Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:4]([Cl:20])[CH:3]=1.Cl[CH2:22][CH2:23][O:24][CH2:25][CH2:26]Cl.[I-].[K+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:20][C:4]1[CH:3]=[C:2]([N:1]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:7]=[C:6]([CH3:8])[C:5]=1[NH:9][C:10](=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1
Reactant: Cc1cc(N)cc(Cl)c1NC(=O)Cc1cccc(F)c1
Reactant: ClCCOCCCl
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCOCC2)cc(Cl)c1NC(=O)Cc1cccc(F)c1
Temperature: 180 °C
Yield: 31 %

Procedure:
N-(4-Amino-2-chloro-6-methyl-phenyl)-2-(3-fluoro-phenyl)-acetamide (616 mg), bis-(2-chloroethyl)ether (260 μL) and potassium iodide (400 mg) were mixed in dry N,N-dimethylformamide (11 mL) and heated to 180° C. for 30 minutes in a sealed microwave process vial. 5% aqueous sodium bicarbonate (100 mL) was added and the mixture was extracted with ethyl acetate (3×80 mL). The combined organic phases were washed with water (2×100 mL), brine (1×100 mL), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 236 mg (31 %) of the title compound as a white solid. LC-MS (m/z) 363 (MH+); tR=2.56, (UV, ELSD) 96%, 99%. 1H NMR (500 MHz, DMSO-d6): 2.04 (s, 3H), 3.10 (m, 4H), 3.65 (s, 2H), 3.70 (m, 4H), 6.79 (d, 1H), 6.85 (d, 1H), 7.07 (dt, 1H), 7.19 (m, 2H), 7.37 (m, 1H), 9.52 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[C:4]1[CH:5]=[C:6]([C:15]#[C:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:7]=[C:8]([C:11]([O:13]C)=[O:12])[C:9]=1[CH3:10])[CH3:2].[OH-].[Na+]>C(O)C.O>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([C:16]#[C:15][C:6]2[CH:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:9]([CH3:10])=[C:8]([CH:7]=2)[C:11]([OH:13])=[O:12])[CH2:18][CH2:19]1)=[O:24])([CH3:28])([CH3:29])[CH3:27]
Reactant: CCN(c1cc(C#CC2CCN(C(=O)OC(C)(C)C)CC2)cc(C(=O)OC)c1C)C1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCN(c1cc(C#CC2CCN(C(=O)OC(C)(C)C)CC2)cc(C(=O)O)c1C)C1CCOCC1
Temperature: 60 °C
Yield: 98.7 %

Procedure:
To a solution of tert-butyl 4-((3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(methoxycarbonyl)-4-methylphenyl)ethynyl)piperidine-1-carboxylate (2.4 g, 4.95 mmol) in ethanol (20.0 mL) was added a solution of sodium hydroxide (0.565 g, 14.1 mmol) in water (3.0 ml) at rt. The reaction mixture was heated at 60° C. for 6 h. The reaction was quenched with 1M HCl (5 mL) and then excess citric acid solution to adjust to the pH to 5. The mixture was concentrated to remove EtOH and the remaining aqueous phase was extracted with AcOEt (2×40 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (10%-100% AcOEt/Heptane) to give the titled compound (2.30 g, 99% yield). 1H-NMR (500 MHz) δ ppm; 7.82 (s, 1H), 7.35 (s, 1H), 3.98 (brd, J=11.3 Hz, 2H), 3.77 (m, 2H), 3.35 (dt, J=1.5, 11.3 Hz, 2H), 3.25 (ddd, J=3.4, 8.3, 12.2 Hz, 2H), 3.11 (brs, 2H), 3.00 (brs, 1H), 2.81 (dddd, J=3.9, 3.9, 3.9, 3.9 Hz, 1H), 2.60 (s, 3H), 1.88 (m, 2H), 1.60-1.78 (m, 6H), 1.48 (s, 9H), 0.90 (t, J=6.8 Hz, 3H); MS (ESI) [M+H]+471.4.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2C=CN([CH2:23][CH2:24][C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28])N=2)C=CC=CC=1>>[C:1]1([C:7]2[N:8]([CH2:23][CH2:24][C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:9]=[CH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)C#CCCn1ccc(-c2ccccc2)n1
Reactant: c1ccc(-c2cc[nH]n2)cc1
Product: C[Si](C)(C)C#CCCn1nccc1-c1ccccc1
Yield: 81 %

Procedure:
