Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[N:3][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: Oc1ccc(F)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(OCc2ccccc2)cn1
Reaction time: 0.67 h
Yield: 73.5 %

Procedure:
A solution of 2-fluoro-5-hydroxypyridine (Combi-block) (1.00 g, 8.84 mmol) in DMF (12 mL) was treated with sodium hydride, 60% dispersion in mineral oil (Alfa-Aesar) (0.88 g, 22.1 mmol) at rt under N2. After stirring for 40 min, benzyl chloride (Aldrich) (3.05 mL, 26.5 mmol) and tetrabutylammonium iodide (Aldrich) (0.33 g, 0.88 mmol) were added, and the reaction mixture was stirred for a further 2 h. Water (2 mL) was added to quench the reaction, and the reaction mixture was partitioned between EtOAc and sat. NaHCO3. The aqueous layer was extracted with EtOAc (2×15 mL). The combined organic extracts were washed with sat. NaHCO3, brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (120 g, 10% to 20% actone in hexanes) to give the product as a colorless liquid (1.32 g). m/z (ESI, +ve ion) 204.0 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 7.91 (br. s., 1H); 7.32-7.51 (m, 6H); 6.86 (dd, J=8.84, 3.29 Hz, 1H); 5.10 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1.[CH3:13][O:14][CH2:15]Cl>C(#N)C.N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:13][O:14][CH3:15])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(S)cc1
Reactant: COCCl
Solvent: CC#N
Solvent: c1ccncc1
Product: COCSc1ccc(CC(=O)OC)cc1
Yield: 78.9 %

Procedure:
A solution of (4-mercapto-phenyl)-acetic acid methyl ester (500 mg, 2.7 mmol) and chloromethyl methyl ether (331 mg, 4.1 mmol) in acetonitrile (3 mL) and pyridine (1 mL) was heated under reflux for 16 h. At this time, the reaction was concentrated in vacuo. The residue was re-dissolved in ethyl acetate (10 mL) and was washed with a 1N aqueous hydrochloric acid solution (2×25 mL) and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10 hexanes/ethyl acetate) afforded (4-methoxymethylsulfanyl-phenyl)-acetic acid methyl ester (482 mg, 77.6%) as a clear oil: EI-HRMS m/e calcd for C11H14O3S (M+) 226.0664, found 226.0664.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[S:14]([NH2:17])(=[O:16])=[O:15])([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCO.CCOC(C)=O.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[S:14]([NH2:17])(=[O:15])=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(N)cc1S(N)(=O)=O
Yield: 102.2 %

