Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3ON=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[S:30]1C=CC=[C:31]1C1C=CC(N)=CC=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[S:30][CH:31]=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: Nc1ccc(-c2cccs2)cc1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2cccs2)cc1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 4-(thiophen-2-yl)aniline in step 1. MS: 410.0 (M+H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH2:13][C:14]([O:16]C)=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>CO.O>[N:1]1([C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: COC(=O)Cc1cccc(N2CCOCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of methyl 3-(morpholin-4-yl)phenylacetate (0.50 g, 2.1 mmol) in methanol (5 mL) and H2O (1 mL) was added lithium hydroxide monohydrate (0.18 g, 2 eq.). After the reaction mixture was stirred at room temperature overnight, it was concentrated to dryness. Acetic acid was then added to the residue and the resulting mixture was partitioned between EtOAc and H2O. The organic layer was washed with NaCl (sat.), dried over Na2SO4, and evaporation under vacuo to give 3-(morpholin-4-yl)phenylacetic acid (0.42 g).
Reaction SMILES: [CH2:1]([N:5]([CH2:26][CH2:27][CH2:28][CH3:29])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:30]([C:32]1[C:33](=[C:40]([C:43]#[N:44])[C:41]#[N:42])[O:34][C:35]([CH3:39])([CH3:38])[C:36]=1[CH3:37])#[N:31].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:26]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:21]([CH3:22])=[CH:20][C:17]([CH:18]=[CH:37][C:36]3[C:35]([CH3:38])([CH3:39])[O:34][C:33](=[C:40]([C:41]#[N:42])[C:43]#[N:44])[C:32]=3[C:30]#[N:31])=[C:16]([CH3:23])[CH:15]=2)=[C:8]([O:24][CH3:25])[CH:7]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(C=O)cc2C)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)cc2C)c(OC)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 55.7 %

Procedure:
In 6 ml of ethanol and 2 ml of tetrahydrofuran were dissolved 250 mg (0.64 mmol) of 4-[2-(4-dibutylamino-2-methoxyphenyl) vinyl]-2,5-dimethylbenzaldehyde and 140 mg (0.70 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene) propanedinitrile. To this mixture was added 49 mg of ammonium acetate, and the mixture was stirred at 70° C. for 4 hours. The solvent was evaporated off, and the residue was purified by silica gel column chromatography and washed with ethanol to give 205 mg of a black powder (yield: 56.2%; mp: 242-244° C.)
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([OH:22])=[C:11](C(OCC)=O)C(OCC)=O>CC(O)=O.O.OS(O)(=O)=O>[Br:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:22])[CH3:11]
Reactant: CCOC(=O)C(C(=O)OCC)=C(O)c1ccc(Cl)c(F)c1Br
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1ccc(Cl)c(F)c1Br
Yield: 84.6 %