The title compounds were prepared in accordance with the general method of Example 108(A), from 3-phenyl-1H-pyrazole (200 mg, 1.39 mmol) to yield 300 mg (1.12 mmol, 81%) of 5-phenyl-1-(4-trimethylsilanyl-but-3-ynyl)-1H-pyrazole and 5-phenyl-2-(4-trimethylsilanyl-but-3-ynyl)-2H-pyrazole.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[CH3:27][C:28]1[N:29]=[C:30]([NH2:43])[S:31][C:32]=1[S:33]([N:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[CH3:27][C:28]1[N:29]=[C:30]([NH:43][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[S:31][C:32]=1[S:33]([N:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1)(=[O:35])=[O:34]
Reactant: Cc1nc(N)sc1S(=O)(=O)N1CCN(C)CC1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)N1CCN(C)CC1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-ylamine (example B.19) according to general procedure II. Yellow solid. MS (ISP) 634.1 [(M+H)+]; mp 273° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:10]([C@H:9]1[C:17](=[O:19])[O:18][CH2:20][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N1COC(=O)[C@@H]1Cc1ccccc1

Procedure:
(4S)-4-Benzyl-N-tert-butyloxycarbonyl-1,3-oxazolidin-5-one (1) was prepared from N-tert-butyloxycarbonyl-(L)-phenylalanine (2.65 g, 10.0 mM) and para-toluene-sulfonic acid (30 mg) following general procedure A and obtained as a white solid after crystallisation from diethyl ether (1.49 g, 54%): [α]D20 +23.5 (c 1.0, CHCl3); mp 84-86° C.; IR (KBr): 1795, 1705 cm-1 ; 1H NMR (500 MHz, d8 -toluene, 90° C.): δ 6.97-7.08 (m, 5H), 4.75 (d, J=4 Hz, 1H), 4.03-4.05 (m, 2H), 3.17 (dd, J=4, 14 Hz, 1H), 2.92 (dd, J=3, 14 Hz, 1H), 1.31 (s, 9H); 13C NMR (50.3 MHz, CDCl3): 6 172.7, 153.2, 135.0, 129.8, 128.9, 127.6, 82.0, 78.0, 56.3, 34.3, 28.6; LRMS (NH3): 295 (MNH4+). Anal. Calcd for C15H19NO4 : C, 64.96; H, 6.90; N, 5.05; found: C, 64.93; H, 6.73; N, 4.83.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:7]=1[O:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][CH:14]([CH3:22])[C:15]([O:20][CH3:21])=[CH:16][C:17](O)=[O:18])=[CH:11][CH:10]=1>CCOCC>[Cl:5][C:6]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:7]=1[O:8][C:9]1[CH:24]=[CH:23][C:12]([O:13][CH:14]([CH3:22])[C:15]([O:20][CH3:21])=[CH:16][C:17]([Cl:3])=[O:18])=[CH:11][CH:10]=1
Reactant: COC(=CC(=O)O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: COC(=CC(=O)Cl)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
Thionyl chloride (20 ml.) is added to 4-[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoic acid (10 mm.) in anhydrous ether (10 ml.). The mixture is refluxed for a few hours. Then, ether and excess thionyl chloride is removed by vacuum to yield 4-[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoyl chloride.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]1[C:15]2([CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[O:14][C:13]2[C:21]([F:26])=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[NH:11][C:10]1=[O:27])C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[NH2:8][CH:9]1[C:15]2([CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[O:14][C:13]2[C:21]([F:26])=[C:22]([F:25])[CH:23]=[CH:24][C:12]=2[NH:11][C:10]1=[O:27]
Reactant: O=C1Nc2ccc(F)c(F)c2OC2(CCOCC2)C1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NC1C(=O)Nc2ccc(F)c(F)c2OC12CCOCC2
Temperature: 40 °C
Reaction time: 6.5 h
Yield: 98.2 %

Procedure:
3-(Dibenzylamino)-8,9-difluoro-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-4(5H)-one (100 mg, 215 μmol, Eq: 1.00) was added to MeOH (10 mL) and the mixture warmed 40° C. to give a light yellow suspension. 20% Pd(OH)2/C (100 mg, 215 μmol, Eq: 1.00) was added, the mixture was degassed and stirred at RT under H2 for 6.5 h. The mixture was filtered through Celite and concentrated under reduced pressure to afford 3-amino-8,9-difluoro-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-4(5 h)-one (60 mg, 98% yield) as colorless oil which was used without purification. MS m/z 285.0 (MH+)
