxylate (JP 2004-002470, Example 21f; 21.2 g) were dissolved in acetic acid (4.5 mL) and anhydrous N,N-dimethylformamide (225 mL), followed by stirring at room temperature for 10 minutes. To this solution, sodium triacetoxyborohydride (17.3 g) was added. The reaction solution was stirred at room temperature for 3 hours. To the reaction solution, an aqueous sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol (300 mL) and the solution was heated at reflux for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography (CHROMATOREX NH (trade name), manufactured by Fuji Silysia Chemical Ltd.) (n-hexane:ethyl acetate=1:1→1:2→0:1→ethyl acetate:ethanol=19:1→9:1) to obtain the title compound (24.4 g) having the following physical properties.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][OH:8].[Br:9]N1C(=O)CCC1=O>C1COCC1>[Br:9][C:6]1[N:2]([CH3:1])[C:3]([CH2:7][OH:8])=[N:4][CH:5]=1
Reactant: Cn1ccnc1CO
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Cn1c(Br)cnc1CO
Temperature: 25 °C
Yield: 40.9 %

Procedure:
1-Methylimidazole-2-methanol (3.15 g; 28 mmol) (R. J. Sundberg; P. V. Nguyen; Med. Chem. Res. 7, 2, 1997, 123-136) was suspensed in THF (75 ml) at −20° C. and treated slowly (within 30 min) with N-bromosuccinimide (4.9 g, 27 mmol). The reaction mixture was allowed to warm up slowly to room temperature and quenched with saturated aqueous NaHCO3 solution (50 ml). The aqueous layer was extracted 3 times with AcOEt. The combined extracts were washed with saturated aqueous NaHCO3 solution, dried, over Na2SO4, filtered and the solvent was removed in vacuo. The residue was chromatographed (silica, elution first with AcOEt/hexane=1:1, then with CH2Cl2/MeOH=95:05) to provide the title compound (2.11 g, 67%) as a white solid. MS: m/e=191.2 (M+).
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[F:16][C:17]1[CH:18]=[CH:19][C:20]([O:43][CH3:44])=[C:21]([C:23]2[N:27]=[C:26]([C:28]3[CH:29]=[C:30]([CH:41]=[O:42])[C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])=[CH:32][CH:33]=3)[O:25][N:24]=2)[CH:22]=1>O.O1CCOCC1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([O:43][CH3:44])=[C:21]([C:23]2[N:27]=[C:26]([C:28]3[CH:29]=[C:30]([C:41]([OH:6])=[O:42])[C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH3:40])=[CH:32][CH:33]=3)[O:25][N:24]=2)[CH:22]=1
Reactant: COc1ccc(F)cc1-c1noc(-c2ccc(-c3ccccc3C)c(C=O)c2)n1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(F)cc1-c1noc(-c2ccc(-c3ccccc3C)c(C(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
A solution of sodium chlorite (59 mg; 0.65 mmol; 5.5 eq.) and sodium dihydrogenphosphate (51 mg; 0.43 mmol; 3.6 eq.) in water (1 mL) was added to a mixture of 2-methyl-2-butene (0.13 mL) and 4-[3-(5-fluoro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]-2′-methylbiphenyl-2-carbaldehyde (46.2 mg; 0.12 mmol; 1 eq.) in dioxane (1 mL) and the reaction was stirred at room temperature for 16 hours. The suspension was partitioned between water and ethyl acetate. The aqueous phase was acidified to pH 3-4 with acetic acid and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (43 mg; 89%) as a white solid.
Reaction SMILES: [O:1]1[C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH:3]=[C:2]1[N:10]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:11]([CH:13]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]=2)=[CH:26][CH:25]=1)[CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)=[O:12]>CCO.[Pd]>[O:1]1[C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH:3]=[C:2]1[N:10]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:11]([CH:13]([C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:28][CH:29]=1)[CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)=[O:12]
Reactant: O=C(O)c1ccc(CC(C(=O)N(c2ccccc2)c2ccc3cccc-3o2)c2ccc(C3=CCCCC3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)c1ccc(CC(C(=O)N(c2ccccc2)c2ccc3cccc-3o2)c2ccc(C3CCCCC3)cc2)cc1
Reaction time: 3 h
Yield: 92 %

Procedure:
To a stirred solution of 4-[2-(4-benzofuran-2yl-phenylcarbamoyl)-2-(4-cyclohex-1-enyl-phenyl)-ethyl]-benzoic acid (Example 1.003, Step F) (0.23 g, 0.42 mmol) in EtOH (15 mL) at room temperature, was added 10% Pd/C (30 mg) and hydrogenated under 1 atm. H2 (gas) for a 3 h period. The reaction mixture was filtered through a celite plug, washed with ethyl acetate (2×50 mL) and concentrated under reduced pressure. The resulting compound was dried under vacuum to afford 4-[2-(4-benzofuran-2yl-phenylcarbamoyl)-2-(4-cyclohexyl-phenyl)-ethyl]-benzoic acid (9) (0.21 g, 92%), 1H NMR (300 MHz, CD3OD): 7.85 (d, J=8.1 Hz, 2H), 7.70 (d, J=8.7 Hz, 2H), 7.50 (d, J=9.0 Hz, 2H), 7.16-7.45 (m, 8H), 7.07 (s, 1H), 3.95 (dd, J=6.0, 9.3 Hz, 1H), 3.51 (dd, J=9.3, 12.0 Hz, 1H), 3.06 (dd, J=5.7, 10.8 Hz, 1H), 2.42-2.48 (m, 1H), 1.72-1.90 (m, 5H), 1.35-1.46 (m, 5H); LC-MS m/z=543 [C37H36NO3+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCO)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(CCC=O)cc1
Yield: 51.8 %