Procedure:
A solution of Intermediate 12B (18.6 g, 47 mmol) in AcOH (200 mL), H2O (150 mL) and H2SO4 (2.0 mL) was stirred at 110° C. for 4 h. Most of the solvent was removed and the residue was diluted with EtOAc (400 mL), washed with H2O (5×20 mL), saturated NaHCO3, 1N NaOH, and brine. The solvent was removed to give Intermediate 12C (10 g, 84% yield) as a low melting solid. 1H NMR (400 MHz, DMSO-d6) δ 7.42 (q, J=6.8, 6.4 Hz, 1H), 7.24 (q, J=6.4, 5.2 Hz, 1H), 2.5 (s, 3H) ppm.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:15]=[C:14]2[C:8]([CH2:9][N:10]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=32)=[CH:7]1)C.[NH3:28]>>[Cl:20][C:18]1[CH:17]=[CH:16][C:13]2[C:14]3[C:8](=[CH:7][N:6]([CH2:5][C:4]([NH2:28])=[O:3])[CH:15]=3)[CH2:9][N:10]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[CH:19]=1
Reactant: CCOC(=O)Cn1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: N
Product: NC(=O)Cn1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
A mixture of 2.3 g (6.5 mmole) of 8-chloro-6-phenyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetic acid ethyl ester and 20 ml of methanolic ammonia (ca 20% v/v) was heated in an autoclave on a steambath overnight. The solvent was removed at reduced pressure to give a light yellow solid. Recrystallization from ethanol-hexane gave a white solid, mp 236°-237°.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]=[C:3]1[C:8]#[N:9].Cl.[NH3:11]>CO>[O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]=[C:3]1[C:8](=[NH:11])[NH2:9]
Reactant: N#Cc1ncc[nH]c1=O
Reactant: N
Agent: Cl
Solvent: CO
Product: N=C(N)c1ncc[nH]c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In 33 ml of methanol was dissolved 1.1 g of 3-oxo-3,4-dihydro-2-pyrazinecarbonitrile synthesized according to the description of J. Heterocycl. Chem., Vol. 19, Pages 1,397-1,402 (1982). While cooling the solution with ice, gaseous hydrogen chloride was introduced until saturation, after which the solution was stirred at the same temperature as above for 8 hours. The solvent was removed under reduced pressure, the residue thus obtained and dissolved in 55 ml of a 7 mol/L solution of ammonia in methanol at an ice-cooled temperature, and the solution thus obtained was stirred at the same temperature as above for 5 minutes. The solid product formed was collected by filtration to obtain 1.1 g of 3-oxo-3,4-dihydro-2-pyrazinecarboximidamide as a light yellow-colored solid product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33](Br)[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][N:39]1[CH2:44][CH2:43][N:42]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([N:48]3[CH2:47][CH2:46][CH:45]([N:42]4[CH2:41][CH2:40][N:39]([CH3:38])[CH2:44][CH2:43]4)[CH2:50][CH2:49]3)[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: C=C(C)c1cc(C(=O)N2Cc3ccc(Br)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=C(C)c1cc(C(=O)N2Cc3ccc(N4CCC(N5CCN(C)CC5)CC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 120 °C
Yield: 44.4 %

Procedure:
A solution of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-(5-bromo-1,3-dihydro-isoindol-2-yl)-methanone (200 mg; 0.36 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (80 mg; 1.2 equiv.) in toluene (5 ml) was treated with (2-biphenyl)-di-tert-butylphosphine (6 mg; 5 mol %), tris(dibenzylidene)palladium(0) (10 mg; 2.5 mol %) and sodium tert-butoxide (50 mg; 1.4 equiv.) then heated at 120° C. for 30 minutes in a CEM explorer microwave synthesiser. The reaction mixture was diluted with DCM, washed with brine, dried (MgSO4) and evaporated. Purification by flash column chromatography (Biotage SP4-25S, 25 ml/min) eluting with DMAW 240-120-90 followed by evaporation of product containing fractions gave 105 mg of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-{5-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-1,3-dihydro-isoindol-2-yl}-methanone as the acetic acid salt.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:27]=[N:26][C:8]2[N:9]([CH3:25])[C:10](=[O:24])[N:11]([CH2:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:12](=[O:13])[C:7]=2[CH:6]=1)([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[CH3:36][CH:37]([CH3:41])[CH2:38][CH:39]=[O:40]>C1COCC1>[OH:40][CH:39]([C:6]1[C:7]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:10](=[O:24])[N:9]([CH3:25])[C:8]=2[N:26]=[CH:27][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2])[CH2:38][CH:37]([CH3:41])[CH3:36]
Reactant: CC(C)CC=O
Reactant: CC(C)Oc1cnc2c(c1)c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC(O)c1c(OC(C)C)cnc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: -78 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
To a solution of 6-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 36, step 3, 150 mg, 0.4 mmol) in THF (6 mL) at −78° C. was added LDA (2M in THF, 1.0 mL, 2.0 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 3-methylbutanal (68.8 mg, 0.8 mmol) in THF (1.5 mL) was added. The reaction was stirred at −78° C. for 1 h, quenched with aq. NH4Cl (5 mL) diluted with water (13 mL) then extracted with EA (30 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (2:1) to give 5-(1-hydroxy-3-methylbutyl)-6-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (60 mg, 32.4% yield) as a white solid. LCMS: [M+-THP-OH] 362 and TR=2.616 min.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[N:11](CC2C=CC(OC)=CC=2)[CH2:10][CH2:9]3)[CH2:5][CH2:4]1.C(OC(=O)C)C.CO>C(O)(C(F)(F)F)=O>[F:26][CH:2]([F:1])[C:3]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[NH:11][CH2:10][CH2:9]3)[CH2:5][CH2:4]1
Reactant: COc1ccc(CN2CCc3cc(C4(C(F)F)CC4)ccc3C2=O)cc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCc2cc(C3(C(F)F)CC3)ccc21
Temperature: 70 °C
Yield: 66.6 %

