Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][C:10]=1[CH2:11][N:12]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[C:13]1[N:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][N:14]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[F:39][C:36]([F:37])([F:38])[C:28]1[CH:27]=[C:26]([CH:31]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:29]=1)[CH2:25][N:12]([CH2:11][C:10]1[CH:40]=[C:41]([C:44]([F:47])([F:46])[F:45])[CH:42]=[CH:43][C:9]=1[OH:8])[C:13]1[N:18]=[CH:17][C:16]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[CH:15][N:14]=1
Reactant: FC(F)(F)c1cc(CN(Cc2cc(C(F)(F)F)ccc2OCc2ccccc2)c2ncc(N3CCOCC3)cn2)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
(2-Benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (2.46 g) is dissolved in ethanol (35 ml), and thereto is added 10% palladium-carbon (750 mg) and the mixture is stirred under hydrogen atmosphere at room temperature for 1 hour and 30 minutes. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1→3:2) to give 2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenol (1.53 g). MS (m/z): 581 [M+H]+
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[CH3:48][C:49]1[CH:53]=[CH:52][S:51][C:50]=1[CH2:54][NH2:55]>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:55][CH2:54][C:50]4[S:51][CH:52]=[CH:53][C:49]=4[CH3:48])=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:46][CH:47]=1
Reactant: Cc1ccsc1CN
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1ccsc1CNC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)cc1C
Yield: 73 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (3-methylthiophen-2-yl)methanamine, the title compound was obtained as a colorless solid in 73% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.13 (d, J=5.0 Hz, 1H), 7.08-6.99 (m, 2H), 6.82 (d, J=5.0 Hz, 1H), 6.08 (s, 1H), 5.83 (br s, 1H), 4.65 (d, J=5.0 Hz, 2H), 4.42 (s, 2H), 3.83-3.74 (m, 2H), 3.47-3.39 (m, 2H), 2.49 (s, 3H), 2.24 (s, 3H); MS (ES+) m/z 444.2 (M+1).
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(OC(=O)C[N:14]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH:16]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=2)[C:15]1=[O:34])C>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([N:14]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH:16]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([C:30]([F:32])([F:33])[F:31])[CH:23]=2)[C:15]1=[O:34])[CH3:8])[CH3:7]
Reactant: CCOC(=O)CN1CC(C)(C)C(Oc2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: CCOC(=O)C(C)Br
Product: CCOC(=O)C(C)N1CC(C)(C)C(Oc2ccc(C#N)c(C(F)(F)F)c2)C1=O

Procedure:
The reaction was carried out as previously described in Step 1 of examples 111-127 using ethyl 2-bromopropionate in place of bromoacetic acid ethyl ester. The diastereomeric mixture of products (3) were separated by column chromatography to afford the diastereomers as either the RS or SR compound or the RR or SS compound. The RS or SR compound was used in the next reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:4][CH:3]=1.[CH3:22][C:23](O)(C#C)C>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]#[CH:23])=[CH:3][CH:4]=1
Reactant: Brc1ccc(OCCCCCCOC2CCCCO2)cc1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C#Cc1ccc(OCCCCCCOC2CCCCO2)cc1
Yield: 72.5 %