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Na].[NH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[O:18][CH2:19][O:20][C:13]=12.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][Cl:37])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1>C1COCC1>[Cl:37][CH2:36][CH2:35][O:34][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([NH:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[O:18][CH2:19][O:20][C:13]=34)=[N:23][CH:24]=[N:25]2)=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCl
Reactant: Nc1ccnc2c1OCO2
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: COc1cc2c(Nc3ccnc4c3OCO4)ncnc2cc1OCCCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
Sodium hexamethyldisilazane (1M solution in THF; 2 ml) was added dropwise to a mixture of 4-amino-2,3-methylenedioxypyridine (0.138 g), 4-chloro-7-(2-chloroethoxy)-6-methoxyquinazoline (0.272 g) and THF (5 ml) that had been cooled to 0° C. The mixture was stirred at 0° C. for 1 hour. The resultant mixture was allowed to warm to ambient temperature and was stirred for 2 hours. The reaction was quenched by the addition of glacial acetic acid (0.12 ml). The solvents were evaporated and the residue was partitioned between methylene chloride and an aqueous ammonium hydroxide solution. The organic layer was collected and concentrated to a small volume. Diethyl ether was added and a precipitate formed. The resultant solid was isolated, washed with diethyl ether and dried. There was thus obtained the title compound (0.245 g); NMR Spectrum: (DMSOd6) 3.97 (s, 3H), 4.04 (m, 2H), 4.45 (m, 2H), 6.12 (s, 2H), 7.13 (br d, 1H), 7.25 (s, 1H), 7.60 (d, 1H), 7.83 (s, 1H), 8.47 (s, 1H), 9.87 (br s, 1H); Mass Spectrum: M+H+ 375.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:18][C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[C:9]=2[CH2:8][N:7]=1)=[O:5])C>C1(C)C(C)=CC=CC=1.[Pd].[C]>[N:18]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10][C:9]=2[CH:8]=[N:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1=NCc2c(c3ccccc3n2S(=O)(=O)c2ccc(C)cc2)N1
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: O=C(O)c1ncc2[nH]c3ccccc3c2n1

Procedure:
Under argon, 10 g of 1,4-dihydro-5-tosyl-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester is refluxed for 10 hours in 200 ml of xylene with 5 g of 10% Pd-carbon. The filtrate is then removed from the palladium-carbon by evaporation, the evaporation residue yielding, after recrystallization from an ethyl acetate/ether mixture, 5 g of 5-tosyl-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester, mp 187°-189° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:12][OH:13].CCO.[OH-].[Na+]>O>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[N:12]/[OH:13]
Reactant: O=Cc1ccc(F)cc1F
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O/N=C/c1ccc(F)cc1F
Temperature: 0 °C
Yield: 49.7 %

Procedure:
2,4-Difluorobenzaldehyde (2.27 g, 16.0 mmol) and hydroxylamine hydrochloride (6.67 g, 96.0 mmol) were added to EtOH (25 mL) and water (25 mL) along with about 40 g of ice. The mixture was stirred and 50% aqueous NaOH (7.68 g, 96 mmol) was added dropwise. The mixture was stirred at ambient temperature for about 15 min then the solid was collected by filtration, washed with water (10 mL) and dried to give the title compound (1.25 g, 50%): 1H NMR (DMSO-d6) δ 11.58 (d, 1H), 8.18 (s, 1H), 7.78 (m, 1H), 7.33 (m, 1H), 7.14 (m, 1H).