Procedure:
2.34 g (14.10 mmoles) of 3-(4-methoxyphenyl)-1-propanol were dissolved in 20 ml of dry dichloromethane and slowly added to a suspension of 4.56 g (21.15 mmoles) of pyridinium chlorochromate in 25 ml of dichloromethane. Once the reaction was completed, which was followed by thin layer chromatography, 3 ml of diethyl ether were added in portions and the mixture was filtered over celite. The ether phase was washed three times with water and left to dry over anhydrous sodium sulphate for an entire night. The 3-(4-methoxyphenyl)-propanal was purified by column chromatography using as eluent ethyl acetate: dichloromethane in increasing polarity, with 1.20 g of an oil being obtained (52% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([CH3:13])([CH3:12])[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]([CH3:12])([CH3:13])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)C(C)(C)CC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CC1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 140 °C
Yield: 79.4 %

Procedure:
2,2-Dimethyl-3-(piperidine-4-yl)-propionic acid methyl ester (156 mg, 0.78 mmol) from above was mixed with 2-chloro-5-nitropyridine (124 mg, 0.78 mol) in tetrahydrofuran (2 mL) containing triethylamine (0.24 mL). The mixture was heated in a microwave at 140° C. for 30 minutes. The mixture was extracted with ethyl acetate and water. The organic layer was washed with brine and dried. Solvents were evaporated and the residue was triturated with ether to give 2,2-dimethyl-3-(5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-propionic acid methyl ester (199 mg) as a crystalline material. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:2]=1[OH:1]
Reactant: O=C(O)c1cccc(O)c1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(O)c1O
Temperature: 25 °C

Procedure:
50 g of 2,3-dihydroxybenzoic acid in 450 ml of methanol is mixed drop by drop with 50 ml of thionyl chloride at room temperature. Then, the solution is heated for five hours to 60° C. and still stirred overnight at room temperature. The solvent is completely removed in a vacuum, and the remaining oil is taken up in diethyl ether and extracted with saturated sodium bicarbonate solution. After washing with brine, drying with sodium sulfate and removal of the solvent in a vacuum, 46 g of 2,3-dihydroxybenzoic acid-methyl ester is obtained. The latter is mixed in 575 ml of DMF and 20.2 ml of dibromomethane with 56.7 g of potassium carbonate, and it is heated for five hours under argon to 100° C. Then, it is stirred overnight at room temperature. After mixing with water, it is extracted three times with ethyl acetate. The organic phase is washed several times with water and dried on sodium sulfate. The solvent is removed in a vacuum, and 50.2 g of 1,3-benzodioxole-4-carboxylic acid-methyl ester is obtained as a brown solid.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH2:7]([O:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[N:13]=1)=[O:11])[CH3:8].[OH:19][C:20]([CH3:53])([CH3:52])[CH2:21][C@@:22]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[O:27][C:26](=[O:28])[N:25]([C@H:29]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH3:30])[CH2:24][CH2:23]1>CN(C)C=O>[CH2:7]([O:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:34]2[CH:33]=[CH:32][C:31]([C@@H:29]([N:25]3[CH2:24][CH2:23][C@:22]([CH2:21][C:20]([OH:19])([CH3:52])[CH3:53])([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[O:27][C:26]3=[O:28])[CH3:30])=[CH:36][CH:35]=2)[N:13]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1cccc(Br)n1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2 M aqueous Na2CO3 solution (1.46 mL) was added to a mixture of 6-bromo-pyridine-2-carboxylic acid ethyl ester (0.50 g) and (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.70 g) in N,N-dimethyl-formamide (8 mL). The resulting mixture was sparged with argon for 10 min, before [1,1′-bis(diphenyl-phosphino)-ferrocene]dichloro-palladium(II) dichloromethane complex (72 mg) was added. The mixture was heated to 100° C. and stirred at this temperature overnight. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and the solvent was evaporated. The residue was purified by HPLC on reversed phase (methanol/water/NH4OH) to afford the title compound. Yield: 0.59 g (80% of theory); Mass spectrum (ESI+): m/z=503 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[NH3:11].[BH4-].[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([NH2:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: N
Reactant: CC(=O)c1ccc(Cl)nc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Product: CC(N)c1ccc(Cl)nc1
Yield: 83.4 %