Procedure:
A degassed mixture of 4-bromo-1-[6-(tetrahydropyran-2-yloxy)hexyloxy]benzene (20 g), 2-methyl-3-butyn-2-ol (18.85 g), triphenylphosphine (TPP, 0.59 g), copper (I) iodide (0.11 g) and bis(triphenylphosphine)palladium dichloride (0.40 g) in 200 ml of triethylamine was refluxed for 4 hours under an atmosphere of argon. After being cooled the reaction mixture was filtered over celite to give a yellowish solution which was evaporated to dryness. The resulting yellow oil was dissolved in 200 ml of a toluene/triethylamine mixture (1:1) to which 14.45 g of KOH was then added. The resulting mixture was heated at reflux for 12 h, cooled and filtered over 260 g of silica gel using diethylether as eluent. This yields a dark oil which was purified by chromatography using a silica gel clolumn and cyclohexane/ethyl acetate (9:1) as eluent to give 12.28 g of 4-[6-(tetrahydropyran-2-yloxy)hexyloxy]phenylacetylene as a red oil.
Reaction SMILES: [I-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C=CC=CC=1.CN(P(N(C)C)(N(C)C)=O)C.[Li]CCCC.O=[C:48]1[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]1>C1COCC1>[C:57]([O:56][C:54]([N:51]1[CH2:52][CH2:53][C:48](=[CH:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:49][CH2:50]1)=[O:55])([CH3:60])([CH3:58])[CH3:59]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: c1ccc(CCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=CCCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a solution of triphenyl(4-phenylbutyl)phosphonium iodide (975 mg, 1.87 mmol) in THF (8 mL) under Ar at −78° C. was added HMPA (1 mL) followed by n-BuLi (1.6 M in hexane; 1.28 mL, 2.05 mmol, 1.1 equiv.). After stirring at room temperature for 2 h, the mixture was cooled to −78° C. again, and tert-butyl 4-oxopiperidine-1-carboxylate (409 mg, 2.05 mmol, 1.1 equiv.) in THF (2 mL) was added. The mixture was allowed to warm to room temperature and to stand for 2 days. The reaction was quenched with H2O, and the mixture was extracted three times with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. After concentration, the residue was purified by CC (SiO2, hexane/EtOAc 10:1) to obtain 1-(tert-butoxycarbonyl)-4-(4-phenylbutylidene)piperidine (216 mg, 37%) as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.25 (m, 2H), 7.15 (m, 3H), 5.22 (t, 1H, J=7.2 Hz), 3.55 (m, 4H), 2.60 (t, 2H, J=8.0 Hz), 2.15 (m, 4H), 2.03 (m, 2H), 1.66 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: OC1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:3]1[NH:12]C(C)=O.[OH:16][CH:17]1O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]1O.C(OC)#N>>[CH2:3]([NH2:12])[CH:4]([OH:5])[CH:6]([OH:7])[CH:8]([OH:9])[CH:10]([OH:11])[CH2:17][OH:16]
Reactant: O=C(O)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: COC#N
Product: NCC(O)C(O)C(O)C(O)CO

Procedure:
1H NMR of IV, Na-salt (500 MHz, D2O, 2 mM NaHCO3, 30° C.): δ=5.473 (m, 2 —CH═CH— of DOPE), 5.328 (m, OCH2CHCH2O of DOPE), 4.574 and 4.473 (m, HA: H-1 of GlcNAc, H-1 of GlcA; CO—OCHCHCH2 of DOPE), 4.246 (dd, J=12.3 Hz, J=6.8 Hz, CO—OCHCHCH2 of DOPE), 4.027 (t, J=5.7 Hz, POCH2CH2N of DOPE), 3.95-3.34 (HA: H-2+H-6 of GlcNAc, H-2+H-5 of GlcA; POCH2CHCH2 of DOPE), 2.413 (m, 2 CH2COO of DOPE), 2.302 (m, 2 CH2CON), 2.049 (m, 2 CH2CH═CHCH2 of DOPE), 2.039 (m, NCOCH3 of GlcNAc), 1.630 (m, 2 CH2CH2CON and 2 CH2CH2COO of DOPE), 1.306 (m, —CH2— of DOPE), 0.892 (˜t, 2 CH3 of DOPE) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:61]=[CH:60][C:53]2[NH:54][C:55]([CH:57]([NH2:59])[CH3:58])=[N:56][C:52]=2[CH:51]=1.BrBr.ClCl>O1CCCC1.C(Cl)Cl.C(O)C>[Cl:49][C:50]1[CH:61]=[CH:60][C:53]2[NH:54][C:55]([CH:57]([NH:59][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([Br:1])[CH:3]=3)[CH3:58])=[N:56][C:52]=2[CH:51]=1
Reactant: CC(N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)c1ccc(C(=O)N2CCCC2)c(Br)c1
Agent: BrBr
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC2)c(Br)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 73 %

Procedure:
Prepared analogously to Example 1g from 3-bromo-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and rac.-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 73%; Rf value: 0.50 (silica gel; methylene chloride/ethanol=9:1); C21H20BrClN4O2 (475.78); mass spectrum: (M−H)−=473/475/477 (bromine/chlorine isotope).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:21])=[N:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:22][CH3:23]>C(Cl)Cl>[OH:21][C:15]1[C:14]2[C:19](=[CH:20][C:11]([O:10][CH2:9][CH2:8][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[C:12]([O:22][CH3:23])[CH:13]=2)[N:18]=[CH:17][N:16]=1
Reactant: COc1cc2c(O)ncnc2cc1OCCCl
Reactant: C1COCCN1
Solvent: ClCCl
Product: COc1cc2c(O)ncnc2cc1OCCN1CCOCC1
Temperature: 100 °C
Yield: 46 %

