Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:18]([O:22][C:23](=[O:34])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=1)([CH3:21])([CH3:20])[CH3:19].[OH-].[K+]>CCO>[C:18]([O:22][C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]1[CH:27]=[CH:28][C:29](/[CH:32]=[CH:16]/[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH:6]3[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]3)=[CH:14][CH:13]=2)=[O:17])=[CH:30][CH:31]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(C2CCN(C)CC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)OC(C)(C)C)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 29.1 %

Procedure:
A mixture of 1-[4-(1-methyl-piperidin-4-yl)-phenyl]-ethanone hydrochloride (544 mg, 2.15 mmol), 4-formylcinnamic acid tert-butyl ester (500 mg, 2.15 mmol) and 1.7 M KOH (3.8 ml, 6.46 mmol) in EtOH (10 ml) was stirred at room temperature for 6 hours. During the reaction, the formation of a precipitate was observed. The solid was then filtered off through a Buchner funnel to obtain 270 mg of (E)-3-(4-{(E)-3-[4-(1-methyl-piperidin-4-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid tert-butyl ester as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:58]([CH3:60])[CH3:59])[C:7]([N:9]1[C@H:14]([C:15]2[NH:19][C:18]3[C:20]4[C:25]([CH:26]=[CH:27][C:17]=3[N:16]=2)=[CH:24][C:23]([C:28]2[CH:29]=[C:30]3[C:54](=[CH:55][CH:56]=2)[C:34]2[NH:35][C:36]([C@@H:38]5[CH2:42][CH2:41][CH2:40][N:39]5[C:43](=[O:53])[C@@H:44]([NH:48][C:49](=[O:52])[O:50][CH3:51])[CH:45]([CH3:47])[CH3:46])=[N:37][C:33]=2[CH:32]=[CH:31]3)=[CH:22][CH:21]=4)[C@@H:13]2[CH2:57][C@H:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4].[CH3:61][O:62][C:63](N[C@@H](C(C)C)C(O)=O)=O>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:58]1[CH2:60][CH2:63][O:62][CH2:61][CH2:59]1)[C:7]([N:9]1[C@H:14]([C:15]2[NH:19][C:18]3[C:20]4[C:25]([CH:26]=[CH:27][C:17]=3[N:16]=2)=[CH:24][C:23]([C:28]2[CH:29]=[C:30]3[C:54](=[CH:55][CH:56]=2)[C:34]2[NH:35][C:36]([C@@H:38]5[CH2:42][CH2:41][CH2:40][N:39]5[C:43](=[O:53])[C@@H:44]([NH:48][C:49](=[O:52])[O:50][CH3:51])[CH:45]([CH3:47])[CH3:46])=[N:37][C:33]=2[CH:32]=[CH:31]3)=[CH:22][CH:21]=4)[C@@H:13]2[CH2:57][C@H:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7[C@H]8CC[C@H](C8)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c65)c4)ccc3c2[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7[C@H]8CC[C@H](C8)N7C(=O)[C@@H](NC(=O)OC)C7CCOCC7)[nH]c65)c4)ccc3c2[nH]1)C(C)C

Procedure:
Title compound was prepared by methods analogous to those described for methyl (S)-1-((S)-2-(2′-((1R,3S,4S)-2-((S)-2-methoxycarbonylamino-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate, substituting (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid for (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid. (ESI) m/z 855 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([O:22]C)=[O:21])=[N:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:24])[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2].O.[OH-].[Li+]>CO.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[N:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:24])[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)nc3)cc2[C@H](N)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
To methyl 5-((2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinate (for a preparation, see Intermediate 54) (550 mg, 1.62 mmol) in MeOH (5 mL) was added lithium hydroxide monohydrate (78 mg, 3.24 mmol) in water (5 mL) and the mixture stirred at room temperature for 90 mins. The mixture was concentrated in vacuo before DCM was added. The mixture was filtered, dried by passing through a hydrophobic frit, and concentrated in vacuo to give 5-((2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinic acid (517 mg, 1.59 mmol, 98% yield).
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10]([N:12]1[CH2:18][CH2:17][C:16](=O)[CH:15]([CH2:20][C:21]([OH:23])=O)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O.[NH2:25][NH2:26]>C1COCC1>[C:5]([O:9][C:10]([N:12]1[CH2:18][CH2:17][C:16]2=[N:25][NH:26][C:21](=[O:23])[CH2:20][CH:15]2[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(CC(=O)O)CC1
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2=NNC(=O)CC2CC1

