Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].[OH-].[Na+].[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13]([CH3:15])=O>O>[CH3:19][CH2:18][O:17][C:12]([C:13]1([CH3:15])[NH:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][S:6]1)=[O:16]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CCOC(=O)C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C1(C)NC(C(=O)O)CS1
Temperature: 40 °C
Reaction time: 4 h
Yield: 19.4 %

Procedure:
L-cysteine hydrochloride monohydrate (50 g, 285 mmol) was dissolved in water (100 ml), and the pH of the solution was adjusted to 5.15 with 6N aqueous sodium hydroxide. The reaction mixture was heated to 40° C., ethyl pyruvate (38 ml, 342 mmol) was gradually added thereto, and the mixture was stirred at 40° C. for 4 hr. Water was added, and the mixture was cooled to room temperature to precipitate the crystals and the crystals were collected by filtration. The obtained crystals were washed with water, and dried under reduced pressure at 50° C. to give 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (trans form:cis form=88:12, 12.1 g, yield 19%). The synthesized 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (5 g, 22.8 mmol) was dissolved in ethyl acetate (40 ml), and triethylamine (6.4 ml, 45.9 mmol) was added under argon. Acetyl chloride (2.4 ml, 33.8 mmol) was slowly added dropwise, and the mixture was stirred at room temperature overnight. After completion of the reaction, water (15 ml) was added thereto, and the pH of the mixture was adjusted to 1.0 with HCl. The aqueous layer was separated, and the organic layer was washed with water (10 ml), washed with saturated brine, and dried over anhydrous magnesium sulfate. The obtained ethyl acetate solution was concentrated to precipitate crystals. The crystals were collected by filtration, washed with heptane/ethyl acetate=1/1 (10 ml), and dried under reduced pressure at 50° C. to give (2S,4R)-N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester as crystals (3.3 g, yield 55%).
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1.[CH2:22]([OH:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C1(C)C=CC=CC=1>[CH2:22]([O:30][C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: O=C1c2ccc(F)cc2C(=O)c2cc3ccccc3cc21
Reactant: CCCCCCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc2c(c1)C(=O)c1cc3ccccc3cc1C2=O

Procedure:
20 g (72.4 mmol) of 2-fluoro-naphthacene-5,12-dione, 94.3 g of 1-octanol, 30.01 g (217.2 mmol) of anhydrous potassium carbonate and 200 ml of dimethyl sulfoxide (DMSO) are stirred at a bath temperature of 100° C. for 20 hours. The reaction mixture is cooled, toluene/dilute hydrochloric acid are added and the organic phase is separated off, washed twice with water, dried with sodium sulfate and evaporated. The residue is washed with pentane and recrystallized from cyclohexane. Yield: 22.9 g (82%), melting point 127°-129° C.
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([C:27]#[C:28][CH2:29][CH2:30][CH3:31])[CH:23]=5)[C:18]4=[O:32])=[CH:13][C:12]=3[F:33])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C2C(=CC=CC=2)C=CC=1>[Pd].N1C=CC=CC=1>[N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22](/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH3:31])[CH:23]=5)[C:18]4=[O:32])=[CH:13][C:12]=3[F:33])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCCC#Cc1ccc2c(=O)n(-c3ccc(N4CC[C@@H](N5CCCC5)C4)c(F)c3)ccc2c1
Agent: [Pd]
Solvent: c1ccncc1
Solvent: c1ccc2ncccc2c1
Product: CCC/C=C\c1ccc2c(=O)n(-c3ccc(N4CC[C@@H](N5CCCC5)C4)c(F)c3)ccc2c1
Reaction time: 2 h

Procedure:
A mixture of 2-((R)-4-[1,3′]bipyrrolidinyl-1′-yl-3-fluorophenyl)-6-pent-1-ynyl-2H-isoquinolin-1-one (2.7 g), quinoline (0.4 g), pyridine (50 mL) and palladium (5% on barium carbonate; 100 mg) was stirred vigorously for 2 hours under a hydrogen atmosphere (balloon flask). It was sucked off of the catalyst and the filtrate was concentrated. The residue was purified by chromatography on silica gel. In this way the product was obtained with molecular weight 445.59 (C28H32FN3O); MS (ESI): 446 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)[CH:16]=[CH:17][N:18](C)C)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:22]1([NH:28]N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(Cl)c2)ccc1=O
Reactant: NNc1ccccc1
Solvent: CO
Product: O=c1ccn(-c2cccc(Cl)c2)nc1-c1ccnn1-c1ccccc1
Yield: 19 %