Procedure:
To morpholine (5 mL) was added 7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ol (600 mg, 2.36 mmol) from Example 35A and the mixture heated at 100° C. for 4 hours. After cooling to room temperature, the mixture was diluted with DCM and filtered. The resulting solid was washed with MeOH and H2O to give 4-hydroxy-6-methoxy-7-(2-morpholinoethoxy)quinazoline (328 mg, 1.07 mmol, 46%). 1H NMR (300 MHz, DMSO-d6) δ 12.08 (br s, 1H), 7.98 (s, 1H), 7.44 (s, 1H), 7.17 (s, 1H), 4.23 (t, 2H), 3.87 (s, 3H), 3.58 (t, 4H), 3.41-3.32 (m, 4H), 2.75 (t, 2H); LC-MS (ESI) m/z 306 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>N1C=CC=CC=1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][NH:10][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[F:13])=[CH:7][CH:8]=1
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)c1ccccc1F
Solvent: c1ccncc1
Product: O=C(NNc1ccc(C(F)(F)F)cc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a stirred solution of 75.0 g of 4-(trifluoromethyl)-phenylhydrazine in 500 ml of dry pyridine, cooled in an ice bath, was added dropwise, under nitrogen, 79.1 g of 2-fluorobenzoyl chloride. Upon completion of the addition, the ice bath was removed and the reaction mixture stirred at ambient temperature for 4 hours. The mixture was poured into water and a precipitate formed. Recrystallization of the precipitate from isopropyl alcohol-water, gave 108 g (84%) of 2-fluorobenzoic acid, 2-(4-(trifluoromethyl)phenyl)hydrazide as a solid. Subsequent recrystallization from isopropyl alcohol-water gave the analytical sample, mp 163°-165°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.[CH2:19]([N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+].O>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>[CH2:19]([N:26]1[CH:30]=[C:29]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=23)[CH:28]=[N:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(Cc4ccccc4)c3)ccnc21
Temperature: 100 °C
Yield: 74.3 %

Procedure:
4-Bromo-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.100 g, 0.000306 mol) was combined with 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.113 g, 0.000398 mol) in toluene (3.0 mL, 0.028 mol) and ethanol (0.5 mL, 0.008 mol). Potassium carbonate (0.084 g, 0.00061 mol) dissolved in water (1.0 mL, 0.056 mol) was added and the reaction mixture was degassed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (0.080 g, 0.000069 mol) was added, and again the mixture was degassed with nitrogen for 5 min. The reaction was heated in sealed tube to 100° C. in a microwave for 30 minutes. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give a crude residue. The product was purified by FCC on silica gel using ethyl acetate:hexane 3:7, to give 4-(1-benzyl-1H-pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine 0.092 g as a semisolid residue, LC/MS (M+H)+: 405.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][NH:23]1>O1CCOCC1>[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][N:23]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4]
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2ncccc21
Reactant: CC1CCCCN1
Solvent: C1COCCO1
Product: CC1CCCCN1CC(=O)N1c2ccccc2NC(=O)c2cccnc21
Reaction time: 2 h
Yield: 37.2 %