Procedure:
Compound (VII) (0.068 g, 0.19 mmole) was dissolved in TFA 1 ml and heated to 70° C. for 1.5 hours. To the reaction mixture cooled to room temperature was added ethylacetate and the solution was washed with brine followed by sodium bicarbonate 5% solution, and again with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel prep TLC with 5% methanol in dichloromethylene affording compound (VIII) 0.030 g, 66% yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([N+:29]([O-:31])=[O:30])=[CH:24][CH:25]=3)[CH2:20]2)[CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.C(NC(N1CCC(CN(CC)C2CCC3C(=CC(NC(=O)C4C=CC(S(C)(=O)=O)=CC=4)=CC=3)C2)CC1)=O)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N+:29]([C:23]1[CH:22]=[C:21]2[C:26]([CH2:27][CH2:28][CH:19]([N:15]([CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:16][CH2:17][CH3:18])[CH2:20]2)=[CH:25][CH:24]=1)([O-:31])=[O:30]
Reactant: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc([N+](=O)[O-])cc2C1
Agent: CCN(CC1CCN(C(=O)NC(C)C)CC1)C1CCc2ccc(NC(=O)c3ccc(S(C)(=O)=O)cc3)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(CC1CCNCC1)C1CCc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester, prepared as in Example 1 (1.12 g, 2.60 mmol) in methylene chloride (30 mL) under a nitrogen atmosphere was added trifluoroacetic acid (10 mL). The reaction was stirred at room temperature for 30 min. and concentrated in vacuo. The residue was partitioned between EtOAc (50 mL) and 10% aq. KOH (50 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated to afford (7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-ylmethyl-propyl-amine (845 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[N:6][C:7]=1[S:8][CH2:9][CH:10]([CH3:12])[CH3:11].S(=O)(=O)(O)O.[CH3:21]O>[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([O:15][CH3:21])=[O:14])=[N:6][C:7]=1[S:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)CSc1nc(C(=O)O)ccc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(Br)c(SCC(C)C)n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
5-Bromo-6-(isobutylthio)picolinic acid (500 mg, 1.72 mmol) was dissolved in methanol (5 mL) to give a yellow solution. Sulfuric acid (169 mg, 92.3 μL, 1.72 mmol) was added. The reaction mixture was heated to 80° C. and stirred for 1 d. The reaction mixture was cooled to 0° C. and poured onto icewater/brine (25 mL). The aqueous layer was extracted with EtOAc (2×40 mL) and washed with icewater/brine (20 mL). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo to give crude title compound as a yellow oil. The oil was purified by flash chromatography (silica gel, 5 g, 0% to 15% EtOAc in heptane) to give the title product (205 mg, 39%) as a colorless oil. MS (EI): m/e=306.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[C:16]([N+:20]([O-])=O)[CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:23])=[CH:4][CH:3]=1.C(O)C.C(O)(=O)C.[H][H]>[C].[Pd].CO>[NH2:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:12]2[C:11]([N:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[C:14](=[O:15])[C:13]=12)=[O:23]
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1CCc1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cccc2c1C(=O)N(CCc1ccc(O)cc1)C2=O
Yield: 24.1 %

