Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+:6].[Na+].[Na+].[OH:9][C@@H:10]([C@H:12]1[C:42](=[O:43])[N:14]2[C:15]([C:29]([O:31]CC3C=CC([N+]([O-])=O)=CC=3)=[O:30])=[C:16]([S:19]/[CH:20]=[CH:21]\[C:22]3[S:26][CH:25]=[N:24][C:23]=3[CH2:27][OH:28])[C@H:17]([CH3:18])[C@H:13]12)[CH3:11]>C1COCC1.[Pd]>[OH:9][C@@H:10]([C@H:12]1[C:42](=[O:43])[N:14]2[C:15]([C:29]([O-:31])=[O:30])=[C:16]([S:19]/[CH:20]=[CH:21]\[C:22]3[S:26][CH:25]=[N:24][C:23]=3[CH2:27][OH:28])[C@H:17]([CH3:18])[C@H:13]12)[CH3:11].[Na+:6]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reaction time: 1.5 h

Procedure:
10% Pd—C (hydrous, water content 53%) (1.42 g) was added to a solution of 40 ml of a 1/15 M sodium phosphate buffer solution (pH 6.8) of 957 mg of 4-nitrobenzyl (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate in 40 ml of THF, and the mixture was stirred under a hydrogen atmosphere for 1.5 hr. The 10% Pd—C was removed by filtration and was washed with water. The filtrate was adjusted to pH 6.6 by the addition of saturated sodium bicarbonate water, followed by washing with 40 ml of ethyl acetate. The aqueous layer was concentrated to about 5 ml, and the concentrate was purified by column chromatography (2% methanol-water) on Cosmosil 40C18-PREP to give 360 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]2[CH2:6][O:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[C:10]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]=3[C:23]([O:25][CH3:26])=[O:24].C([O-])=O.[NH4+]>[Pd].C(O)C>[CH3:19][C:18]([CH3:21])([CH3:20])[C:17]([NH:16][C:10]1[C:9]([C:23]([O:25][CH3:26])=[O:24])=[C:8]2[C:13]([C:14]3[CH:15]=[CH:2][N:3]=[N:4][C:5]=3[CH2:6][O:7]2)=[CH:12][CH:11]=1)=[O:22]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCc1nnc(Cl)cc1-2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCc1nnccc1-2
Yield: 76.8 %

Procedure:
A suspension of methyl 3-chloro-7-(2,2-dimethylpropionylamino)-10H-9-oxa-1,2-diazaphenanthrene-8-carboxylate (Intermediate 8, 1.01 g), ammonium formate (0.848 g) and 10% palladium on carbon (0.150 g) in ethanol (60 mL) was stirred and heated at reflux under nitrogen for one hour. After cooling, the suspension was filtered and the filtrate was evaporated. The residue was dissolved in ethyl acetate and washed with water (with warming to dissolve all of the solid), dried (Na2SO4) and filtered. The filtrate was evaporated in vacuo and the residue was triturated with ether. The solid was collected by filtration and purified by chromatography on silica, eluting with ethyl acetate to give methyl 7-(2,2-dimethylpropionylamino)-10H-9-oxa-1,2-diazaphenanthrene-8-carboxylate (0.705 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[O:11][CH2:12][CH2:13][CH:14](OCC)OCC.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>CC(O)=O.[Zn]>[Br:1][C:2]1[C:3]2[O:11][CH2:12][CH2:13][CH2:14][NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CCOc1c(Br)cccc1[N+](=O)[O-])OCC
Agent: CC[SiH](CC)CC
Agent: [Zn]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Brc1cccc2c1OCCCN2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
To a solution of 1-bromo-2-(3,3-diethoxypropoxy)-3-nitrobenzene (500 mg, 1.436 mmol) in AcOH (5.0 mL) was added zinc (939 mg, 14.36 mmol) and the mixture was stirred at room temperature for 90 min. After this time, the reaction mixture was filtered and the filtrate was concentrated. The resulting residue was dissolved in DCM (5 mL) and treated with TFA (5 mL) and triethylsilane (1.147 mL, 7.18 mmol). The resulting mixture was stirred at room temperature for 1 h and then concentrated. The resulting residue was purified by preparative HPLC (PHENOMENEX® Axia Luna, 5μ, C18 30×100 mm; 10 min gradient from 80% A:20% B to 0% A:100% B and 5 min 100% B (A=90% H2O/10% MeOH+0.1% TFA); (B=90% MeOH/10% H2O+0.1% TFA); detection at 220 nm). The purified product was free based with a solution of saturated sodium bicarbonate (15 ml) and was then extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound (181 mg, 53% yield). LCMS, [M+Na]+=228.0. 1H NMR (400 MHz, CDCl3) δ 7.01 (dd, J=7.8, 1.6 Hz, 1H), 6.68 (t, J=7.9 Hz, 1H), 6.62 (dd, J=7.9, 1.6 Hz, 1H), 4.20-4.13 (m, 2H), 3.31-3.22 (m, 2H), 2.08-1.98 (m, 2H).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([N:20]1[C:26]([CH3:28])([CH3:27])[C:24](=[O:25])[N:23]([CH2:29][CH:30]2[O:32][CH2:31]2)[C:21]1=[O:22])[N:7]1[C:13]([CH3:15])([CH3:14])[C:11](=[O:12])[N:10]([CH2:16][CH:17]2[O:19][CH2:18]2)[C:8]1=[O:9]>>[CH2:6]([N:20]1[C:26]([CH3:27])([CH3:28])[C:24](=[O:25])[N:23]([CH2:29][CH:30]([OH:32])[CH2:31][O:5][C:1](=[O:4])[CH:2]=[CH2:3])[C:21]1=[O:22])[N:7]1[C:13]([CH3:14])([CH3:15])[C:11](=[O:12])[N:10]([CH2:16][CH:17]([OH:19])[CH2:18][O:4][C:1](=[O:5])[CH:2]=[CH2:3])[C:8]1=[O:9]
Reactant: CC1(C)C(=O)N(CC2CO2)C(=O)N1CN1C(=O)N(CC2CO2)C(=O)C1(C)C
Reactant: C=CC(=O)O
Product: C=CC(=O)OCC(O)CN1C(=O)N(CN2C(=O)N(CC(O)COC(=O)C=C)C(=O)C2(C)C)C(C)(C)C1=O