Reaction SMILES: [N:1]1([CH:6]=[N:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[OH:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:22][N:23]([CH3:27])[C:24](Cl)=[O:25]>O1CCCC1>[CH3:22][N:23]([CH3:27])[C:24]([O:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:7]=[CH:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:25]
Reactant: CN(C)C(=O)Cl
Reactant: Oc1cnccc1N=CN1CCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)Oc1cnccc1N=CN1CCCC1

Procedure:
A mixture prepared from 4-[[(1-pyrrolidinyl)methylene]amino]-3-pyridinol (3.79 g), triethylamine (4.29 mL), dimethylcarbamyl chloride (2.74 mL) and tetrahydrofuran (130 mL) was refluxed for 1 hour, cooled, poured directly onto a silica column and eluted successively with ethyl acetate and 5% Et3N/ethyl acetate. Recrystallization from ethyl acetate and drying under high vacuum and refluxing acetone for 4 hours yielded 3.55 g of crystals, m.p. 99°-100° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:27][CH2:28][CH3:29])=[C:4]([C:17]([CH2:25][CH3:26])=[C:18]([F:24])[C:19](OCC)=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15].ClC1C(OCC)=C(/C(/CC)=C(/F)\C(OCC)=O)C=C2C=1OC(C)(C)C=C2C(C)C.[H-].C([Al+]CC(C)C)C(C)C>>[Cl:1][C:2]1[C:3]([O:27][CH2:28][CH3:29])=[C:4](/[C:17](/[CH2:25][CH3:26])=[C:18](/[F:24])\[CH2:19][OH:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:15])[CH3:16]
Reactant: CCOC(=O)C(F)=C(CC)c1cc2c(c(Cl)c1OCC)OC(C)(C)C=C2C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: CCOC(=O)/C(F)=C(/CC)c1cc2c(c(Cl)c1OCC)OC(C)(C)C=C2C(C)C
Agent: [H-]
Product: CCOc1c(/C(CC)=C(/F)CO)cc2c(c1Cl)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure L, ethyl 3-(8-chloro-4-isopropyl-7-ethoxy-2,2-dimethyl-2H-chromen-6-yl)-2-fluoro-pent-2-enoate (Compound 149, 79 mg, 0.19 mmol) and diisobutylaluminum hydride (1M in hexanes, 1.4 mL, 1.4 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 1:9 to 1:4 ethyl acetate/hexane).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:36])[CH:11]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)=[O:14])=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:13](=[O:14])[CH2:12][CH:11]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:34])([F:35])[F:33])=[CH:27][CH:26]=2)[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:37])=[O:2])=[CH:5][CH:6]=2)=[O:36])=[CH:20][CH:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)c1ccc(C(=O)C(CC(=O)c2ccc(C(C)(C)C)cc2)c2ccc(OC(F)(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1ccc(C(=O)CC(C(=O)c2ccc(C(=O)O)cc2)c2ccc(OC(F)(F)F)cc2)cc1
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
4-[4-(4-tert-Butylphenyl)-4-oxo-2-(4-trifluoromethoxyphenyl)butyryl]benzoic acid methyl ester (13.9 g, 27.2 mmol) was suspended in ethanol (120 mL, 96%) and added sodium hydroxide (4N, 27,2 mL). After 4½ h the reaction was evaporated to dryness. The residue was added water (200 mL) and hydrochloric acid (4N, 30 mL) to pH 1-2 causing precipitation. The mixture was stirred for ½ h. The precipitate was filtered, washed carefully with water, and dried the night over at 40° C. in vacuo. The residue was crystallised from methanol and water to afford 4-[4-(4-tert-butylphenyl)-4-oxo-2-(4-trifluoromethoxyphenyl)butyryl]benzoic acid (10.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.[CH3:19][N:20]([CH3:33])[CH2:21][CH2:22][CH2:23][C:24]1[C:25]([CH3:32])=[C:26]([CH:30]=O)[NH:27][C:28]=1[CH3:29]>>[CH3:33][N:20]([CH3:19])[CH2:21][CH2:22][CH2:23][C:24]1[C:25]([CH3:32])=[C:26]([CH:30]=[C:13]2[C:12]3[C:16](=[CH:17][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][CH:11]=3)[NH:15][C:14]2=[O:18])[NH:27][C:28]=1[CH3:29]