Procedure:
10% Palladium-carbon catalyst (water content 50%, 200 mg) was added to a mixed solution of N-[2-(4-hydroxyphenyl)ethyl]-3-nitrophthalimide (1.67 g, 0.0053 mol, 1 eq) in methanol (20 ml)-ethanol (50 ml)-acetic acid (20 ml), and the mixture was stirred for 3 hours at room temperature in a stream of hydrogen. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (chloroform/methanol=50/1) to give 3-amino-N-[2-(4-hydroxyphenyl)ethyl]phthalimide (360 mg, 24.1%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:17]=[CH2:18].CCN(C(C)C)C(C)C>CCOC(C)=O>[CH2:16]([N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH:14]=[CH2:15])[CH:17]=[CH2:18]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=CCNc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N(CC=C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 55.1 %

Procedure:
A solution of N-propylphosphonic acid anhydride cyclic trimer (50% reagent in EtOAc solution, 1.26 mL, 2.14 mmol) was added to a degassed solution of (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (230 mg, 1.07 mmol), N-allylaniline (142 mg, 1.07 mmol), and Hunig's Base (0.560 mL, 3.21 mmol) at 0° C. The reaction mixture was stirred under argon for 2 min at 0° C. and then warmed to rt and stirred for 1 hr. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-30% EtOAc/Hex to give (S)-tert-butyl 1-(allyl(phenyl)amino)-1-oxopent-4-en-2-ylcarbamate (195 mg, 0.590 mmol, 55.2% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.43 (t, J=7.4 Hz, 2H), 7.36 (t, J=7.3 Hz, 1H), 7.24 (d, J=7.5 Hz, 2H), 5.91-5.78 (m, 1H), 5.63-5.49 (m, 1H), 5.23 (d, J=8.4 Hz, 1H), 5.18-5.05 (m, 2H), 5.05-4.94 (m, 2H), 4.43-4.19 (m, 3H), 2.33-2.23 (m, 1H), 2.20-2.08 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=4)[CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=4)[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2nccn2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.9 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-[(1-methylimidazol-2-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylate (367 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 3 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutralize, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-[(1-methylimidazol-2-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (285 mg) as yellow crystals.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:11]#N)=[C:7]([C:9]#[N:10])[N:8]=1)[CH2:2][CH3:3].[CH:13]([Mg]I)([CH3:15])[CH3:14].C([O:20]CC)C>>[C:11]([C:6]1[N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[NH:8][C:7]=1[C:9]#[N:10])(=[O:20])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)[Mg]I
Reactant: CCOCC
Reactant: CCCc1nc(C#N)c(C#N)[nH]1
Product: CCCc1nc(C(=O)C(C)C)c(C#N)[nH]1

Procedure:
Following a procedure similar to that described in Preparation 23(i), but using 8.24 g of 2-propylimidazole-4,5-dicarbonitrile (prepared as described in Preparation 10) and 103 ml of a 2M solution of isopropylmagnesium iodide in diethyl ether, 45.0 g of the title compound were obtained as crystals, melting at 90.5°-91° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Reaction time: 1.5 h
Yield: 57.1 %