Procedure:
1,1'-Methylene-bis[3-(3-acryloyloxy-2-hydroxypropyl)-5,5-dimethylhydantoin] is prepared by the reaction of acrylic acid and 1,1'-methylene-bis[3-glycidyl-5,5-dimethylhydantoin], see preparation in Example 3b, according to Example 1 of U.S. Pat. No. 3,808,226.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:10][C:11]([CH:13]2[CH2:17][CH:16]([O:18][C:19]3[C:28]4[C:23](=[C:24]([Cl:38])[C:25]([O:29][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:26][CH:27]=4)[N:22]=[C:21]([C:39]4[N:40]=[C:41]([NH:44][CH:45]([CH3:47])[CH3:46])[S:42][CH:43]=4)[CH:20]=3)[CH2:15][N:14]2[C:48](=[O:64])[CH:49]([NH:54][C:55]([O:57][CH:58]2[CH2:63][CH:62]3[CH:60]([CH2:61]3)[CH2:59]2)=[O:56])[C:50]([CH3:53])([CH3:52])[CH3:51])=[O:12])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:4].[Li+].[OH-].CO.Cl>O>[CH:60]12[CH2:61][CH:62]1[CH2:63][CH:58]([O:57][C:55]([NH:54][CH:49]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:48]([N:14]1[CH2:15][CH:16]([O:18][C:19]3[C:28]4[C:23](=[C:24]([Cl:38])[C:25]([O:29][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:26][CH:27]=4)[N:22]=[C:21]([C:39]4[N:40]=[C:41]([NH:44][CH:45]([CH3:46])[CH3:47])[S:42][CH:43]=4)[CH:20]=3)[CH2:17][CH:13]1[C:11]([NH:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:12])=[O:64])=[O:56])[CH2:59]2
Reactant: CCC1CC1(NC(=O)C1CC(Oc2cc(-c3csc(NC(C)C)n3)nc3c(Cl)c(OCCN4CCOCC4)ccc23)CN1C(=O)C(NC(=O)OC1CC2CC2C1)C(C)(C)C)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC1CC1(NC(=O)C1CC(Oc2cc(-c3csc(NC(C)C)n3)nc3c(Cl)c(OCCN4CCOCC4)ccc23)CN1C(=O)C(NC(=O)OC1CC2CC2C1)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.9 %