Procedure:
A solution of 2-tert-butyl-5-nitrobenzene-1-sulfonamide (32 mg, 0.12 mmol) and SnCl2.2H2O (138 mg, 0.61 mmol) in EtOH (1.5 mL) was heated in microwave oven at 100° C. for 30 min. The mixture was diluted with EtOAc and water, basified with sat. NaHCO3 and filtered through Celite. The organic layer was separated from water and dried over Na2SO4. Solvent was removed by evaporation to provide 2-tert-butyl-5-aminobenzene-1-sulfonamide (E-7) (28 mg, 100%), which was used without further purification. HPLC ret. time 1.99 min, 10-99% CH3CN, 5 min run; ESI-MS 229.3 m/z (MH+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][CH2:6][C:7]([NH:9][C:10]1[C:15]([O:16][CH3:17])=[C:14]([C:18](=[O:21])[NH:19][CH3:20])[CH:13]=[C:12]([O:22][CH3:23])[C:11]=1[C:24](=[O:27])[NH:25][CH3:26])=[O:8]>>[Cl:5][CH2:6][C:7]([NH:9][C:10]1[C:15]([O:16][CH3:17])=[C:14]([C:18](=[O:21])[NH:19][CH3:20])[C:13]([N+:1]([O-:4])=[O:2])=[C:12]([O:22][CH3:23])[C:11]=1[C:24](=[O:27])[NH:25][CH3:26])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: CNC(=O)c1cc(OC)c(C(=O)NC)c(NC(=O)CCl)c1OC
Product: CNC(=O)c1c(NC(=O)CCl)c(OC)c(C(=O)NC)c([N+](=O)[O-])c1OC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To 50 mL of red fuming nitric acid, chilled to 0° C., was added 2.3 g (6.69 mmol) of 30. After stirring at 0° C. for 45 minutes, 100 mL of ice water was added and the mixture quickly extracted with ethyl acetate. The ethyl acetate extract was dried over Na2SO4, evaporated down to a small volume, and placed on a silica gel column. Gradient chromatography (ethyl acetate to 5% methanolic ethyl acetate) afforded the desired product as a pure white solid: 1.5 g (58%) yield; TLC (ethyl acetate-methanol [9:1]), Rf =0,40; mp 259°-260° C.; IR (KBr pellet) 3370, 1676, 1651, 1568, 1534, 1472, 1404, 1373, 1315, 1054 cm-1 ; 1H NMR (dimethyl-d6 sulfoxide) δ9.99 (1H, s, acetamido proton), 8.64 and 8.28[2H, 2 s, J=2.3 Hz, 1- and 4-carbamyl protons, no assignments made), 4.25 (2H, s, methylene), 3.79 and 3.68 (6H, 2 s, 3- and 6-methoxys, no assignments made), 2.73 (6H, 2 overlapping d, J=4.4 Hz, 1- and 4-carbamyl methyls, no assignments made); mass spectrum (EI mode), m/z 388 (P+, 390 (P+, 37Cl).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([O:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([O:19]C(C)(C)C)=[O:18])([CH3:16])[CH3:15])=[CH:9][CH:8]=1)[CH3:2].C(OC(=O)[C@@H](OC)CC1C=CC(OCC(O)=O)=CC=1)C>>[CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([O:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=[O:18])([CH3:15])[CH3:16])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1)OC
Agent: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Product: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OC

Procedure:
The title compound was prepared from (2S)-3-[4-(1-tert-butoxycarbonyl-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (PREPARATION 5, step 1) via the same procedure used to prepare (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (example 121, step 2) to produce a yellow oil. 1H-NMR (CDCl3, 200.15 MHz): 7.10 (d, 2H, J=8.3), 6.77 (d, 2H, J=8.3), 4.14 (c, 2H, J=6.9), 3.89 (t, 1H, J=6.5), 3.34 (s, 3H), 2.94 (d, 2H, J=6.5), 1.55 (s, 6H), 1.19 (t, 3H, J=6.9).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[NH2:13]Cl.S([O-])([O-])(=O)=S.[Cl-].[NH4+]>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([NH2:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2cc[nH]c2c1
Reactant: NCl
Agent: O=S([O-])([O-])=S
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nn1ccc2ncc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of 6-Bromo-1H-pyrrolo[3,2-b]pyridine (1.9 g, 10 mmol) in 20 mL of DMF at 0° C. was added NaH (60% in oil, 0.49 g, 12 mmol) in three portions. The mixture was stirred at room temperature for 30 min. A solution of NH2Cl in Et2O (prepared according to the procedure described in J. Org. Chem. 2004, 1371: ˜0.15 M, 80 mL) was added at −20° C. The mixture was warmed up to room temperature for 15 min and was poured into a saturated solution of thiosulfate and ammonium chloride, and extracted with ethyl acetate. The organic layer was concentrated and the residue washed with small amount of ethyl acetate to give pink solid (1.3 g, 62% yield)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][C:3]=1[N:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18](=[O:23])[C:17]([C:24](N(OC)C)=[O:25])=[N:16]1.[CH3:30][Mg+].[Br-]>C1COCC1>[C:24]([C:17]1[C:18](=[O:23])[C:19]([O:21][CH3:22])=[CH:20][N:15]([C:3]2[CH:4]=[CH:5][C:6]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[C:7]([F:8])[C:2]=2[F:1])[N:16]=1)(=[O:25])[CH3:30]
Reactant: C[Mg+]
Reactant: COc1cn(-c2ccc(N3CCOCC3)c(F)c2F)nc(C(=O)N(C)OC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2ccc(N3CCOCC3)c(F)c2F)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A solution of 1-(2,3-difluoro-4-morpholin-4-ylphenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (1.1 g, 2.6 mmol) in THF (25 mL) was added dropwise to MeMgBr (1.0 M in THF, 11 mL, 11 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 1 h. The reaction was quenched with 1 M HCl aqueous solution (11 mL) at −78° C. The mixture warmed up to room temperature, diluted with AcOEt, and washed with brine. The organic layer was dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from iPr2O/AcOEt to give the title compound (870 mg, 92% yield) as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6): δ ppm 2.49 (3H, s), 2.90-3.28 (4H, m), 3.64-4.01 (7H, m), 7.05 (1H, td, J=8.9, 2.3 Hz), 7.53 (1H, td, J=8.6, 2.5 Hz), 8.50 (1H, d, J=1.9 Hz). LC-MS (ESI) m/z 366 [M+H]+.
Reaction SMILES: C[O:2][CH:3](OC)[CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:13][C:12]=3[N:23]([CH3:33])[S:24]([C:27]2[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=2)(=[O:26])=[O:25])=[N:6][CH2:5]1.FC(F)(F)C(O)=O.S(=O)(=O)(O)O.[BH4-].[Na+]>O1CCCC1.C(O)C.O>[OH:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[CH:13][C:12]=3[N:23]([CH3:33])[S:24]([C:27]2[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=2)(=[O:25])=[O:26])=[N:6][CH2:5]1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2nccn2C)c2[nH]c(C3=NCC(C(OC)OC)S3)cc2c1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COCCOc1cc(N(C)S(=O)(=O)c2nccn2C)c2[nH]c(C3=NCC(CO)S3)cc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 10 %