Procedure:
60 mL acetic acid was added to 16 g 4-carboxymethyl-5-oxo-azepane-1-carboxylic acid tert-butyl ester in 120 mL THF at 5° C. 14 mL hydrazine hydrate was added to the reaction and the mixture was refluxed over night. After completion of the reaction, volatiles were removed and the residue was basified with sodium carbonate and extracted with chloroform. The organic layer was dried and concentrated under reduced pressure to afford 11 g of the desired product
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Cl[CH2:23][C:24]([CH3:26])=[CH2:25].Cl>O1CCCC1.CCCCCC.CCOCC>[C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH2:25][C:24]([CH3:26])=[CH2:23])[C:8]([OH:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C(C)CCl
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(C)CC(C(=O)O)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 114.9 %

Procedure:
A solution of diphenylacetic acid (14 g, 66 mmol.) in 150 mL of tetrahydrofuran was stirred at 0° C. under argon while 55.5 mL of a 2.5 M solution of n-butyllithium in hexane was added dropwise. After 15 minutes, 3-chloro-2-methylpropene (6.51 mL, 66 mmol.) was added in one portion. After 10 minutes, 25 mL of 4N hydrochloric acid was added, along with ether (250 mL). The layers were separated, the organic layer was washed with water (2×100 mL), brine (2×100 mL) dried (MgSO4), and filtered. Concentration afforded 20.2 g (99%) of a yellow oil. 1H NMR (CDCl3)δ 7.4-7.2 (m, 10H), 4.7 (s, IH), 4.6 (s, lH), 3.2 (s, 2H), 1.4 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH:10]([F:17])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[OH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[O:20].[CH2:25]([N:32]1[CH2:41][CH2:40][C:39]2[C:34](=[N:35][C:36](Cl)=[C:37]([NH:42][CH:43]([CH3:45])[CH3:44])[N:38]=2)[CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:25]([N:32]1[CH2:41][CH2:40][C:39]2[C:34](=[N:35][C:36]([N:14]3[CH2:15][CH2:16][CH:11]([CH:10]([C:4]4[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=4[F:2])[F:17])[CH2:12][CH2:13]3)=[C:37]([NH:42][CH:43]([CH3:45])[CH3:44])[N:38]=2)[CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1.[C:19]([OH:20])([C:21]([F:24])([F:23])[F:22])=[O:18]
Reactant: CC(C)Nc1nc2c(nc1Cl)CN(Cc1ccccc1)CC2
Reactant: Fc1ccc(C(F)C2CCNCC2)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CN(Cc1ccccc1)CC2
Temperature: 100 °C

