Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH:35]([C:37]1([C:43]([OH:45])=[O:44])[CH2:42][CH2:41][CH2:40][O:39][CH2:38]1)=[CH2:36].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:32][C@@H:28]([CH:29]([CH3:31])[CH3:30])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2](/[CH:36]=[CH:35]/[C:37]4([C:43]([OH:45])=[O:44])[CH2:42][CH2:41][CH2:40][O:39][CH2:38]4)=[CH:3][CH:4]=3)[N:9]=2)[CH3:13])=[O:16])[NH:18]1)=[O:34])=[O:33]
Reactant: C=CC1(C(=O)O)CCCOC1
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/C4(C(=O)O)CCCOC4)cc3n2)N1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (600 mg, 1.122 mmol), 3-vinyl-tetrahydro-pyran-3-carboxylic acid (175.3 mg, 1.122 mmol), tri(o-tolyl)phosphine (68.3 mg, 0.224 mmol) and triethylamine (0.47 mL, 3.366 mmol) in 1,4-dioxane (15 mL) was degassed by bubbling nitrogen through for 5 minutes then warmed to 50° C. and treated with tris(dibenzylideneacetone)dipalladium(0) (102.7 mg, 0.112 mmol). After stirring at 100° C. for 45 minutes the reaction was cooled to room temperature, filtered through a pad of Celite, which was rinsed with ethyl acetate. The volatiles were removed in vacuo to provide crude title compound as an orange foam that was used without further purification. LCMS (m/z) 610.2 [M+H], Tr=1.97 min.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].[CH3:6]COCC.[C:11]([C:13](=[CH:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=[O:15])#[N:12]>C1COCC1>[CH3:6][O:15][C:14](=[O:16])[CH:13]([C:11]#[N:12])[CH:17]([CH:18]([CH3:20])[CH3:19])[CH2:1][CH2:2][CH3:3]
Reactant: CC(C)C=C(C#N)C(=O)O
Reactant: CCOCC
Reactant: CCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCC(C(C)C)C(C#N)C(=O)OC
Temperature: -40 °C
Reaction time: 4 h

Procedure:
A 2.0 M solution of propyl magnesium chloride in Et2O (9.8 mL, 19.6 mmol) is added to a solution of 2-cyano-4-methyl-2-pentenoic acid (3.0 g, 19.6 mmol) in 50 mL of THF which is cooled in an IPA/dry ice bath to −40° C. under argon. The solution is stirred for 4 hours, and the reaction is quenched by addition of 50 mL of saturated KH2PO4. The THF is evaporated, and the remaining oil is chromatographed under medium pressure over silica gel with 50% CH2Cl2/hexane. Yield=1.9 g (50%) of 2-cyano-3-isopropyl-hexanoic acid methyl ester as an oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=1.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]2[N:16]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)[N:14]=2)[CH:17]=1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2nc(-c3ccc([N+](=O)[O-])cc3)cn2c1

Procedure:
59.5 g (0.2 mole) of 1-bromo-2-(4-nitrophenyl)-2-ethanone, 21.6 g (0.2 mole) of 2-amino-5-methylpyridine and 34 g of sodium bicarbonate are reacted in 200 ml of 95% strength ethanol. Stirring and refluxing are maintained for 3 hours, and the reaction mixture is then cooled and the ethanol evaporated off under reduced pressure. The evaporation residue is stirred in 700 ml of water at 70° C. for 3 hours, and the insoluble material is then filtered off, washed with 50 ml of ethanol and then ether and dried. M.p. 237°-239° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([O:17][CH2:18][C@@H:19]3[CH2:22][CH2:21][N:20]3C(OC(C)(C)C)=O)[CH:16]=2)[O:8][N:7]=1.[ClH:31]>CO.CCOCC>[ClH:31].[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([O:17][CH2:18][C@@H:19]3[CH2:22][CH2:21][NH:20]3)[CH:16]=2)[O:8][N:7]=1
Reactant: COC(=O)CCc1cc(-c2cncc(OC[C@@H]3CCN3C(=O)OC(C)(C)C)c2)on1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)CCc1cc(-c2cncc(OC[C@@H]3CCN3)c2)on1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
To a solution of 3-[5-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]-3-isoxazolyl]propionic acid methyl ester (100 mg, 0.24 mmol) in MeOH (34 mL) was added at 0° C. 2M anhydrous HCl in ether (12 mL). The reaction mixture was stirred at 0° C. for 7 h, then concentrated in vacuo. The residue was purified by HPLC to give the hydrochloride (90 mg). 1H NMR (CD3OD, 400 MHz) δ 8.70 (s, 1H), 8.46 (s, 1H), 7.93 (d, 1H, J=1.6 Hz), 6.93 (s, 1H), 4.92 (s, 1H), 4.49 (m, 2H), 4.10 (m, 2H), 3.69 (s, 3H), 3.04 (t, 2H, J=7.2 Hz), 2.80 (t, 2H, J=7.2 Hz), 2.70 (m, 2H). 13C NMR (CDCl3, 100 MHz) δ 174.3, 165.8, 164.6, 158.5, 134.0, 133.1, 129.5, 128.5, 105.8, 70.1, 60.3, 52.5, 45.1, 32.7, 22.6, 22.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:10][C:9](=[O:19])[NH:8][C:7]1=[O:20])=[O:5])[CH3:2].CI.[C:23](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[CH2:10][C:9](=[O:19])[N:8]([CH3:23])[C:7]1=[O:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C(=O)NC(=O)C[C@H]1c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@H]1C(=O)N(C)C(=O)C[C@H]1c1ccc(F)cc1
Reaction time: 7.5 h