Procedure:
To a mixture of N-[2-[5-(dimethoxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-5-(2-methoxyethoxy)-1H-indol-7-yl]-N,1-dimethyl-1H-imidazole-2-sulfonamide (335 mg), trifluoroacetic acid (4 mL) and water (12 mL) was added concentrated sulfuric acid (4 mL), and the mixture was stirred at 60° C. for 2 hr. The excess trifluoroacetic acid was evaporated under reduced pressure, and the residue was neutralized with sodium hydrogencarbonate. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained crude product was dissolved in a mixed solvent of tetrahydrofuran (3 mL) and ethanol (2 mL), and sodium borohydride (26.5 mg) was added under ice-cooling. The reaction solution was stirred at room temperature for 2 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-90:10), and the obtained crude product was further purified by preparative HPLC to give the title compound (30.8 mg, yield 10%) as a white solid. MS: 480(MH+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([O:14][CH3:15])=[O:13])=[N:4][C:3]=1[C:16]([O:18]C)=O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[C:23]([S:29][CH3:30])[CH:22]=1.CN(C=O)C>C1(C)C=CC=CC=1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:16]([C:3]2[N:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[C:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:11]=3[C:2]=2[OH:1])=[O:18])=[C:23]([S:29][CH3:30])[CH:22]=1
Reactant: CSc1cc(F)ccc1CN
Reactant: COC(=O)c1nc(C(=O)OC)c2cccnc2c1O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C(=O)NCc2ccc(F)cc2SC)c(O)c2ncccc12
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A slurry of dimethyl 8-hydroxy-1,6-naphthyridine-5,7-dicarboxylate (0.25 g, 0.953 mmol), 1-[4-fluoro-2-(methylthio)phenyl]methanamine (0.326 g, 1.91 mmol) and N,N,N-diisopropylethylamine (170 uL, 0.953 mmol) in toluene (4.0 mL) were heated in a pressure tube at 110 degrees C. for 18 hrs. The reaction was incomplete by LCMS analysis and solids remained undissolved. DMF (1 mL) was added to solubilize the reagents and the reaction was again heated in a pressure tube at 110 degrees C. for 18 hrs. Upon cooling to room temperature, the resulting solution was transferred to a round bottom flask and reduced to a small volume. The residue was partitioned between methylene chloride and water. The organic layer was dried with Na2SO4, filtered and reduced in vacuo. The material was crystallized with a small amount of chloroform. The solid was filtered and dried in vacuo to afford the desired compound as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH:48][C:49]([NH2:51])=[O:50])=[CH:38][CH:37]=2)[CH2:9]1)=O)(C)(C)C.Cl.CO>>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH:48][C:49]([NH2:51])=[O:50])=[CH:38][CH:37]=2)=[CH:15][CH:16]=1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCNC(N)=O)CCC3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc(C2CCNCC2OCc2ccc3c(c2)N(CCNC(N)=O)CCC3)cc1