Procedure:
A mixture of 4-((2,4-difluorophenyl)fluoromethyl)piperidine hydrochloride (74.0 mg, 0.279 mmol), 6-benzyl-3-chloro-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (100 mg, 0.232 mmol), sodium tert-butoxide (66.9 mg, 0.696 mmol), BINAP (21.7 mg, 0.035 mmol) and Pd2(dba)3 (10.6 mg, 0.012 mmol) in toluene (1.2 mL) was heated at 100° C. in a sealed tube for 14 h. The mixture was purified by HPLC Method A to give the title compound as a TFA salt (108.3 mg, 74.8%) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ ppm 1.23 (dd, J=6.4, 2.4 Hz, 6H), 1.39-1.47 (m, 1H), 1.51-1.72 (m, 2H), 1.95-2.12 (m, 2H), 2.58-2.70 (m, 2H), 3.04 (br s, 2H), 3.36-3.83 (m, 4H), 4.09-4.21 (m, 3H), 4.51 (br s, 2H), 5.52 (dd, J=46.2, 7.3 Hz, 1H), 6.97-7.07 (m, 2H), 7.45-7.59 (m, 6H); ESI-MS m/z [M+H]+ 510.4.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[H-].[Na+].[CH3:13][O:14][C:15](=O)[O:16]C.Cl>O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:15](=[O:16])[O:14][CH3:13])[N:7]=1
Reactant: COc1cc(C)nc(N)n1
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Nc1nc(C)cc(OC)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a suspension of 50 g of 2-amino-4-methoxy-6-methylpyrimidine in 1000 ml of tetrahydrofuran was added portionwise, under a nitrogen atmosphere, 42.8 g of 50% sodium hydride while cooling the reaction flask in an ice-water bath. After stirring one hour at 25° C., 58.5 g of dimethylcarbonate was added dropwise at 5° to 25° C. The suspension was stirred about 16 hours at ambient temperature, then 80 ml of concentrated hydrochloric acid was added dropwise while maintaining a reaction temperature of 20° to 25° C. with external ice-bath cooling. The suspension was stirred 0.5 hour, filtered, and the filtrate was dried over sodium sulfate and then concentrated in vacuo. The residue was recrystallized from hexane to yield 54 g of the title compound, m.p. 89°-92.5° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[CH:4]=[CH:5][C:6]=1[CH:7]=[O:8].[Br:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:18][C:4]1[N:3]([S:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:11])[C:2]([CH3:1])=[C:6]([CH:7]=[O:8])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(C=O)ccn1S(=O)(=O)c1cccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C=O)cc(Br)n1S(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
To a solution of 2-methyl-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (974 mg) in N,N-dimethylformamide (10 mL) was added N-bromosuccinimide (1.17 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as white crystals (yield 675 mg, 53%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[OH:27][CH2:26][CH2:25][CH:22]1[CH2:23][CH2:24][N:19]([C:16]([C:13]2[S:14][CH:15]=[C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])[N:12]=2)=[O:17])[CH2:20][CH2:21]1
Reactant: OCCC1CCNCC1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCC(CCO)CC3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (200 mg, 0.66 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). 4-Piperidineethanol (Aldrich)(85.6 mg; 0.66 mmol; 1 eq.) and triethylamine (0.19 ml; 1.33 mmol; 2 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is crystallized in MeOH, affording Compound (28) as a brown solid (117.2 mg; 43%). 1H NMR (DMSO-d6, 300 MHz) δ 1.05-1.30 (m, 2H), 1.38 (m, 2H), 1.75 (m, 2H), 2.13 (s, 3H), 2.48 (s, 3H), 2.85 (m, 1H), 3.22 (m, 1H), 3.45 (m, 2H), 4.38 (t, J=6 Hz, 1H), 4.42 (m, 1H), 5.15 (m, 1H), 7.97 (s, 1H), 12.16 (s, 1H). M− (ESI): 393.21; M+ (ESI): 395.20. HPLC (method A), Rt: 2.69 min (purity: 95.7%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Cl.[NH2:22][OH:23].N1C=CC=CC=1>CO.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]=[N:22][OH:23])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: NO
Reactant: O=Cc1ccc(-c2ccc(O)c(F)c2)c2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: CCOCC
Product: ON=Cc1ccc(-c2ccc(O)c(F)c2)c2ccccc12
Yield: 66.8 %