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1[nH]c(C)c(CCCN(C)C)c1C
Yield: 77.5 %

Procedure:
6-(2-Methoxyphenyl)-1,3-dihydroindol-2-one (239 mg, 1.0 mmol)was condensed with 4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (208 mg, 1.0 mmol) using method B to give 333 mg (83%) of 3-[4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-6-(2-methoxyphenyl)-1,3-dihydroindol-2-one as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:3]3[N:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:18][CH:19]=1
Reactant: Nc1cccnc1Nc1ccccc1C(=O)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(C2=Nc3cccnc3Nc3ccccc32)cc1
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 11.5 g (0.037 mole) of [2-[(3-amino-2-pyridinyl)amino]phenyl](4-fluorophenyl)methanone and 0.6 g of para toluene sulfonic acid in toluene was refluxed for 24 hr using a Dean-Stark trap to collect water. At the end of reflux, some of the toluene (300 ml) was distilled off and the hot solution was filtered. Pet.-ether (30°-60°) was added to cloud point. The solution was refrigerated overnight (0° C.) and filtered to give 10.7 g crystals. A portion of the material was recrystallized from isopropyl alcohol and dried in vacuo overnight at 65° C., m.p. 203°-205° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22])=[CH:15][CH:14]=1>N1C=CC=CC=1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][S:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:23])=[O:22])=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)CCc1ccc(Cl)cc1
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.7 %

Procedure:
2-Aminobenzenesulfonamide (0.52 g, 3 mmol) was dissolved in pyridine (20 mL) followed by addition of 2-(4-chlorophenyl)ethanesulfonyl chloride (0.80 g, 3.3 mmol) and the reaction was stirred at RT overnight. The solvent was then removed under reduced pressure and the crude material was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (87 mg, 8%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[O:26]([C:33]1[N:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[C:21]([NH:20][C:16]1[CH:15]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[N:41][C:33]=3[O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=1)(=[O:25])[CH:22]([CH3:23])[CH3:24]
Reactant: O=C(Cl)c1cccnc1Oc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)c3cccnc3Oc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 2-phenoxynicotinoyl chloride: ESMS m/e: 543.3 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([NH2:10])([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]=O.[BH4-].[Na+]>C1C=CC=CC=1.CO>[CH3:11][NH:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:9])[CH3:8]
Reactant: C=O