Procedure:
A solution of compound E1 (±)-trans-3-ethoxycarbonyl-4(4'-fluorophenyl)piperidin-2,6-dione (1.0 g) in anhydrous dimethylformamide was stirred and cooled to about 0° and methyl iodide (0.67 g) and anhydrous potassium carbonate (0.51 g) added. The mixture was stirred at 0°-2° for 7.5 hours, after which it was diluted with water and extracted with ethyl acetate (100 ml). The extract was washed with water, brine and dried over anhydrous sodium sulphate. Evaporation gave the title compound as a pale yellow oil, ca. 90% pure by n.m.r. spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].I[CH2:11][CH2:12][CH2:13][CH3:14].[K+].[Br-].[Br:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1>C(#N)C>[Br-:17].[CH2:11]([C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([CH3:18])[C:28]=1[N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[NH:5][CH:4]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCI
Reactant: BrCc1ccc2ccccc2c1
Reactant: Clc1nc[nH]c1Cl
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCc1c(-[n+]2c[nH]c(Cl)c2Cl)c(C)cc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) was dissolved into 27 mL of acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) was added and the mixture was allowed to stir for 0.5 h. 1-iodobutane (1 mL, 9 mmol) was added and the solution was allowed to reflux overnight. The solution was filtered hot to remove a white precipitate (presumed to be KBr) and 2-bromomethylnaphthalene (1.98 g, 9 mmol) was added and the mixture was returned to reflux overnight. The mixture was then allowed to cool to room temperature, resulting in a yellow precipitate (1.125, 31% yield). 1H NMR (500 MHz, DMSO-d6) 9.66 (1H, s, NCHN), 8.02 (4H, m, Ar), 7.57 (3H, m, Ar), 5.66 (2H, s, NCH2), 4.24 (2H, t, NCH2), 1.80 (2H, tt, CH2), 1.37 (2H, tq, CH2), 0.93 (3H, t, CH3). 13C{1H} NMR (125 MHz, DMSO-d6) 136.4 (NCN), 132.8 (Ar), 132.6 (Ar), 130.0 (Ar), 128.8 (Ar), 127.8 (Ar), 127.7 (Ar), 127.6 (Ar), 126.8 (Ar), 126.7 (Ar), 125.5 (Ar), 119.1 (Ar), 118.7 (Ar), 51.6 (CH2), 48.3 (CH2), 30.1 (CH2), 18.7 (CH2), 13.2 (CH3). MS: m/z=332.9 (theor for C18H19Cl2N2Br1=414.17).
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:11]([O-])=O.[Na+]>O.Cl>[Cl:1][C:2]1[C:8]([Cl:9])=[C:7]([Cl:10])[CH:6]=[CH:5][C:3]=1[NH:4][NH2:11]
Reactant: O=N[O-]
Reactant: Nc1ccc(Cl)c(Cl)c1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Cl)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Fifty grams of 2,3,4-trichloroaniline was added portionwise to a solution of 200 ml of concentrated hydrochloric acid at approximately 0° C. To the reaction mixture was added 17.6 g of sodium nitrite dissolved in 100 ml of water dropwise over 1 hour. Next, 94.8 g of stannous chloride dissolved in 100 ml of concentrated hydrochloric acid was added dropwise to the reaction mixture over a 1 hour period while maintaining the temperature at approximately 0° C. The reaction mixture was stirred for approximately 1 hour at this temperature and then warmed to room temperature and stirred for 20 additional hours. The precipitated solid was collected by filtration and dried. The collected solid was added to a cold solution of 300 ml of 25% aqueous sodium hydroxide and this solution was stirred at approximately 5° C. for 1 hour. This aqueous solution was then extracted with ether and the organic phase was washed with water and saturated sodium chloride, and finally dried over anhydrous magnesium sulfate. The organic phase was evaporated under reduced pressure and the residue was recrystallized from ethanol to afford 35 g of 2,3,4-trichlorophenylhydrazine. Yield 66%. mp=138°-140° C.
Reaction SMILES: [OH-:1].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:15])[N:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](Cl)[N+:18]=1[O-]>CS(C)=O>[Cl:16][C:17]1[N:18]=[C:19]([O:3][C:4]2[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:15])[N+:12]([O-:1])([CH3:13])[CH3:14])=[CH:8][CH:9]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CN(C)C(=O)Nc1ccc(O)cc1
Reactant: [OH-]
Reactant: [O-][n+]1c(Cl)cccc1Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: C[N+](C)([O-])C(=O)Nc1ccc(Oc2cccc(Cl)n2)cc1
Temperature: 60 °C