Procedure:
A mixture of 4-(3-fluoro-4-hydroxyphenyl)-naphthalene-1-carbaldehyde (570 mg, 2.13 mmol), hydroxylamine hydrochloride (297 mg, 4.27 mmol), and anhydrous pyridine (0.35 ml, 4.27 mmol) in MeOH (13 ml) was heated to reflux for 1.5 h. The mixture was then diluted with ether, washed with water, the organic layer was dried over anhydrous Na2SO4, passed through a silica plug and concentrated. Purification by reverse phase HPLC (water-CH3CN-0.1% TFA) afforded 400 mg (67%) of product as a white solid: mp 187–188° C.; 1H NMR (300 MHz, DMSO-d6): δ 7.12 (2H, m), 7.28 (1H, d, J=11.4 Hz), 7.45 (1H, d, J=7.4 Hz), 7.53–7.64 (2H, m). 7.83 (1H, d, J=7.5 Hz), 7.90 (1H, d, J=7.6), 8.73 (1H, d, J=8.1 Hz), 8.81 (1H, s), 10.08 (1H, s), 11.46 (1H, s); MS m/z 282 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9](C#N)[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl>C(O)(=O)C>[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N#CN1CCc2cccc(Cl)c2CC1
Agent: Cl
Solvent: CC(=O)O
Product: Clc1cccc2c1CCNCC2

Procedure:
The 6-chloro-3-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine was refluxed for 19 hours in a mixture of 30 ml. of glacial acetic acid and 30 ml. of 6N hydrochloric acid. The mixture was concentrated in vacuo to yield 6-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine as the hydrochloride salt of m.p. 214°-215° from ethanol. This salt in turn gave the base 6-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine on treatment with dilute sodium hydroxide solution.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Cl[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]=1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: FC(F)(F)c1cccc(Cl)n1
Product: O=Cc1ccc(Oc2cccc(C(F)(F)F)n2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3-fluoro-4-hydroxybenzaldehyde and 2-chloro-6-(trifluoromethyl)pyridine.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]2[N:13]=[C:14]([C:17]([N:19]3[CH2:33][CH2:32][CH2:31][C@H:20]3[C:21]([NH:23][CH:24]([CH:29]=[O:30])[CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[O:18])[NH:15][CH:16]=2)=[CH:5][CH:4]=1.[K+].[Br-]>CO>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]2[N:13]=[C:14]([C:17]([N:19]3[CH2:33][CH2:32][CH2:31][C@H:20]3[C:21]([NH:23][CH:24]([CH:29]=[O:30])[CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[O:18])[NH:15][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCc2c[nH]c(C(=O)N3CCC[C@H]3C(=O)NC(C=O)CC(=O)O)n2)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: O=CC(CC(=O)O)NC(=O)[C@@H]1CCCN1C(=O)c1nc(CCCc2ccc(O)cc2)c[nH]1