Procedure:
To a solution of 1-(3-chlorophenyl)-3-[3-(dimethylamino)prop-2-enoyl]pyridazin-4(1H)-one (crude 573 mg, 1.89 mmol) in 20 mL of methanol was added phenylhydrazine (306 mg, 2.84 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(3-chlorophenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (125 mg, 19% for two steps) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][NH:14][C:15]1C=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].COC(=O)C[N:28]1C2C=CC=CC=2NC[C@H](NC(OC(C)(C)C)=O)C1=O>>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][NH:14][C:15]1[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][N:28]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(CNc1ccccc1[N+](=O)[O-])C(=O)O
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Product: CC(C)(C)OC(=O)NC(CNc1ncccc1N)C(=O)O

Procedure:
was prepared by a similar method to (2S) 2-tert-Butoxycarbonylamino-3-(2-aminophenylamino)-propionic acid in Step B of the synthesis of 600a/103 to give 3.68 g (quant.) as a dark solid.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:25]1([NH2:28])[CH2:27][CH2:26]1>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([NH:28][CH:25]3[CH2:27][CH2:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: NC1CC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)NC3CC3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (76 mg, 0.20 mmol), cyclopropylamine (35 uL, 29 mg, 0.50 mmol) and DMAP (82 mg, 0.67 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 34 mg (43% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.45-0.51 (m, 2 H), 0.51-0.58 (m, 2 H), 1.49-1.65 (m, 4 H), 1.68 (s, 9 H), 2.10-2.22 (m, 1 H), 2.30-2.45 (m, 1 H), 3.31-3.41 (m, 2 H), 3.89-3.99 (m, 2 H), 4.54 (d, J=7.62 Hz, 2 H), 7.99 (dd, J=8.8, 1.8 Hz, 1 H), 8.07 (d, J=8.8 Hz, 1 H), 8.24 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=392.0; Anal. Calcd for C20H29N3O3S+1.30 TFA+0.40 EtOAc+0.5H2O (584.02): C, 49.77; H, 5.95; N, 7.20. Found: C, 49.78; H, 5.86; N, 7.20.
Reaction SMILES: C(Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](=[O:19])([O:15][CH2:16][CH:17]=[CH2:18])OCC=C>[Cl-].[Zn+2].[Cl-]>[C:10]([O:15][CH2:16][CH:17]=[CH2:18])(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCOC(=O)OCC=C
Agent: [Cl-]
Agent: [Zn+2]
Product: C=CCOC(=O)c1ccccc1
Temperature: 60 °C
Yield: 82 %

Procedure:
In a glass reactor benzoyl chloride (7.03 g, 0.05 mole), diallyl carbonate (7.1 g, 0.05 mole) and zinc chloride (0.136 g, 0.001 mole) were combined. The reacinitiated at room temperature. After heating at 60° C. for 3 hours and heating at 80° C. for an additional 3 hours, the reaction was discontinued. Distillation gave 6.65 g (78 percent yield) of allyl benzoate which was identified by nuclear magnetic resonance spectroscopy.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][N:18]([C@@H:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH3:21])[C:17](=[O:30])[CH2:16]2)[CH3:14])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[Cl:11])[CH:7]=1.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([C:44]2[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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.O>[Cl:11][C:10]1[CH:9]=[N:8][N:6]2[CH:7]=[C:2]([C:47]3[CH:46]=[CH:45][C:44]([N:41]4[CH2:40][CH2:39][N:38]([C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[CH2:43][CH2:42]4)=[CH:49][CH:48]=3)[CH:3]=[C:4]([O:12][C@@H:13]([C@@H:15]3[CH2:16][C:17](=[O:30])[N:18]([C@@H:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH3:21])[CH2:19]3)[CH3:14])[C:5]=12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cn4ncc(Cl)c34)CC2=O)cc1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cn4ncc(Cl)c34)CC2=O)cc1
Temperature: 100 °C