Procedure:
Dry powdered sodium hydroxide (2.44 grams; 0.061 mole) was dissolved in 110 ml. of warm dimethylsulfoxide and N'-(4-hydroxyphenyl)-N,N-dimethyl urea (11.0 grams; 0.061 mole) and 2,6-dichloropyridine-N-oxide added thereto. The reaction mixture was stirred at a temperature of about 60° C. for a period of 5 and one-half hours. After this period, about three-fourths of the solvent carrier was removed by vacuum distillation and the residual oil thus obtained poured into ice water. The aqueous mixture was extracted with three 250 ml. portions of warm methylene chloride and the extracts combined. Evaporation of the solvent from the extract left a brown, syrupy residue which was washed with cold water and then with dry benzene to give the desired N'-(4-((6-chloro-2-pyridinyl)oxy)phenyl)-N,N-dimethyl urea-1-oxide compound as a crystalline solid melting at 190°-191° C. and having carbon, hydrogen, nitrogen and chlorine contents of 53.83, 4.63, 13.25 and 12.78 percent, respectively, as compared with contents of 54.64, 4.58, 13.65 and 11.52 percent, respectively, calculated for the named structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[C:19]([O:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:26])([CH3:22])([CH3:21])[CH3:20]>CO.C(Cl)Cl>[C:19]([O:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:26][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(=O)OC(C)(C)C

Procedure:
Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-leucine tert-butyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=128° C.). The reaction was monitored by tlc (Rf=0.85 in 5% MeOH/methylene chloride) and the product was purified by flash column chromatography using 5% MeOH/methylene chloride as the eluent.
Reaction SMILES: [CH2:1](P(CCCC)CCCC)CCC.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=1.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39]/[CH:40]=[CH:41]/CO)=[CH:35][CH:34]=2)=[CH:29][CH:28]=1>C1COCC1>[CH3:25][O:24][C:22](=[O:23])[CH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:41]/[CH:40]=[C:39](/[C:36]2[CH:35]=[CH:34][C:33]([C:30]3[CH:29]=[CH:28][C:27]([Br:26])=[CH:32][CH:31]=3)=[CH:38][CH:37]=2)\[CH3:1])=[CH:20][CH:19]=1
Reactant: OC/C=C/Cc1ccc(-c2ccc(Br)cc2)cc1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(Br)cc3)cc2)cc1
Reaction time: 16 h
Yield: 83.6 %

Procedure:
Under an atmosphere of nitrogen, azodicarboxylic dipiperidide (353 mg, 1.4 mmol) was added at 0-5° C. to a stirred solution of tributylphosphine (0.4 mL, 1.4 mmol), methyl 4-hydroxyphenylacetate (110 mg, 0.7 mmol) and (E)-4-(4′-Bromo-biphenyl-4-yl)-but-2-en-1-ol (example 22 step A-B)(200 mg, 0.7 mmol) in dry THF (10 mL), the mixture stirred for 16 h, filtered and concentrated in vacuo. The crude product was then purified by column chromatography on silica (eluent: 20% ethyl acetate in heptane) to give 264 mg (84%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]2[C:10]([C:13]([NH:15][C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[C:18]([CH3:33])=[N:19][N:20]4[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)=[O:14])=[CH:11][N:12]=[C:6]2[CH:5]=1)(=O)[CH3:2].[CH2:34]([CH2:36][NH2:37])[OH:35]>>[OH:35][CH2:34][CH2:36][NH:37][CH:1]([C:4]1[CH:9]=[CH:8][N:7]2[C:10]([C:13]([NH:15][C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[C:18]([CH3:33])=[N:19][N:20]4[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)=[O:14])=[CH:11][N:12]=[C:6]2[CH:5]=1)[CH3:2]
Reactant: NCCO
Reactant: CC(=O)c1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3cccc(C)n3)cnc2c1
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(C(C)NCCO)ccn45)cccc32)n1