Procedure:
3-{N-[4-[3-(4-Methoxyphenyl)propyl]imidazole-2-carbonyl]-L-prolinyl}amino-4-oxobutanoic acid (21e), was isolated (65%) as a white glassy solid: mp. 101-105° C.; [α]D23 −60.6 (c 0.05, MeOH); IR (KBr) 3231, 1784, 1726, 1611, 1512, 1245; 1H NMR(CD3OD) δ 7.09 (2H, d, J=8.6), 6.92, 6.85 (1H, 2×s), 6.81 (2H, d, J=8.6), 5.45-5.30 (1H, m), 4.64-4.46 (1H, m), 4.28-4.10 (2H, m), 3.75 (3H, s), 3.74-3.66 (1H, m), 2.67-1.84 (13H, m). Anal. Calcd for C23H28N4O6 H2O: C, 58.22; H, 6.37; N, 11.81. Found: C, 58.39; H, 6.34; N, 11.45; FABMS m/e 457 (M+), 405, 312, 243, 215, 176, 154 (100%) (3S) 3-{N-[4-[3-(4-Hydroxyphenyl)propyl]imidazole-2-carbonyl]-L-prolinyl}amino-4-oxobutanoic acid (21f), was isolated (43%) as a white glassy solid: mp. 114-118° C.; [α]D25-55.7° (c 0.05, MeOH); IR (KBr) 3288, 2935, 1780, 1715, 1662, 1610, 1515, 1441; 1H NMR(CD3OD) δ 6.99 (2H, d, J=8.5), 6.91, 6.85 (1H, 2×s), 6.68 (2H, d, J=8.5), 5.45-5.30 (1H, m), 4.60-4.47 (1H, m), 4.30-4.10 (2H, m), 3.80-3.55 (1H, m), 2.70-1.80 (13H, m). Anal. Calcd for C22H26N4O6 H2O: C, 57.38; H, 6.13; N, 12.17. Found: C, 57.68; H, 6.25; N, 11.66. FABMS m/e 443 (M+), 298, 229, 154 (100%). 3(S)-[(1-{5-[3-(4-Methoxyphenyl)propyl]-1H-imidazole-2-carbonyl}-4(R)-phenoxy pyrrolidine-2(S)-carbonyl)amino]-4-oxobutanoic acid (22e) was isolated (43%) as a beige solid: 1H NMR (CD3OD) δ 7.35-7.2 (3H, m), 7.15-7.0 (2H, m), 6.98-6.85 (3H, m), 6.83-6.77 (2H, d), 5.4-5.1 (1H, m), 4.65-4.5 (1H, m), 4.35-4.2 (2H, m), 4.15-3.90 (1H, m), 3.78 (3H, s), 3.62-3.48 (1H, m), 2.78-2.25 (8H, m), 2.02-1.9 (2H, m).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([NH:8]C(=O)C2C=CC=CC=2)[CH:4]=1.Cl>C(O)CO>[F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([NH2:8])[CH:4]=1
Reactant: O=C(Nc1cc(C(F)(F)F)on1)c1ccccc1
Agent: Cl
Solvent: OCCO
Product: Nc1cc(C(F)(F)F)on1

Procedure:
The reaction was carried out according to the same procedure as described in Example 50 except that 5-trifluoromethyl-3-benzoylaminoisoxazole (0.8738 g, 3.41 mmole), 36% hydrochloric acid (0.87 g, 8.53 mmole) and ethylene glycol (3.4 ml) were used. The product was then purified by column chromatography on silica gel to give the title compound. Yield: 0.3686 g (75.7%). The structure of this product was confirmed by NMR.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cccnc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccnc1CBr
Temperature: 25 °C
Yield: 59.4 %

Procedure:
Under a nitrogen atmosphere, ethyl 2-methylnicotinate (1.65 g, 10 mmol) was dissolved in carbon tetrachloride, and N-bromosuccinimide (2.31 g, 13 mmol) and azoisobutyronitrile (164 mg, 1 mmol) were added thereto. The mixture was refluxed for 8 hours. After the completion of the reaction was confirmed by HPLC, the reaction mixture was allowed to cool down to a room temperature. The organic layer was washed with water 3 times and then with a saturated saline solution, and dried over magnesium sulfate. After the solvent was distilled off, the resulting residue was purified by flash column chromatography (Yamazen, Hi-Flash column, silica gel, hexane/ethyl acetate (volume ratio)=10:1) to give the title compound (1.45 g, 59.4%) as an oily substance.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:7]2.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[NH2:32])=[CH:20][CH:19]=1>>[CH2:12]([C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:32][C:26]3[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:25]=3[S:24][C:21]3[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: COc1ccc(Sc2ccc(C)cc2N)cc1
Reactant: CC(C)Cc1ccc2c(Cl)ccnc2n1
Product: COc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(CC(C)C)ccc23)cc1