Procedure:
In analogy to the procedure described in example 4(b), the (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[1-(2-ureido-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl/methanol to yield the (3R,4R)-[[2-[7-[4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidin-3-yloxymethyl]-3,4-dihydro-2H-quinolin-1-yl]-ethyl]-urea as yellow oil; MS: 603 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[N:3]=1.[Na+].[I-].[CH2:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)[CH3:13].C(N(C(C)C)C(C)C)C>CCO>[CH3:9][NH:8][C:4]1[N:3]=[C:2]([NH:24][C:23]2[CH:22]=[CH:21][C:20]([N:17]3[CH2:16][CH2:15][N:14]([CH2:12][CH3:13])[CH2:19][CH2:18]3)=[CH:26][CH:25]=2)[N:7]=[CH:6][N:5]=1
Reactant: CNc1ncnc(Cl)n1
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCN1CCN(c2ccc(Nc3ncnc(NC)n3)cc2)CC1
Temperature: 80 °C

Procedure:
A mixture of (4-chloro-[1,3,5]triazin-2-yl)-methyl-amine (290 mg, 2.00 mmol), NaI (28 mg) and 4-(4-ethylpiperazin-1-yl)-aniline (410 mg, 2.0 mmol) in EtOH (20 ml) and N-ethyl-diisopropyl amine (350 μl, 2.0 mmol) is heated to 80° C. for 3 h under a nitrogen atmosphere. The reaction mixture is cooled to RT, concentrated partially in vacuo and diluted with hexane at 0° C. The precipitate is filtered off, washed with Et2O and re-dissolved in EE and water. The separated off aqueous phase is extracted twice with EE, the organic layer washed with water and brine, dried (Na2SO4) and concentrated, yielding the title compound: ESI-MS: 314 [MH]+; TLC: Rf=0.10 (DCM/MeOH 9:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.C([Cl:26])(=O)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[Cl:26])=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: Fc1ccc(C(Cl)(c2ccccc2)c2ccc(F)cc2)cc1
Reaction time: 12 h

Procedure:
Bis(4-fluorophenyl)phenylmethanol (0.092 mol) was added to a 20% solution of acetyl chloride in dichloromethane (50 mL) at rt. The resulting purple solution was stirred for 12 h after which the solvent was removed by evaporation. Toluene (100 mL) was added to the residue and then evaporated, affording crude bis(4-fluorophenyl)phenylchloromethane which was used without purification in the following step.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@@H:6]1[CH2:24][CH2:25][P:26](=[O:29])([O-:28])[O-:27])(=O)C.[CH2:30]([NH+:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[CH3:31].[CH2:37]([NH+:39]([CH2:42][CH3:43])[CH2:40][CH3:41])[CH3:38]>O.CO.CCN(CC)CC>[C@H:6]1([CH2:24][CH2:25][P:26](=[O:27])([O-:29])[O-:28])[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4].[CH2:30]([NH+:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[CH3:31].[CH2:37]([NH+:39]([CH2:42][CH3:43])[CH2:40][CH3:41])[CH3:38]
Reactant: CC(=O)OC[C@H]1O[C@H](CCP(=O)([O-])[O-])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC[NH+](CC)CC
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: O=P([O-])([O-])CC[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 57.5 %