Procedure:
Periodinane (36.1 g, 85.2 mmol) was added to 4-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (15.0 g, 65.5 mmol) in CH2Cl2 (230 mL) and stirred for 90 min. Diethyl ether (560 ml) was added and precipitates were removed by extraction with 10% Na2S2O3/saturated NaHCO3 (1:1, 350 mL). The organic layer was washed with 0.5 M NaOH solution and brine. The organic phase was dried and concentrated under reduced pressure to yield 4-(2-Oxo-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (8.50 g, 57%).
Reaction SMILES: ClC1C=C(N2C(C3C=CC=C(OCC[CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)C=3)=CC([C:28]([OH:30])=[O:29])=N2)C=CC=1.[Cl:31][C:32]1[CH:33]=[C:34]([N:38]2[C:42]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH2:50][CH2:51]O)[CH:44]=3)=[CH:41][C:40]([C:53]([N:55]3[CH2:59][C:58](=[O:60])[NH:57][CH2:56]3)=[O:54])=[N:39]2)[CH:35]=[CH:36][CH:37]=1>>[CH:28]([OH:30])=[O:29].[Cl:31][C:32]1[CH:33]=[C:34]([N:38]2[C:42]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH2:50][CH2:51][CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:44]=3)=[CH:41][C:40]([C:53]([N:55]3[CH2:59][C:58](=[O:60])[NH:57][CH2:56]3)=[O:54])=[N:39]2)[CH:35]=[CH:36][CH:37]=1
Reactant: O=C(O)c1cc(-c2cccc(OCCCN3CCCC3)c2)n(-c2cccc(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Product: O=C1CN(C(=O)c2cc(-c3cccc(OCCCN4CCCC4)c3)n(-c3cccc(Cl)c3)n2)CN1
Product: O=CO

Procedure:
The preparation of the title compound takes place starting from the compound of Example 118A in analogy to the synthesis of the compound of Example 23. 3.2 mg (33% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([N:7]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:8](=[O:50])[CH2:9][C@@H:10]2[O:15]C(C)(C)[O:13][C@H:12]([CH2:18][CH2:19][N:20]3[C:24]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[C:23]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:22]([C:38]([NH:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:39])=[C:21]3[CH:47]([CH3:49])[CH3:48])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CO>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]2[N:20]([CH2:19][CH2:18][CH:12]([OH:13])[CH2:11][CH:10]([OH:15])[CH2:9][C:8]([N:7]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:50])[C:21]([CH:47]([CH3:49])[CH3:48])=[C:22]([C:38]([NH:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:39])[C:23]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][CH:27]=1
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)N(c2ccccc2)c2ccccc2)OC(C)(C)O1
Agent: Cl
Solvent: CO
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCC(O)CC(O)CC(=O)N(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(4R-cis)-1-[2-[6-[2-(diphenylamino)-2-oxoethyl]-2,2-dimethyl-1,3-dioxan-4-yl]ethyl]-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide is dissolved in methanol (300 mL) and reacted by adding 1.0 N hydrochloric acid (100 mL) and stirring for 12 hours at room temperature. The white crystalline solid [R-(R*,R*)]-5-(4-fluorophenyl)-β,δ-dihydroxy-2-(1-methylethyl)-N,N,4-triphenyl-3-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanamide is isolated by filtration (mp 228.5°-232.9° C., uncorrected).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[CH2:27]([O:34]CCO)[C:28]1C=CC=CC=1>[Pd].[H][H]>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:28][CH2:27][OH:34])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Reactant: OCCOCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCO)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was synthesized from Compound 157 and 2-(benzyloxy)ethanol using an analogous procedure to that outlined in the preparation of Compound 210 followed by debenzylation using Pd/C—H2. 1H NMR (400 MHz, Methanol-d4) δ 8.30 (s, 1 H) 8.19 (m, 1 H) 8.06 (m, 1 H) 8.00 (m, 2 H) 7.87 (t, J=8.0 Hz, 1 H) 7.26 (m, 2 H) 4.38 (t, J=4 Hz, 2 H) 4.08 (t, J=4 Hz, 2 H) 3.30 (q, J=7.5 Hz, 2 H) 2.41 (s, 3 H) 1.31 (t, J=7.5 Hz, 3 H). [M+H] calc'd for C22H23N2O4S, 411; found, 411.