Procedure:
1-({1-[2-(Bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-[8-chloro-2-(2-isopropylaminothiazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)quinolin-4-yloxy]pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid methyl ester (12 g, 13 mmol) was dissolved in TI-IF (200 ml), LiOH (11 g, 260 mmol) in H2O (200 ml) was added, followed by MeOH (200 ml). The mixture was kept stirring at room temperature for 20 h. Upon completion of the reaction, 4 N HCl in H2O was added to adjust pH to 7 at 0° C. The mixture was extracted with EtOAc (2×400 ml). The combined organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to give 1-({1-[2-(bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethyl-butyryl]-4-[8-chloro-2-(2-isopropylamino-thiazol-4-yl)-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid as a yellow solid (11 g, 93% yield). LCMS found 911.52 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12](=[O:17])[N:11]([CH2:18][C:19]([O:21]C(C)C)=[O:20])[C:10]1=[O:25].[N+:26]([O-])([OH:28])=[O:27]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:26]([O-:28])=[O:27])=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12](=[O:17])[N:11]([CH2:18][C:19]([OH:21])=[O:20])[C:10]1=[O:25]
Reactant: O=[N+]([O-])O
Reactant: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2ccc(F)cc2Cl)c1=O
Agent: O=S(=O)(O)O
Product: Cn1c(=O)n(CC(=O)O)c(=O)n(-c2cc([N+](=O)[O-])c(F)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of isopropyl 3-(2-chloro-4-fluorophenyl)tetrahydro-5-methyl-2,4,6-trioxo-s-triazine-1(2H)-acetate (48.7 g, 0.0508 mol) in concentrated sulfuric acid is cooled to 0° C., treated with 90% nitric acid (2.6 mL), stirred at room temperature overnight, treated with 90% nitric acid (1.0 mL), stirred for 4 hours, treated with 90% nitric acid (2.0 mL), stirred at room temperature overnight, treated with 90% nitric acid (1.0 mL), stirred for 1 hour and poured onto ice. The resultant aqueous solution is filtered to obtain a solid. A solution of the solid in ether is dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a yellow foam which is identified by NMR spectral analyses.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.[N+:17]([CH:20]([CH3:22])[CH3:21])([O-:19])=[O:18].CC[O-].[Na+].[Na]>C(O)C>[CH3:21][C:20]([N+:17]([O-:19])=[O:18])([CH3:22])[CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: CC(C)[N+](=O)[O-]
Reactant: O=C(C=Cc1cccnc1)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CC(C)(C(CC(=O)c1ccccc1)c1cccnc1)[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
A solution of 51.8 g. of 3-(3-pyridyl)-acrylophenone and 44.2 g. of 2-nitropropane in 496 ml. of ethanol are heated at reflux with stirring in a nitrogen atmosphere. Then, a sodium ethylate solution manufactured from 2.54 g. of sodium and 49.6 ml. of ethanol is added dropwise within 1 hour. The reaction mixture is left standing for an additional half hour to react further and then evaporated under reduced pressure. The resulting residue is taken up in 1000 ml. of methylene chloride, washed three times with 300 ml. of water each time, dried over sodium sulfate, evaporated under reduced pressure and crystallized from methanol to yield 4-methyl-4-nitro-3-(3-pyridyl)-valerophenone with a melting point of 134°-135° C.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[C:27]1([C:33]2[O:34][C:35]([CH3:51])=[C:36]([CH2:38][CH2:39]OS(C3C=CC(C)=CC=3)(=O)=O)[N:37]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:25][S:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][C@@:5]([CH3:14])([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:39][CH2:38][C:36]3[N:37]=[C:33]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:34][C:35]=3[CH3:51])=[CH:9][CH:8]=2)[C:4]([OH:3])=[O:26])=[CH:21][CH:20]=1)(=[O:24])=[O:23]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(S(C)(=O)=O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@](C)(Oc2ccc(S(C)(=O)=O)cc2)C(=O)O)cc1

Procedure:
Standard Procedure (B) was utilized to prepare the title compound from 3-(4-hydroxyphenyl)-2-(4-methanesulfonyl-phenoxy)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].I[C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[CH:24]([NH2:27])([CH3:26])[CH3:25].C(C1CCCCC1=O)(=O)C(C)C>CN(C)C=O.C(OCC)(=O)C.[Cu](I)I>[CH:24]([NH:27][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: O=C(OCc1ccccc1)c1cccc(I)c1
Agent: I[Cu]I
Agent: CC(C)C(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Nc1cccc(C(=O)OCc2ccccc2)c1
Temperature: 100 °C