Procedure:
To an appropriate sized microwave vial, (R)-4-((R)-1-((6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 6.36 (118 mg, 0.239 mmol), (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (73.3 mg, 0.239 mmol), cesium carbonate (234 mg, 0.718 mmol), dioxane (2.0 mL) and water (0.5 mL) were added. The mixture was degassed with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) catalyst (27.7 mg, 0.0239 mmol) was added and the solution was heated at 100° C. for 18 h. After cooling to room temperature, the reaction was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl 4-(4-(3-chloro-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)phenyl)piperazine-1-carboxylate 6.38.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:14]=[CH:15][C:16]2[C:17]([CH:28]=1)=[C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[O:19][N:20]=2.[CH3:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1>C1COCC1>[Cl:27][C:23]1[CH:22]=[C:21]([C:18]2[O:19][N:20]=[C:16]3[CH:15]=[CH:14][C:13]([CH:34]([C:33]4[CH:36]=[CH:37][C:30]([CH3:29])=[CH:31][CH:32]=4)[OH:35])=[CH:28][C:17]=23)[CH:26]=[CH:25][CH:24]=1
Reactant: Clc1cccc(-c2onc3ccc(Br)cc23)c1
Reactant: Cc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C(O)c2ccc3noc(-c4cccc(Cl)c4)c3c2)cc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 38.3 %

Procedure:
nBuLi 1.6 M in hexane (0.112 mol) was added dropwise at −70° C. under N2 flow to a mixture of 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole (0.097 mol) in THF (300 ml). The mixture was stirred at −70° C. for 15 min. A mixture of 4-methylbenzaldehyde (0.112 mol) in THF (100 ml) was added dropwise. The mixture was stirred at −70° C. for 30 min, then hydrolized and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue was purified by column chromatography over silica gel (20-45 μm) (eluent: DCM/EtOAc 96/4). The pure fractions were collected and the solvent was evaporated, yielding 13 g (38.3%) of 3-(3-chlorophenyl)-α-(4-methylphenyl)-2,1-benzisoxazole-5-methanol (intermediate 18).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[C:12]([CH:18]=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[C:12]([CH:18]=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(C=O)c3sccc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1ccc(-c2ccc(O)cc2)c2ccsc12
Temperature: 25 °C
Yield: 51.7 %