Procedure:
A solution of 6 (49.3 mg, 0.11 mmol) in H2O/MeOH/Et3N (7:3:1, 11 mL) was stirred for 16 h at room temperature. The reaction was evaporated to dryness and the residual white powder was purified by Purification Method 1 (100% 0.05 M TEAB) to afford the triethylammonium salt of 7 as a colorless foam (30 mg, 99%): Rf 0.2 (iPrOH/H2O/aq. NH4OH 6:3:1); δH (400 MHz, D2O) 3.82-3.70 (m, 3H, H-3, H-6, H-7), 3.59 (dd, 1H, J1,2 3.4 Hz, J2,3 9.5 Hz, H-4), 3.54-3.43 (m, 3H, H-5, H-8a, H-8b), 2.97 (q, J=7.3 Hz, NCH2CH3, 1.4 equiv.), 1.70-1.20 (m, 4H, H-1a, H-1b, H-2a, H-2b), 1.04 (t, J=7.3 Hz, NCH2CH3, 1.4 equiv.); δC (100 MHz, D2O) 76.2 (d, JC,P 16.3 Hz, C-3), 71.6 (C-7), 69.6, 69.2 (C-5/C-6), 68.3 (C-4), 61.3 (C-8), 46.7 (NCH2CH3), 23.9 (d, JC,P 134.2 Hz, C-1), 18.4 (C-2), 8.3 (NCH2CH3); δP (161.9 MHz, D2O) 24.9. m/z (ESI) 271.0590 [M−H]−, C8H16O8P requires 271.0588.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[N+:18]([C:21]1[CH:35]=[CH:34][C:24]2[N:25]=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:27][C:23]=2[CH:22]=1)([O-:20])=[O:19]>O1CCCC1>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:31]1[CH2:32][CH2:33][N:28]([C:26]2[S:27][C:23]3[CH:22]=[C:21]([N+:18]([O-:20])=[O:19])[CH:35]=[CH:34][C:24]=3[N:25]=2)[CH2:29][CH2:30]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: O=[N+]([O-])c1ccc2nc(N3CCNCC3)sc2c1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc3ccc([N+](=O)[O-])cc3s2)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-Isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 6-Nitro-2-piperazin-1-yl-benzothiazole in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate), and the residue was then triturated in ether to yield the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[CH3:20][O:21][C:22](=[O:27])[CH2:23][C:24](Cl)=[O:25]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]([C:24](=[O:25])[CH2:23][C:22]([O:21][CH3:20])=[O:27])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)cn1NCc1ccc(Cl)cc1
Reactant: COC(=O)CC(=O)Cl
Product: COC(=O)CC(=O)N(Cc1ccc(Cl)cc1)n1cc(Cl)cc1C(=O)OC

Procedure:
Prepared according to the acylation condition used in Example 2 step f) from 4-chloro-1-(4-chloro-benzylamino)-1H-pyrrole-2-carboxylic acid methyl ester and chlorocarbonyl-acetic acid methyl ester (1.5 eq.). 1H NMR (CDCl3, δ in ppm): 7.26 (d, 2H, J=8.2 Hz), 7.08 (d, 2H, J=8.8 Hz), 6.83 (d, 1H, J=2.2 Hz), 6.47 (d, 1H, J=1.8 Hz), 5.27 (d, 1H, J=14.6 Hz), 4.27 (d, 1H, J=14.6 Hz), 3.75 (s, 3H), 3.69 (s, 3H), 3.18 (m, 2H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=O.C1(=O)OCCC1>>[C:4]1(=[O:6])[O:8][CH2:1][CH2:2][CH2:3]1.[C:4]1(=[O:6])[O:8][C:1](=[O:7])[CH2:2][CH2:3]1
Reactant: O=C(O)CCC(=O)O
Solvent: O=C1CCCO1
Product: O=C1CCC(=O)O1
Reaction time: 4 h