Procedure:
Stir a mixture of 1-(6-chloro-pyridin-3-yl)-ethanone (5 g, 32.14 mmol) in titanium tetra(isopropoxide) (18.27 g, 64.27 mmol) and ammonia (160.7 mmol, 2 M in MeOH) under N2 for 6 hours at room temperature. To this mixture add sodium tetrahydroborate (1.82 g, 48.21 mmol) and stir overnight. Quench the reaction mixture with ammonium hydroxide and filter the mixture. From the filtrate remove the solvent and extract the residue with dichloromethane, wash with saturated aqueous sodium chloride and dry over Na2SO4, filter and remove the solvent to obtain a dark yellow oil (4.2 g). MS (ES) m/z 157 [M+1]+.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)O)=[CH:11][C:10]2[CH:21]=[CH:22][CH:23]=[CH:24][C:9]1=2.[BH4-].[Na+].[OH-].[Na+]>CCOCC>[CH2:13]([C:12]1[S:8][C:9]2[CH:24]=[CH:23][CH:22]=[CH:21][C:10]=2[CH:11]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OC(c1ccccc1)c1cc2ccccc2s1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: c1ccc(Cc2cc3ccccc3s2)cc1
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Trifluoroacetic acid (105 mL) was added dropwise over a 35 minute period to a stirred suspension of benzo[b]thiophene-2-yl-(phenyl)-methanol (17.6 g, 73.2 mmol), sodium borohydride (13.75 g, 364 mmol) and ether (1.3 L). After an additional 5 hours the reaction mixture was added to 10% aqueous sodium hydroxide (1.3 L) and stirred for 30 minutes. The layers were separated and the ether phase was washed with brine (500 mL) and dried (MgSO4). The ether phase was concentrated to provide the title compound as a white solid (15.2 g, 92%): NMR (CDCl3); δ 7.73 (d, J=6 Hz, 1H, thiopheneH), 7.65 (d, J=7 Hz, 1H, thiopheneH), 7.20-7.38 (m, 7H), 7.00 (s, 1H, thiopheneH), 4.22 (s, 2H, CH2).
Reaction SMILES: [K].CC(C)([O-])C.[I-].[CH:8]1([CH2:14][CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH2:35]([O:37][C:38](=[O:49])[C:39]([C:41]1[CH:46]=[CH:45][C:44]([S:47][CH3:48])=[CH:43][CH:42]=1)=O)[CH3:36]>C1COCC1>[CH2:35]([O:37][C:38](=[O:49])/[C:39](/[C:41]1[CH:46]=[CH:45][C:44]([S:47][CH3:48])=[CH:43][CH:42]=1)=[CH:15]/[CH2:14][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:36]
Reactant: c1ccc([P+](CCC2CCCCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)C(=O)c1ccc(SC)cc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K]
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/CC1CCCCC1)c1ccc(SC)cc1
Reaction time: 1 h

Procedure:
Add potassium-tert.-butoxide (4.3 mL, 1.0 M in THF, 4.3 mmol) to a suspension of (2-cyclohexyl-ethyl)-triphenyl-phosphonium iodide (2.15 g, 4.3 mmol) at room temperature and stir the reaction mixture for 1 h. Dissolve (4-methylsulfanyl-phenyl)-oxo-acetic acid ethyl ester (prepared as described by I. T. Barnish et. al. J. Med. Chem. 1981, 24, 399-404) in THF and add the resulting solution to the reaction mixture. Stir at room temperature over night. Evaporate the solvent and add 15 mL hexane to the remaining solid. Stir at 40° C. for 30 minutes, filter and concentrate the filtrate under vacuum to afford 1.3 g raw material as a yellow oil. Further purify this material via silica gel chromatography, eluting with a gradient from 98:2 to 90:10 hexane:ethyl acetate to afford a colorless oil (379 mg).
Reaction SMILES: NC1C=C([N:10]2[C:18](=[O:19])[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]2=[O:20])C(F)=CC=1Br.BrCC(OCC)=O.C(N(CC)CC)C.O>O1CCOCC1.C1(C)C=CC=CC=1>[C:11]1(=[O:20])[C:12]2[CH:17]([CH2:16][CH2:15][CH2:14][CH:13]=2)[C:18](=[O:19])[NH:10]1
Reactant: Nc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Br
Agent: CCOC(=O)CBr
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C2CCCC=C12

Procedure:
2-(3-Amino-4-bromo-6-fluorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.85 g) was dissolved in 1,4-dioxane (5 ml), and ethyl bromoacetate (3.3 g) was added thereto. The resultant mixture was refluxed for 6 hours. Triethylamine (0.2 g) was added thereto, and the mixture was refluxed for 1 hour. After being allowed to cool, water and toluene were added to the mixture, which was then extracted with toluene. The toluene layer was dried and concentrated. The residue was purified by silica gel column chromatography to give 1.0 g of 2-(4-bromo-2-fluoro-5-ethoxycarbonylmethylaminophenyl)-4,5,6,7-(tetrahydro-2H-isoindole-1,3-dione (Compound No. 89). nD26.0 1.5281.