Procedure:
A suspension of 11-(2-chloroacetyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one (2.9 g) and 2-methylpiperidine (2.37 ml) in dioxane (30 ml) was refluxed under stirred for two hours. After cooling and filtration, the collected solid was crystallized from absolute ethanol to give 1.3 g (37.2%) of 11-[2-(2-methylpiperidin-1-yl)acetyl]-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one melting at 248°-249° C. (dec.).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[CH3:18][NH2:19]>CO>[CH3:1][C:2]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:19][CH3:18])=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: CN
Reactant: CC(C)(c1ccccc1)c1ccc(C=O)cc1
Solvent: CO
Product: CNCc1ccc(C(C)(C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
4-(1-Methyl-1-phenylethyl)benzaldehyde (3.61 g; 16.1 mmol) and molecular sieves (4 angstroms: about five granules) were added to 40% methylamine in methanol (40 ml), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was taken up in ether (100 ml), and the organic layer was washed with saturated brine, followed by drying over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (25 ml). Sodium borohydride (0.70 g) was added to the solution, and the thus-obtained mixture was heated for 1 hour at 50° C. The solvent was evaporated under reduced pressure, and the residue was taken up in ether (100 ml). The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethanol (10 ml). Excess amount of 4N hydrochloric acid—ethyl acetate was added to the solution, and the solvent was evaporated under reduced pressure. The residue was taken up in isopropyl ether (100 ml), and white crystals that precipitated were collected by filtration. The crystals were converted into their free forms by use of aqueous sodium hydroxide solution, followed by extraction with ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, to thereby yield 2.49 g of the target compound as orange oily matter (yield: 64.6%).
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:39][C@H:40]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH2:41][CH:42]([CH3:44])[CH3:43]>C1COCC1.C(N(CC)CC)C>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([NH:39][C@H:40]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH2:41][CH:42]([CH3:44])[CH3:43])=[O:13])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Z-Asp(OtBu)-OH (10.23 g) in THF (50 mL) was added N-methylmorpholine (3.30 mL) and isobutyl chloroformate (3.90 mL) at −20° C. After 10 min, the reaction mixture was added to the solution of H-Leu-OBzl (11.81 g in 50 mL HCl3) at −20° C., followed by addition of triethylamine (4.18 mL). The resulting mixture was allowed to warm to room temp. After filtering off the salt, the filtrate was concentrated to an oil. The oil was dissolved in 100 mL of ethyl acetate; washed with 0.2 N HCl, 5% NaHCO3 and sat. NaCl; dried over Na2SO4. After filtration, the solvent was evaporated to give Z-Asp(OtBu)-Leu-OBzl as an oil of 14.81 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O.C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:10]2[S:9][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cccs1
Reactant: Clc1cc(I)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1cc(-c2cccs2)ccn1
Temperature: 70 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A round-bottomed flask was charged with 2-chloro-4-iodopyridine (600 mg, 2.5 mmol), thiophen-2-ylboronic acid (385 mg, 3.0 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (176 mg, 0.251 mmol), THF (9 mL) and 2M aqueous sodium carbonate (3.0 mL, 6.0 mmol). The reaction mixture was stirred at 70° C. overnight. The reaction mixture was cooled to room temperature then diluted with 20 mL water and extracted with 100 mL EtOAc (2×). The combined organic layers were washed with 20 mL water and 20 mL brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on ˜2 g SiO2 and chromatographed over 24 g SiO2 with EtOAc/hexanes (gradient: 0-10% EtOAc). All fractions containing product were combined and concentrated to give 430 mg (88%) of 2-chloro-4-thiophen-2-yl-pyridine as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.O[CH:10]1[CH2:14][CH2:13][O:12][CH2:11]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: OC1CCOC1
Reactant: Oc1ccc(Br)cn1
Product: Brc1ccc(OC2CCOC2)nc1

Procedure:
The title compound was prepared from 5-bromo-2-hydroxypyridine and rac-3-hydroxy-tetrahydrofuran in analogy to Example 9c): colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:15][NH2:16].O1CCCC1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([S:8]([NH:16][CH3:15])(=[O:10])=[O:9])[CH:7]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(F)cc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cc(F)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
A solution of 5-fluoro-2-nitrobenzene-1-sulfonyl chloride (2.0 g, 8.35 mmol) in dichloromethane (50 mL) was cooled using an ice water bath. 2M methylamine in tetrahydrofuran (5.0 mL, 10.0 mmol) was added. The resulting solution was stirred for 2 hours. The reaction mixture was washed with 2N HCl solution (2×100 mL), brine (100 mL) and then dried over magnesium sulphate. The solution was filtered before concentrating under reduced pressure to afford 5-fluoro-N-methyl-2-nitrobenzenesulfonamide (1.79 g, 7.64 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:7][C:5]=1[NH2:6])([O-])=O.CO.C(=O)([O-])[O-].[Na+].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:1][C:4]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:7][C:5]=1[NH2:6]
Reactant: COCCOc1ccc([N+](=O)[O-])c(N)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCCOc1ccc(N)c(N)c1

Procedure:
A mixture of 11 g. of 2-nitro-5-(2-methoxyethoxy) aniline, 220 ml. of methanol, 460 ml. of water, 40 g. sodium carbonate and 60 g. sodium hydrosulfite is refluxed for 15 minutes. The solution is concentrated, diluted with water and extracted with chloroform. Evaporation of the chloroform leaves 1,2-diamino-4-(2-methoxyethoxy) benzene as an oil, sufficiently pure for the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20](OC)=[O:21])[CH:16]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31]([S:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:38])=[O:37])[CH:30]=[CH:29]2>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([C:20]([N:42]3[CH2:41][CH2:40][N:39]([S:36]([C:31]4[CH:30]=[CH:29][C:28]5[C:33](=[CH:34][CH:35]=[C:26]([Cl:25])[CH:27]=5)[CH:32]=4)(=[O:37])=[O:38])[CH2:44][CH2:43]3)=[O:21])[CH:14]=[CH:13][C:12]=2[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2c(c1)CCC(CNC(=O)OC(C)(C)C)C2
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: CC(C)(C)OC(=O)NCC1CCc2cc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)ccc2C1

Procedure:
In a similar manner to Referential Example 48 except for the use of (2RS)-2-(N-tert-butoxycarbonylaminomethyl)-6-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride, the reaction was conducted, whereby the title compound was obtained.