Procedure:
Prepared from 7-acetyl-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 79) and ethanolamine following procedure in Example 72, Step C. MS (ES+APCI) m/z=484 (M+H) detected.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([C:25](=[O:35])[CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([O:19]C)=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:24]=[C:23]([C:25](=[O:35])[CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5]
Reactant: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Yield: 82.5 %

Procedure:
A solution of N-[2-chloro-4-[1-oxo-3-(3-hydroxyphenyl)propyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester (120 mg, 0.23 mmol) and lithium hydroxide monohydrate (40 mg, 0.95 mmol) in tetrahydrofuran/methanol/water (2:2:1; 2.5 mL) was stirred at room temperature for 90 min. The solvent was evaporated, then water was added, followed by 1 M HCl (1.1 mL). The resulting solid was filtered off, washed with water, dried, and purified by HPLC to give N-[2-chloro-4-[1-oxo-3-(3-hydroxyphenyl)propyl]-benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine (95 mg, 81%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[C:9](=[O:19])[NH:8][C:7]1=[O:20].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:28]=[CH:27][C:26]([C@:29]23[CH2:34][C@H:33]2[CH2:32][NH:31][CH2:30]3)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CCO>[ClH:1].[ClH:1].[CH3:18][C:14]1[N:13]=[C:12]([C:10]2[C:9](=[O:19])[NH:8][C:7](=[O:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:32][C@H:33]4[C@:29]([C:26]5[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:36])[F:35])=[CH:28][CH:27]=5)([CH2:34]4)[CH2:30]3)[CH:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccc(-c2cn(CCCCCl)c(=O)[nH]c2=O)n1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cccc(-c2cn(CCCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c(=O)[nH]c2=O)n1
Product: Cl
Reaction time: 2 h

Procedure:
A solution of 1-(4-chloro-butyl)-5-(6-methyl-pyridin-2-yl)-1H-pyrimidine-2,4-dione (Prep51, 95 mg, 0.32 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 74 mg, 0.32 mmol), and TEA (98 μl, 1 mmol) in absolute EtOH (4 mL) was refluxed for 48 h. Then dry DIPEA (83.6 mg, 0.64 mmol) was added and the mixture placed in a microwave oven and irradiated at 125° C. for 4 hours. The solvent was removed under vacuum and the residue was partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated. The residue was dissolved in DCM and treated with PS-isocyanate resin (250 mg) under stirring for 2 h. After filtration and evaporation of the solvent, the crude was purified by flash chromatography with DCM-MeOH—NH4OH (98-2-0.2) to give the title compound as free base.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].[C:17]([S:20][CH2:21][CH:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23](Cl)=[O:24])(=[O:19])[CH3:18].Cl>O.O1CCCC1>[C:17]([S:20][CH2:21][CH:22]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:23]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)=[O:24])(=[O:19])[CH3:18]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Cl
Reactant: NCc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)SCC(Cc1ccccc1)C(=O)NCc1ccc(C(=O)O)cc1
Yield: 32.6 %