Procedure:
The product from Example 12d (60 mg, 0.271 mmol) was reacted with the product from Example 50b (66 mg, 0.271 mmol) for 25 h giving following the procedure from Example 1g the crude title compound that was triturated with 3:1 ether/THF providing the title compound as a hydrochloride salt (121 mg, 96%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (d, J=6.62 Hz, 6H) 2.24 (m, J=6.62 Hz, 1 H) 2.34 (s, 3 H) 2.89 (d, J=7.35 Hz, 2 H) 3.72 (s, 3 H) 6.27 (d, J=6.99 Hz, 1 H) 6.84 (d, J=8.46 Hz, 2 H) 7.10 (d, J=8.09 Hz, 1 H) 7.23-7.32 (m, 4 H) 7.81 (d, J=8.46 Hz, 1 H) 8.41 (d, J=6.99 Hz, 1 H) 9.07 (d, J=8.46 Hz, 1 H) 11.09 (br s, 1 H) 14.40 (br s, 1 H); MS (ESI+) m/z 430 (M−Cl)+; (ESI−) m/z 428 (M−HCl)−.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[OH:14])(=[O:3])[CH3:2].[K].CN(C)C=O.[CH2:21]([N:23]([CH2:26][CH2:27]Cl)[CH2:24][CH3:25])[CH3:22]>O>[CH2:21]([N:23]([CH2:26][CH2:27][O:14][C:6]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])[CH2:24][CH3:25])[CH3:22]
Reactant: CCN(CC)CCCl
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1O
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1NC(C)=O
Temperature: 60 °C

Procedure:
117 g (0.5 mol) of 2-acetylamino-4-nitrophenol, in the form of the potassium salt, are introduced into 350 ml of dimethylformamide and the mixture is then heated to 60° C., whilst stirring. 88.2 g (0.65 mol) of diethylaminoethyl chloride are then added; the reaction medium is heated at 95° C. for 150 minutes and is then poured into 1,500 ml of iced water; the expected product precipitates. This product is filtered off and washed with a 0.5 N sodium carbonate solution and then with water. After filtration, the product is finally dried in vacuo at 45° C. It melts at 117° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][N:20](C(OCC)=O)[CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][NH:20][CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)N1Cc2sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c3c2C1
Agent: [K+]
Agent: [OH-]
Product: Clc1ccc(Nc2ncnc3sc4c(c23)CNC4)cc1Cl
Yield: 58.9 %

Procedure:
In analogy to Example 23A, ethyl 4-[(3,4-dichlorophenyl)amino]-5,7-dihydro-6H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylate from Example 24A (324 mg, 0.79 mmol) was treated with aqueous potassium hydroxide solution to yield 157 mg (59%) of the title compound.
Reaction SMILES: [CH2:1]=O.[CH:3]1[C:15]2[CH:14]([CH2:16][O:17][C:18]([NH:20][C@@H:21]([CH2:25][O:26][C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)[C:22]([OH:24])=[O:23])=[O:19])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:23]=[C:22]1[O:24][CH2:1][N:20]([C:18]([O:17][CH2:16][CH:14]2[C:15]3[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]3[C:13]2=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:19])[C@H:21]1[CH2:25][O:26][C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cccc(OC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c1
Reactant: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1cccc(OC[C@H]2C(=O)OCN2C(=O)OCC2c3ccccc3-c3ccccc32)c1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
Using a Dean-Stark setup, a mixture containing paraformaldehyde (340 mg, 11.34 mmol), (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(m-tolyloxy)propanoic acid (789 mg, 1.890 mmol), and p-toluenesulfonic acid (32.5 mg, 0.189 mmol) was refluxed in Toluene (15 mL) for 2 hrs. The reaction was then cooled to RT, washed with sat. sodium bicarbonate solution, followed by brine, dried with MgSO4, filtered and concentrated to get the product (S)-(9H-fluoren-9-yl)methyl 5-oxo-4-((m-tolyloxy)methyl)oxazolidine-3-carboxylate (812 mg, 1.891 mmol, 100% yield) as a yellow oil. ESI-MS(+) m/z=430 (M+H).