Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[OH:18]>C(Cl)Cl>[C:5]([O:18][C:12]1[C:13]([CH3:17])=[CH:14][C:15]([C:5](=[O:8])[CH2:6][CH3:7])=[CH:16][C:11]=1[CH3:10])(=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)Cl
Reactant: Cc1cccc(C)c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)Oc1c(C)cc(C(=O)CC)cc1C
Reaction time: 2 h
Yield: 170.5 %

Procedure:
To a mixture of aluminum chloride (32.0 g, 24 mmol) in methylene chloride (100 mL) was added propionyl chloride (3.56 mL, 40.95 mmol) all at once followed by 2,6-dimethylphenol (5.0 g, 40.93 mmol in 25 mL of methylene chloride) over 5 min. After stirring 1 h at ambient temperature a second equivalent of propionyl chloride was added (3.56 mL). The reaction was stirred 2 h more and then carefully quenched with water. The mixture was extracted with ether (3x) and the combined organic phase was washed with aqueous bicarbonate and brine; then it was dried over magnesium sulfate and concentrated to give 8.18 g (85%) of 2,6-dimethyl-4-propionylphenyl propionate as a waxy tan solid which had: NMR δ7.68 (s, 2 H), 2.95 (q, J=7.3 Hz, 2 H), 2.65 (q, J=7.5 Hz, 2 H), 2.19 (s, 6 H), 1.32 (t, J=7.6 Hz, 3 H), 1.20 (t, J=7.3 Hz, 3 H). This product also contained some minor impurities in the NMR spectrum but was found suitable for use without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([O:10][C:11]([C:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][C:18](Cl)=[C:19]([F:24])[CH:20]=2)[N:15]([CH:26]=[CH2:27])[CH:14]=1)=[O:12])[CH3:9]>N1C=CC=CC=1>[CH2:8]([O:10][C:11]([C:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][C:18]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[C:19]([F:24])[CH:20]=2)[N:15]([CH:26]=[CH2:27])[CH:14]=1)=[O:12])[CH3:9]
Reactant: C=Cn1cc(C(=O)OCC)c(=O)c2cc(F)c(Cl)cc21
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: C=Cn1cc(C(=O)OCC)c(=O)c2cc(F)c(N3CCN(C)CC3)cc21
Yield: 68.6 %

Procedure:
1-Methylpiperazine (1.6 g) and 1-vinyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (1.2 g) were added to a 3 ml of pyridine, and the mixture was refluxed for 5 hrs. The reaction mixture was concentrated in vacuo, water was added to the residue, and the mixture was adjusted to pH 4 with acetic acid. After filtering, the filtrate made alkali with sodium hydroxide solution. The crude crystals were recrystallized from a mixture of chloroform and benzene to give 1.0 g (68.5% yield) of 1-vinyl-6-fluoro-7-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester. mp: 186.5°-187.5° C.
Reaction SMILES: [CH:1]([CH:4]1[N:9]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20](=[O:22])[CH3:21])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:23]3[CH:29]=[C:28]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:27]=[CH:26][C:24]=3[N:25]=[C:5]12)([CH3:3])[CH3:2].[CH3:34][Mg+].[Br-]>C1COCC1>[CH:1]([CH:4]1[N:9]([C:10]2[N:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[C:13]([C:20]([OH:22])([CH3:34])[CH3:21])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:23]3[CH:29]=[C:28]([S:30]([CH3:33])(=[O:31])=[O:32])[CH:27]=[CH:26][C:24]=3[N:25]=[C:5]12)([CH3:3])[CH3:2]
Reactant: C[Mg+]
Reactant: CC(=O)c1cnc(N2CCn3c(nc4ccc(S(C)(=O)=O)cc43)C2C(C)C)nc1C(F)(F)F
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)C1c2nc3ccc(S(C)(=O)=O)cc3n2CCN1c1ncc(C(C)(C)O)c(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
To a solution of 1-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)ethanone (20 mg, 0.04 mmol, prepared according to example 1) in THF (5 mL) was added MeMgBr (0.6 mL, 0.20 mmol) dropwise at 0° C. under N2. The mixture was stirred at 0° C. for 2 h. The mixture was quenched with sat. aq. NH4Cl (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated and then purified by preparative TLC to afford a racemic mixture of 2-(2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidin-5-yl)propan-2-ol (6.90 mg, 33% yield) as a white solid. LC-MS m/z 498.2 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 8.79 (s, 1H), 7.99 (d, J=1.2 Hz, 1H), 7.90-7.81 (m, 2H), 6.08 (d, J=8.0 Hz, 1H), 5.35 (dd, J=4.4 and 14.0 Hz, 1H), 4.33-4.27 (m, 1H), 4.25-4.12 (m, 1H), 3.88-3.73 (m, 1H), 3.09 (s, 3H), 2.57-2.48 (m, 1H), 1.99 (s, 1H), 1.66 (s, 6H), 1.32 (d, J=6.8 Hz, 3H), 1.09 (d, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:27])=[CH:21][CH:20]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)Nc4ccc(F)cc4)nc23)CC1
Yield: 73.7 %