Procedure:
A mixture of 2000 g of succinic acid (water-wet, 82.5%) and 400 g of butyrolactone is heated to the boil in a fractionating column having 10 theoretical trays. The rising vapor is removed at a reflux ratio of 3:1 and is condensed. The bottoms temperature is initially 115°C and rises over 4 hours at a constant rate to 170°C. The temperature at the top of the column remains at 100°C during this period and 500 g of water are distilled off. The reflux ratio is now raised to 5:1. After a further hour a total of 560 g of water has distilled off. The temperature of the vapors at the top of the column rises to 200°C and dehydration is complete. The butyrolactone is distilled off at 110°C/35 mm Hg to give 392 g thereof. The vacuum is then increased to 17 mm Hg and an intermediate run of butyrolactone/succinic anhydride gives a total of 54 g distilled off. At a constant boiling temperature of 142°C, 1094 g of succinic anhydride then distil over, this being equivalent to 78% of theory.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[Br:12]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]([Br:12])=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1cc(Br)c(C(=O)O)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
A mixture of 3-amino-4-methylbenzoic acid (13) (5.1525 g, 34.08 mmol)) and DMF (30 mL) is cooled to about 5° C., whereupon N-bromosuccinimide (6.230 g, 35 mmol) is added in small portions, at a rate such that the reaction temperature stays below 10° C. The reaction mixture is then stirred at ambient temperature for about 3 hours and is then added to ice water (150 mL). The solids that form are filtered and dried to provide 3-Amino-6-bromo-4-methylbenzoic Acid (19) (6.5439 g, 83% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.[C:12]1(C=CCO)C=CC=CC=1.N>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][C@H:9]2[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: OC/C=C/c1ccc(Br)cc1
Reactant: OCC=Cc1ccccc1
Agent: N
Product: OC[C@@H]1C[C@H]1c1ccc(Br)cc1

Procedure:
The title compound was prepared by the method of A. B. Charette and H. Lebel (Organic Synthesis, 1998, 76, 86-96) substituting trans-3-(4-Bromophenyl) prop-2-en-1-ol (the product from Example 1A) for 3-Phenyl-prop-2-en-1-ol. 1H NMR (300 MHz, CDCl3): δ 0.92-1.0 (m, 2H), 1.45-1.48 (m, 2H), 1.76-1.85 (m, 1H), 3.61 (d, J=7.5 Hz, 2H), 6.95 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 228 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][C:6]1[CH:7]=[C:8]2[C:14]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:13][N:12]([C:27]3[C:28]4[C@H:35]([CH3:36])[CH2:34][CH2:33][C:29]=4[N:30]=[CH:31][N:32]=3)[C:9]2=[CH:10][CH:11]=1)C.O[Li].O>C1COCC1.O>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C:14]2([C:8]3[C:9](=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:37])=[O:3])[CH:7]=3)[N:12]([C:27]3[C:28]4[C@H:35]([CH3:36])[CH2:34][CH2:33][C:29]=4[N:30]=[CH:31][N:32]=3)[CH2:13]2)[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)Cc1ccc2c(c1)C1(CCN(C(=O)OC(C)(C)C)CC1)CN2c1ncnc2c1[C@H](C)CC2
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(CC(=O)O)ccc43)c21

Procedure:
A solution of (R)-tert-butyl 5-(2-ethoxy-2-oxoethyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.325 g, 0.641 mmol) in THF:H2O (2:1, 3 mL) was treated with LiOH—H2O (0.067 g, 1.6 mmol) at about 0° C. The reaction was stirred with warming to about room temperature overnight. The reaction was concentrated and diluted with EtOAc. The organic was washed with saturated NaHCO3, acidified with 1N HCl, and extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to yield (R)-2-(1′-(tert-butoxycarbonyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-5-yl)acetic acid. LCMS (APCI+) m/z 479.3 [M+H]+; Rt=2.82 min.