Procedure:
To a 10 ml round bottom flask a solution of 62.5% pure 4-(4-methoxyphenyl)-1-benzothiophene-7-carbaldehyde (remainder 37.5% 4-(4-methoxyphenyl)-1-benzothiophene-2-carbaldehyde) (102 mg, 0.38 mmol) and CH2Cl2 (2 ml) was cooled to −78° C. Then BBr3 (0.8 ml 1.0 M in CH2Cl2, 0.8 mmol) was added dropwise after which the reaction turned dark red in color. The reaction was allowed to warm to room temperature and after 1 h the reaction was complete by TLC then quenched by pouring into water (15 ml). The mixture was diluted with ether, the layers separated and the aqueous was further extracted with ether. The organic layers were combined, dried over anhydrous Na2SO4, passed through a silica plug and concentrated to a greenish solid. Reverse phase HPLC (CH3CN 0.1% TFA, water 0.1% TFA) afforded 50 mg (52%) desired product as a yellow solid: mp 203–204° C.; 1H NMR (300 MHz, DMSO-d6): δ 6.96 (2H, d, J=8.5 Hz), 7.50 (2H, d, J=8.5 Hz), 7.56 (1H, d, J=5.6 Hz), 7.62 (1H, d, J=7.5 Hz), 7.97 (1H, d, J=5.6 Hz), 8.16 (1H, d, J=7.5 Hz), 9.84 (1H, s), 10.25 (1H, s); MS (ESI) m/z 253 ([M−H])
Reaction SMILES: C1(C)C=CC(S([O:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.[N:31]12[C:37](=[O:38])[CH2:36][CH:35]1[CH2:34][C:33](=O)[CH:32]2[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=1)=[O:41]>C(Cl)Cl>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([S:11]([O:10][C:33]2[CH2:34][CH:35]3[N:31]([C:37](=[O:38])[CH2:36]3)[C:32]=2[C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=2)=[O:41])(=[O:12])=[O:13])=[CH:19][CH:18]=1
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)CC3C2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
p-toluenesulfonic anhydride (520 mg, 1.59 mmol) and N,N-diisopropylethylamine (300 μl, 1.72 mmol) are added to an ice-cold, stirring solution of p-nitrobenzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (484 mg, 1.59 mmol) in anhydrous methylene chloride (17 ml). The resulting solution is stirred in the cold for 2 hours, then diluted with more methylene chloride, washed with water, 1μ ph 3.4 phosphate buffer and saturated aqueous sodium bicarbonate, dried with magnesium sulfate, filtered, and evaporated under vacuum. Addition of cold ethyl acetate and a few seed crystals to the oily residue induces crystallization. The product is collected, washed with cold ethyl acetate, and dried under vacuum to afford p-nitrobenzyl 3-(p-toluenesulfonyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (446 mg, 61%) as off-white crystals: mp 99°-102° (dec.); IR (neat) 1790, 1725, 1521, 1345, and 1172 cm-1 ; UV (CH2Cl2) 272 nm; NMR (CDCl3) δ 2.40 (s, 3, ArCH3), 3.06 (dd, 1, J=3.0 and 17.2, H6β), 3.16 (dd, 1, J=9.0 and 9.0, H4a), 3.31 (dd, 1, J=9.0 and 10.0, H4b), 3.59 (dd, 1, J=5.8 and 17.2, H6α), 4.24 (m, I, H5), 5.20 and 5.32 (ABq, 2, J=14.0, CH2Ar), 7.32 and 7.77 (two d's, 4, J=8.0, p-MeC6H4), 7.51 and 8.19 (two d's, 4, J=8.0, p-NO2C6H4).
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:30])[CH:13]=[C:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>C(O)(=O)C.[Fe]>[CH2:1]([NH:11][C:12](=[O:30])[CH:13]=[C:14]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)C=C(c1ccccc1)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: CCCCCCCCCCNC(=O)C=C(c1ccccc1)c1cccc(N)c1

Procedure:
Reduction of 10.7 g. of N-decyl-3-phenyl-3-(3-nitrophenyl)propenamide with 7.3 g. of iron powder in acetic acid, according to the procedure of Preparation 25, afforded the title compound as an oil. This product was chromatographed on 370 g. of silica gel, eluting with chloroform containing 1% ethanol. This gave 2.2 g. of trans-N-decyl-3-phenyl-3-(3-aminophenyl)propenamide and 0.7 g of cis-N-decyl-3-phenyl-3-(3-aminophenyl)propenamide. The NMR spectrum of the trans-isomer (in CDCl3) showed absorptions at 0.95 (m), 1.25 (s), 3.10 (m), 3.75 (b), 6.35 (s), 6.65 (m) and 7.30 (s) ppm. The NMR spectrum of the cis-isomer (in CDCl3) showed absorptions at 0.90 (m), 1.25 (s), 3.05 (b), 3.65 (b), 5.20 (b), 6.35 (s), 6.65 (m) and 7.15 (m) ppm.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].CC(C)([O-])C.[K+].C(O[CH2:16][C:17]1[O:18][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:20][CH:21]=1)(=O)C>CN(C)C=O.CO>[CH3:28][N:26]([CH3:27])[CH2:25][CH2:24][CH2:23][CH2:22][C:19]1[O:18][C:17]([CH2:16][S:5][CH2:4][CH2:3][NH2:2])=[CH:21][CH:20]=1
Reactant: NCCS
Reactant: CC(=O)OCc1ccc(CCCCN(C)C)o1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)CCCCc1ccc(CSCCN)o1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Cysteamine hydrochloride (4.5 g) was added to a cooled solution of potassium-t-butoxide (8.98 g) in dry dimethylformamide (125 ml). The mixture was stirred for 20 min and [5-[4-(dimethylamino)butyl]-2-furanyl]methyl ethanoate (9.6 g) was added. The reaction was heated at 90° for 4 hr, poured onto an ice-water mixture and extracted with chloroform. Distillation of the organic extract gave a yellow oil which after column chromatography on silica, using methanol/0.880 ammonia (9:1) as eluent, and a further distillation afforded a colourless oil b.p. 140°/0.05 mm Hg. Found: C, 60.81; H, 9.86; N, 10.44. Calc. for C13H24N2OS: C, 60.91; H, 9.44; N, 10.93%.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][C:9]1[N:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1>N1C=CC=CC=1>[C:1]([NH:8][C:9]1[N:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: Nc1ncc([N+](=O)[O-])cn1
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1ncc([N+](=O)[O-])cn1
Yield: 82.2 %