Procedure:
Beginning with 0.15 gm (0.65 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.096 mL (0.85 mMol) 4-fluorophenyl isocyanate, 0.176 gm (74%) of the title compound were recovered essentially by the procedure of Example 122. An analytical sample was crystallized from methanol.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]([NH:27][NH2:28])=[O:26])[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:37](Cl)(Cl)=[O:38]>C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:20]3[CH:21]=[C:22]([C:25]4[O:26][C:37](=[O:38])[NH:28][N:27]=4)[CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(C(=O)NN)cc32)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(-c4n[nH]c(=O)o4)cc32)cc1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
To a solution of 6-[(4-tert-butylphenyl)sulfonyl]-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine-8-carbohydrazide (intermediate 57, 0.040 g, 0.0771 mmol) in DCM (0.2 mL) at −78° C. was added phosgene (0.081 mL of a ˜20% solution in toluene) dropwise. After stirring at −20° C. overnight, the reaction was quenched with saturated aqueous NaHCO3, and the product was extracted with EtOAc and DCM. The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified via SiO2 column chromatography, eluting with mixtures of EtOAc and hexane, to afford the title compound. LC/MS: m/e 546.1 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.96 (1H, d, J=6.4 Hz), 7.62 (11-1, d, J=8.4 Hz), 7.54 (1H, d, J=7.8 Hz), 7.29 (1H, d, J=5.5 Hz), 7.03-7.04 (3H, m), 6.86-6.89 (3H, m), 4.50-4.90 (2H, br), 1.14 (9H, s).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].CC([N:35]([CH2:39][CH2:40][N:41]1[CH:45]=[C:44](I)[N:43]=[CH:42]1)[C:36](=[O:38])[O-:37])(C)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)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>[CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:44]3[N:43]=[CH:42][N:41]([CH2:40][CH2:39][NH:35][C:36]([O:37][C:16]([CH3:11])([CH3:7])[CH3:15])=[O:38])[CH:45]=3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CC(C)(C)N(CCn1cnc(I)c1)C(=O)[O-]
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: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3cn(CCNC(=O)OC(C)(C)C)cn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Yield: 12 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 52) (333 mg, 0.80 mmol), 1,1-dimethylethyl[2-(4-iodo-1H-imidazol-1-yl)ethyl]carbamate (for a preparation see Intermediate 80) (270 mg, 0.8 mmol), potassium carbonate (443 mg, 3.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.040 mmol) in toluene (10 ml) and ethanol (10 ml) was refluxed under nitrogen for 16 h then cooled to room temperature and the insoluble were filtered off. Potassium carbonate (443 mg, 3.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (46 mg, 0.040 mmol) were added to the filtrate and the resulting mixture refluxed for 7 h then cooled to room temperature and the insoluble filtered off. The resulting solution was concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 6% MeOH in DCM) gave 1-methylethyl((2S,4R)-1-acetyl-6-{1-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1H-imidazol-4-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (47 mg, 0.094 mmol, 12%) as a light brown solid.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[OH-].[CH2:7]([N+:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10]>>[C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3].[CH2:20]([N+:11]([CH2:7][CH2:8][CH2:9][CH3:10])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:21][CH2:22][CH3:23]
Reactant: C=CC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Product: C=CC(=O)[O-]
Temperature: 65 °C
Reaction time: 6 h