Reactant: CC(C)(N)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: CNC(C)(C)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-phenylpropan-2-amine (1 eq.) in benzene (0.25 M) was added formaldehyde (37% w/w aqueous solution, 2 eq.). The vessel attached a Dean-Stark apparatus and heated at 80° C. for 36 h. The reaction mixture was cooled to RT, dried with Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the crude imine. This was then taken up in methanol (1.4 M) and added sodium borohydride (10 eq.). The resulting mixture was stirred at RT for 2 h and then quenched with 1 N aq. HCl. The volatiles were removed in vacuo and the pH of the resulting residue was carefully brought up to ˜12 with 1 N aq. NaOH. The mixture was then extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO2, 2:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]2[C:12]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].[CH:23]([C@H:25]1[CH2:30][CH2:29][C@H:28]([C:31]([O:33][CH3:34])=[O:32])[CH2:27][CH2:26]1)=O.C(C1(C(OC)=O)CCCC1)=O>>[CH2:1]([O:5][C:6]1[C:11]2[C:12]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][C@H:25]4[CH2:26][CH2:27][C@H:28]([C:31]([O:33][CH3:34])=[O:32])[CH2:29][CH2:30]4)[CH2:19][CH2:18]3)=[N:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)[C@H]1CC[C@H](C=O)CC1
Reactant: CC(C)COc1cccc2onc(OCC3CCNCC3)c12
Agent: COC(=O)C1(C=O)CCCC1
Product: COC(=O)[C@H]1CC[C@H](CN2CCC(COc3noc4cccc(OCC(C)C)c34)CC2)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 4-isobutoxy-3-(piperidin-4-ylmethoxy)-1,2-benzisoxazole (EXAMPLE 10, Step 1) and methyl trans-4-formylcyclohexanecarboxylate (JP 49048639) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclopentanecarboxylate.
Reaction SMILES: [CH3:1][CH:2]([CH2:39][CH2:40][CH3:41])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:28][C:29](=[O:38])[C@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:31])[CH2:12][NH:13][CH2:14][C:15]2([NH:20]C(=O)OC(C)(C)C)[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:20][C:15]1([CH2:14][NH:13][CH2:12][C@H:11]([NH:28][C:29](=[O:38])[C@H:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:31])[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([CH3:1])[CH2:39][CH2:40][CH3:41])=[CH:6][CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCCC(C)COc1ccc([C@H](CNCC2(NC(=O)OC(C)(C)C)CCCC2)NC(=O)[C@@H](C)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)COc1ccc([C@H](CNCC2(N)CCCC2)NC(=O)[C@@H](C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
To a solution of crude t-butyl 1-(((2R)-2-(4-(2-methylpentyloxy)phenyl)-2-((S)-2-phenylpropanamido)ethylamino)methyl)cyclopentylcarbamate from Part A (195 mg, 0.345 mmol) in dichloromethane (2 mL) at 0° C. was added TFA (1 mL, 12.98 mmol). The reaction mixture was stirred for 1.5 h while being allowed to warm to room temperature. The mixture was concentrated and the product was purified by reverse phase HPLC (acetonitrile/water with 0.1% TFA). The organic solvent was removed on the rotovapor and the aqueous mixture was frozen and placed on the lyophilizer to afford (2S)-N-((1R)-2-((1-aminocyclopentyl)methylamino)-1-(4-(2-methylpentyloxy)phenyl)ethyl)-2-phenylpropanamide (154 mg, 63% yield, 2 steps) as a colorless amorphous solid: 1H NMR (300 MHz, 100° C., DMSO-d6) δ 7.95 (d, J=8.1 Hz, 1H), 7.16-7.34 (m, 5H), 7.11 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.8 Hz, 2H), 6.87 (br. s., 5H), 4.94-5.06 (m, 1H), 3.68-3.88 (m, 3H), 2.96-3.13 (m, 2H), 2.93 (s, 2H), 1.59-1.95 (m, 9H), 1.40 (d, J=7.0 Hz, 3H), 1.17-1.49 (m, 4H), 0.97 (d, J=7.0 Hz, 3H), 0.90 (t, J=7.0 Hz, 3H); HPLC tR=2.68 min (Method A); LRMS (ESI) m/e 466.5 [(M+H)+, calcd for C29H44N3O2 466.4].