Procedure:
Valeroyl chloride (861 mg, 7.14 mmol) was added dropwise to a stirred suspension of 2-amino-5-nitropyrimidine (500 mg, 3.57 mmol) in pyridine (10 ml) and the reaction was heated at reflux for 4 hours under an inert atmosphere. The solvent was removed in vacuo and the residue stirred in 2N hydrochloric acid (100 ml) and extracted with ethyl acetate. Solvent evaporation in vacuo yielded 2-(N-pentanoyl)amino-5-nitropyrimidine (658 mg, 82% yield) as a brown solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:4]=1[CH2:5][N:6]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:21])=[C:17]([CH:20]=2)[C:18]#[N:19])[N:9]2[CH:22]=[C:23]([C:25]3[C:33]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[N:27](S(C4C=CC=CC=4)(=O)=O)[CH:26]=3)[CH:24]=[C:8]2[C:7]1=[O:43].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:4]=1[CH2:5][N:6]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:21])=[C:17]([CH:20]=2)[C:18]#[N:19])[N:9]2[CH:22]=[C:23]([C:25]3[C:33]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH:24]=[C:8]2[C:7]1=[O:43]
Reactant: COc1ccc(Cn2cc(Cc3ccc(F)c(C#N)c3)n3cc(-c4cn(S(=O)(=O)c5ccccc5)c5ncccc45)cc3c2=O)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cn2cc(Cc3ccc(F)c(C#N)c3)n3cc(-c4c[nH]c5ncccc45)cc3c2=O)c(OC)c1
Temperature: 50 °C

Procedure:
To a solution of EXAMPLE 2A (90 mg, 0.13 mmol) in dioxane (10 ml) was added NaOH (52 mg, 1.3 mmol) in water (1 ml). The mixture was heated at 50° C. overnight, and partitioned between ethyl acetate and water. The organic phase was concentrated to afford the title compound. MS (DCI/NH3) m/z 534 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:40])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([OH:38])[C:35]3[C:30](=[CH:31][C:32]([CH3:39])=[CH:33][CH:34]=3)[CH:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:47]([O:54][C:55](=[O:58])[CH2:56]Br)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:40])[C@@H:15]([NH:25][C:26]([C:28]2[CH:37]=[C:36]([O:38][CH2:56][C:55]([O:54][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:58])[C:35]3[C:30](=[CH:31][C:32]([CH3:39])=[CH:33][CH:34]=3)[CH:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)c3ccc(C)cc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.0 g 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-naphthalene-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester in 12 ml of DMF, 645 mg of cesium carbonate and 447 mg of Bromo-acetic acid benzyl ester were added and the reaction mixture was stirred for 2 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step. Yield: 710 mg.
Reaction SMILES: CO[C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[NH2:24][C:25]([NH2:27])=[O:26].C[O-].[Mg+2].C[O-].CO>>[C:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:16][C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([NH:24][C:25]([NH2:27])=[O:26])=[O:23])=[CH:12][CH:13]=1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Reactant: NC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: NC(=O)NC(=O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 14.9 %

Procedure:
A mixture of 2-biphenyl-4-yl-3-cyclopentylpropionic acid methyl ester (415.5 mg, 1.35 mmol) and urea (202.3 mg, 3.37 mmol, 2.5 equiv) was treated with a solution of magnesium methoxide in methanol (7.4 wt. %, 7.7 mL, 5.39 mmol). The resulting reaction mixture was then heated under reflux for 23 h. The reaction mixture was allowed to cool to 25° C. and then filtered through celite. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate then 1/1 hexanes/ethyl acetate) afforded (2-biphenyl-4-yl-3-cyclopentyl-propionyl) urea (67.8 mg, 15%) as a white solid: mp 184-185° C.; FAB-HRMS m/e calcd for C21H24N2O2 (M+H)+ 337.1917, found 337.1924.