Procedure:
A 5 liter glass reaction vessel, fitted with a magnetic stirrer, a hose connector, and a septum were purged with nitrogen. Operating in an atmosphere of nitrogen, 297 grams of poly(isobutylene-co-para-bromomethylstyrene) (Mv=1.2M, 1.7% para-bromomethylstyrene) was placed into the vessel along with 3.5 liters of xylenes. The polymer was dissolved with stirring under a partial vacuum of 100 mm Hg with a nitrogen sparge attached at the bottom of the solution. A xylene solution of tetrabutylammonium acrylate was prepared in a second flask under nitrogen by placing 100 ml xylenes, 60 ml tetrabutylammonium hydroxide (1 M in methanol) and 6.0 g acrylic acid together with stirring. The contents of the flask was concentrated to half its volume and then diluted to 0.5 liters with more xylenes. This solution was then added to the flask containing the poly(isobutylene-co-para-bromomethylstyrene) and the temperature of the solution was raised to 65° C. The reaction was complete in six hours and the polymer was isolated by precipitation in isopropanol. The polymer was dried in a vacuum oven at 1 mm Hg, 40° C. The analysis for the acrylate content (FTIR and NMR) indicate that the modified polymer has 0.24 meq/gram which is consistent with the complete conversion of acrylic acid to acrylic ester and total conversion of the benzylbromide.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([CH3:27])([C:21]1[N:25]=[C:24]([CH3:26])[O:23][N:22]=1)[NH2:20]>>[CH3:18][C:19]([NH:20][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:21]1[N:25]=[C:24]([CH3:26])[O:23][N:22]=1)[CH3:27]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (LC/MS): 357.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][C:15](=[O:22])[C:14]=2[C:13]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:10])=[O:9].[CH3:27]OC(OC)OC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH:16]=[C:15]([O:22][CH3:27])[C:14]=2[C:13]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:10])=[O:9]
Reactant: COC(OC)OC
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1C(=O)CCC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1C(OC)=CCC2
Temperature: 25 °C
Yield: 83.8 %

Procedure:
A mixture of Example 458A (240 mg, 0.64 mmol), trimethylorthoformate (0.7 mL, 6.4 mmol) and pyridinium p-toluenesulfonate (80 mg, 0.32 mmol) in methanol (7 mL) was refluxed overnight, cooled to room temperature, and partitioned between diethyl ether and brine. The organic phase was dried (MgSO4), filtered, concentrated, and passed through a silica gel plug eluting with 30% acetone/hexanes to provide the desired product (210 mg, 83% yield). MS (ESI) m/e 390 (M−H)−, 1H NMR (300 MHz, DMSO-d6) δ 9.82 (s, 1H), 7.73-7.62 (m, 2H), 7.44 (m, 1H), 7.31 (t, 1H), 7.22 (d, 1H), 7.02 (d, 1H), 5.19 (t, 1H), 3.54 (s, 3H), 3.50 (s, 3H), 2.64 (t, 2H), 2.19 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[C:7]([C:9]3[N:14]=[C:13]([OH:15])[C:12]([N+:16]([O-])=O)=[CH:11][CH:10]=3)[N:8]=2)[CH2:3][CH2:2]1>C(O)C>[NH2:16][C:12]1[C:13]([OH:15])=[N:14][C:9]([C:7]2[N:8]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[NH:5][C:6]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(C3CC3)[nH]c2-c2ccc(F)cc2F)nc1O
Solvent: CCO
Product: Nc1ccc(-c2nc(C3CC3)[nH]c2-c2ccc(F)cc2F)nc1O
Temperature: 25 °C
Yield: 95.7 %