Procedure:
4-Aminomethylbenzoic acid (1.50 g) and sodium hydrogen carbonate (1.68 g) are suspended in water (20 ml), and thereto is added dropwise a solution of 2-acetylthiomethyl-3-phenylpropionyl chloride (2.86 g) in tetrahydrofuran (6 ml) with vigorously stirring. After the reaction is completed, the reaction mixture is acidified with hydrochloric acid and is extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue is recrystallized from ethanol to give the title compound (1.2 g).
Reaction SMILES: [CH:1](=[C:8]1[CH2:12][N:11]([C:13]([O:15]C(C)(C)C)=O)[C@H:10]([C:20]([OH:22])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)C(Cl)=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:39]([N:41]([CH2:45][CH3:46])[CH2:42][CH2:43][NH2:44])[CH3:40]>>[CH:1](=[C:8]1[CH2:12][N:11]([C:13](=[O:15])[CH:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C@H:10]([C:20]([NH:44][CH2:43][CH2:42][N:41]([CH2:45][CH3:46])[CH2:39][CH3:40])=[O:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CCN
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=Cc2ccccc2)C[C@H]1C(=O)O
Product: CCN(CC)CCNC(=O)[C@@H]1CC(=Cc2ccccc2)CN1C(=O)C(c1ccccc1)c1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 71% purity by LC/MS. MS(ESI+): m/z=496.4.
Reaction SMILES: Cl.C1C2C(COC([N:19]3[CH2:24][C@@H:23]([C:25](=[O:44])[N:26]([CH:41]4[CH2:43][CH2:42]4)[CH2:27][C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=4)[CH2:22][C@@H:21]([NH2:45])[CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH2:46]([N:53]=[C:54]=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CC#N>[CH:41]1([N:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=2)[C:25]([C@H:23]2[CH2:22][C@@H:21]([NH:45][C:54]([NH:53][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:55])[CH2:20][NH:19][CH2:24]2)=[O:44])[CH2:42][CH2:43]1
Reactant: O=C=NCc1ccccc1
Reactant: COCCCOc1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)ccc1C
Agent: Cl
Solvent: CC#N
Product: COCCCOc1cc(CN(C(=O)[C@@H]2CNC[C@H](NC(=O)NCc3ccccc3)C2)C2CC2)ccc1C

Procedure:
The title compound is prepared analogously as described in Example 98 using (3R*,5S*)-3-amino-5-{cyclopropyl-[3-(3-methoxy-propoxy)-4-methyl-benzyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, hydrochloride (Example 98A.) and benzylisocyanate. MS: 509.6 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.22 min.
Reaction SMILES: [CH3:1][C:2]1[C:17]([CH3:18])=[C:16]([O:19][CH2:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:15]=[CH:14][C:3]=1[O:4][CH2:5][C:6](C1C=CC=CC=1)=O.BrCC([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=O.O>C1(C)C(C)=CC=CC=1>[CH3:18][C:17]1[C:16]2[O:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]=2[C:14]2[C:6]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:5][O:4][C:3]=2[C:2]=1[CH3:1]
Reactant: Cc1c(OCC(=O)c2ccccc2)ccc(OCC(=O)c2ccccc2)c1C
Reactant: O=C(CBr)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1c(C)c2occ(-c3ccccc3)c2c2c(-c3ccccc3)coc12

Procedure:
A mixture of 2-[2,3-Dimethyl-4-(2-oxo-2-phenyl-ethoxy)-phenoxy]-1-phenyl-ethanone (480 mg, 1.28 mmol) synthesized as described in Example 11, an excess of bromoacetophenone, and polyphosphoric acid (PPA, 100 mg) in xylene (10 mL) was stirred at 150° C. for 10 h. The mixture was then poured into water, extracted with EtOAc, the organic layer was washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column eluting with 10-20% EtOAc in hexane to give 190 mg of 4,5-dimethyl-1,8-diphenyl-benzo[1,2-b;4,3-b′]difuran (250 mg). 1H NMR (CDCl3, 300 MHz) δ: 7.60 (s, 2H), 7.05 (m, 4H), 6.90 (m, 2H), 6.85 (m, 4H), 2.60 (s, 6H) ppm. 13C NMR (CDCl3, 75 MHz) δ: 152.57,141.48, 133.19, 128.42, 127.52, 126.87, 124.05, 117.40, 116.29, 11.80 ppm. MS (m/z): 339 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16]C)=[CH:13][CH:14]=3)[C:9](SC(C)(C)C)=[C:8]2[CH2:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])=[CH:4][CH:3]=1.[CH2:32](S)C.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:23][C:24]([CH3:29])([CH3:28])[C:25]([O:27][CH3:32])=[O:26])=[CH:4][CH:3]=1
Reactant: CCS
Reactant: COc1ccc2c(c1)c(SC(C)(C)C)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(C)(C)Cc1cc2cc(O)ccc2n1Cc1ccc(Cl)cc1

Procedure:
A suspension of 1.0 g of 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-methoxyindol-2-yl]-2,2-dimethylpropanoic acid (from Example 1 Step B) in 50 mL of CH2Cl2 was treated with 1.3 mL of ethanethiol and 3.47 g of AlCl3 at 0° C. under argon. After 40 min the mixture was poured onto 50 mL 1N HCl, extracted with 3×50 mL of CH2Cl2 washed with 2×50 mL of H2O, dried with MgSO4 and the solvent removed. The residue was dissolved in 10 mL ether and ethereal diazomethane added until all the acid was consumed. The excess solvent was removed and the residue chromatographed on silica gel to afford the title compound.