Procedure:
6-[2-Cyclopropyl-5-(2,4-difluorophenyl)-1H-imidazol-4-yl]-3-nitro-pyridin-2-ol (4.525 g, 12.63 mmol) is dissolved in ethanol (63 mL). The solution is degassed with bubbling nitrogen gas. 10% Pd/C (920 mg) is added portionwise to the mixture and the mixture is saturated with hydrogen. The mixture is stirred under a hydrogen atmosphere (balloon) at RT over the weekend, at which time LC/MS shows complete conversion. The suspension is filtered through a pad of CELITE® to remove the catalyst and the solution is concentrated under reduced pressure to afford the title compound (3.97 g, 89%). LC-ES/MS m/z 328.9 (M+1).
Reaction SMILES: [C:1]1([P:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:21]=CC(O)=[CH:18][CH:17]=1.C(O)C>>[C:1]1([P:7]([O:11][C:12]2[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:13]=2)[O:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(O)cc1
Reactant: CCOP(OCC)c1ccccc1
Solvent: CCO
Product: CCOP(Oc1ccc(OC)cc1)c1ccccc1
Temperature: 160 °C

Procedure:
99 g (0.5 mol) of diethyl phenylphosphonite and 62 g (0.5 mol) of 4-methoxyphenol were mixed and heated with stirring at 415 mbar. Ethanol distilled off at 115° C. via a small column. The temperature was then increased stepwise to 160° C., and the vacuum was simultaneously increased to 70 mbar. In total, 21.5 g (0.467 mol) of ethanol distilled off. The batch was then cooled and distilled. After a first fraction of 29 g, which essentially contained the unreacted starting materials, 103 g were obtained having a boiling point from 135° to 138° C. at 0.1 to 0.2 mbar. The yield was thus 75% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9](O)[C:10]2([F:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:28]2[C:24](=[O:34])[C:25]3[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:27]2=[O:29])[C:10]2([F:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(C(O)c2ccc(F)c(Cl)c2)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(F)(C(c2ccc(F)c(Cl)c2)N2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
To a solution of 77 (194.9 mg, 0.560 mmol) and THF (5.6 mL) cooled to 0° C. was added phthalimide (90.70 mg, 0.616 mmol) and Ph3P (191.1 mg, 0.729 mmol). The reaction mixture was then treated with DEAD (331.8 μL, 0.729 mmol) and warmed to RT and stirred for 16 h. The reaction mixture was concentrated in vacuo. The crude product was purified by SiO2 Biotage chromatography eluting with hexanes/acetone to afford 238.5 mg (89.2%) of tert-butyl 3-((3-chloro-4-fluorophenyl)(1,3-dioxoisoindolin-2-yl)methyl)-3-fluoropyrrolidine-1-carboxylate (79): LC/MS: [M+1-100] m/z 377.0, 379.0.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19]Cl>CN(C)C=O>[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][N:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)[CH3:1]
Reactant: COCCOCCCl
Reactant: CNCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: COCCOCCN(C)Cc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
5.0 g of 4-methylaminomethyl-nitrobenzene are dissolved in 30 ml of dimethylformamide and 4.6 g of 2-(2-methoxy-ethoxy)-ethyl chloride are added. After six hours' stirring at 100° C. the solvent is removed and the residue is taken up in ethyl acetate. The organic phase is washed with water and dried over sodium sulphate. After the elimination of the solvent the residue is purified over an aluminium oxide column (activity 2-3) with toluene/ethyl acetate 5:1 as eluant.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1.I[CH2:12][C:13]1[O:17][N:16]=[C:15]([CH3:18])[N:14]=1>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][CH2:9][O:10][CH2:12][C:13]2[O:17][N:16]=[C:15]([CH3:18])[N:14]=2)[N:7]=1
Reactant: Cc1noc(CI)n1
Reactant: OCCc1cccc(Br)n1
Product: Cc1noc(COCCc2cccc(Br)n2)n1

Procedure:
The title compound was prepared as described in Example 236, Step 1 using 2-(6-bromopyridin-2-yl)ethanol (Example 235 Step 3) (50 mg, 0.25 mmol) and 5-(iodomethyl)-3-methyl-1,2,4-oxadiazole (110 mg, 0.50 mmol) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([C:12]2[N:13]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:14]3[C:19]([C:20]=2C)=[CH:18][C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:43][CH2:44][CH2:45][CH2:46]I>C(#N)C>[Cl:1][C:2]1[C:10]([O:11][CH2:46][CH2:45][CH2:44][Cl:43])=[CH:9][C:8]([C:12]2[N:13]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:36]
Reactant: ClCCCI
Reactant: Cc1c(-c2cc(O)c(Cl)c3c2C(=O)NC3)n(C(=O)OC(C)(C)C)c2ccc(CN3CCCCC3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCCCCl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 84.5 %

Procedure:
In a similar manner to Step 1 of Example 433, 4-chloro-5-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)methylindol-2-yl]isoindolinone (100 mg, 0.202 mmol) was suspended in acetonitrile (5.0 mL), and the suspension was treated with cesium carbonate (98.7 mg, 0.303 mmol) and 1-chloro-3-iodopropane (0.026 mL, 0.242 mmol), followed by purification by flash column chromatography (chloroform/methanol=19/1, 4/1) to obtain 4-chloro-5-(3-chloropropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (97.7 mg, yield 84%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:6]([C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1nc[nH]c1C
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Yield: 69.6 %

Procedure:
Ethyl 5-methyl-4-1H-imidazolecarboxylate (6.16 g) in toluene (100 ml), triphenylmethyl chloride (11.12 g) and triethylamine (5.6 ml) were heated at reflux for 18 h. Toluene was removed under reduced pressure and the residue was dissolved in dichloromethane (100 ml), washed with water (4×50 ml) dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica using 1% methanol in dichloromethane as eluant with a trace of triethylamine. This afforded the title compound (11 g), m.p. 188°-190° C. δH (250 MHz, CDCl3) 1.38-1.42 (3 H, t, J=6.5 Hz, CH3), 1.86 (3 H, s, CH3), 4.36-4.40 (2 H, q, J=7.2 Hz, CH2), 7.10-7.46 (16 H, m, ArH); m/z (NoM+), 243 (Ph3C+, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]2[NH:18][C:17]3[C:19]4[C:24]([CH2:25][CH2:26][C:16]=3[N:15]=2)=[CH:23][C:22]([Br:27])=[CH:21][CH:20]=4)[C@@H:12]2[CH2:28][C@H:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]2[NH:18][C:17]3[C:19]4[C:24]([CH:25]=[CH:26][C:16]=3[N:15]=2)=[CH:23][C:22]([Br:27])=[CH:21][CH:20]=4)[C@@H:12]2[CH2:28][C@H:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2c([nH]1)-c1ccc(Br)cc1CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1
Yield: 88.5 %

Procedure:
(1R,3S,4S)-tert-butyl-3-(7-bromo-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.25 g, 2.81 mmol) was diluted in benzene (50 mL). DDQ (0.7 g, 3.1 mmol) was added and the solution was heated to reflux for 1.5 h. After cooling, the reaction mixture was concentrated and the residue was purified by silica gel chromatography to yield product (1.1 g).
Reaction SMILES: [CH2:1]([N:8]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:9]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](N)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.N#[O+:39]>CC#N>[CH2:1]([N:8]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:9]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:39])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#[O+]
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C(N)=O)cccc2C(F)(F)F)cc1
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C(=O)O)cccc2C(F)(F)F)cc1
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a suspension of 0.192 g (0.41 mmol) of the product of Example 123 in 2.5 mL of dry CH3CN was added 0.068 g(0.58 mmol) of nitrosonium tetrafluoroborate. The resulting mixture was stirred for 1 h and then added 0.040 g(0.34 mmol) of the same reagent and stirred for additional 1 h. The reaction was quenched with water and filtered to provide 0.141 g (74%) of the desired carboxylic acid as a white solid. Electrospray Mass Spec 466.2(M+H).