Procedure:
Copper iodide (1.0 equiv) and cesium carbonate (2.0 equiv) were added to a microwave vial and the vial was evacuated and filled with argon three times. Benzyl 3-iodobenzoate (4) in dry dimethylformamide (2 M), isopropylamine (2.0 equiv) and 2-isobutyrylcyclohexanone (0.2 equiv) were then added to the vial, the vial was sealed and the resulting mixture is heated to 100° C. under microwave irradiation for 2 hours. At that time, the vial was cooled to room temperature and the reaction mixture was diluted with ethyl acetate and filtered through a pad of Celite with aid of ethyl acetate. The filtrate was washed with brine (3×), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (ethyl acetate/hexanes as elutant) to provide benzyl 3-(isopropylamino)benzoate (5).
Reaction SMILES: [C:1](=[O:11])([O:9][CH3:10])[NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Rh].CC(O)C>[CH:3]1([NH:2][C:1](=[O:11])[O:9][CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)Nc1ccccc1
Agent: [Rh]
Solvent: CC(C)O
Product: COC(=O)NC1CCCCC1
Reaction time: 0.8 h
Yield: 96 %

Procedure:
A mixture of 15.1 g. (0.10 mole) of methyl carbanilate, 105 ml. of 2-propanol, and 0.60 g. of 5% Rh on carbon was added to a 300-ml. Magne Drive (tradmark) autoclave. The vessel was sealed, purged first with nitrogen and then with hydrogen, and pressured with hydrogen to 600 psig. The autoclave was heated with agitation at 500-800 psig for 0.3 hr. at 25°-75°, followed by an additional 0.8 hr. at 75° with little or no gas absorption. The autoclave was cooled and depressurized. The reaction product was removed and filtered through Celite (trademark) filter aid to remove the catalyst. The solvent was removed in a rotary evaporator under vacuum. The white solid residue was dried in a vacuum dessicator and consisted of 15.1 g. (96% yield) of methyl cyclohexylcarbamate, m.p. 73°-74°. An authentic sample prepared from cyclohexyl isocyanate and methanol melted at 73.5°-74°.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([CH3:20])([CH3:19])[CH2:3]1.[H-].[Na+].CS(C)=O.[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>O1CCCC1>[CH2:11]([O:10][N:5]1[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([O:1][CH2:27][CH:29]2[O:31][CH2:30]2)[CH2:3][C:4]1([CH3:19])[CH3:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCCCCCCCON1C(C)(C)CC(OCC2CO2)CC1(C)C
Temperature: 25 °C
Yield: 16.3 %

Procedure:
A mixture of 20.0 grams (70 mmol) of 4-hydroxy-1-octyloxy-2,2,6,6-tetramethylpiperidine (prepared in Example 5), 1.68 gram (70 mmol) of sodium hydride, 2 ml of dimethyl sulfoxide, and 150 ml of tetrahydrofuran is heated at reflux for three hours. The reaction mixture is cooled to room temperature, and a solution of 6.5 grams (70 mmol) of epichlorohydrin in 50 ml of tetrahydrofuran is added over a 5-minute period. The reaction mixture is stirred sixteen hours at room temperature and then partitioned between ether and water. The aqueous layer is extracted with ether and the combined ether solutions are dried over anhydrous magnesium sulfate before concentrating to yield an oil. Purification by flash chromatography (4:1 hexane:ethyl acetate) affords 3.9 grams (16% yield) of the title compound as a colorless oil.
Reaction SMILES: N#N.[CH:3]1[C:20]2[CH:19]=[CH:18][C:17]3[C:8](=[CH:9][CH:10]=[C:11]4[C:16]=3[CH:15]=[CH:14][CH:13]=[CH:12]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[Sn](Cl)(Cl)Cl.ClC[CH:28]([O:31]C(CCl)CCl)CCl>O.ClC1C=CC=CC=1Cl>[CH:3]1[C:20]2[CH:19]=[CH:18][C:17]3[C:8](=[CH:9][C:10]([CH:28]=[O:31])=[C:11]4[C:16]=3[CH:15]=[CH:14][CH:13]=[CH:12]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc2c(c1)ccc1c3ccccc3ccc21
Reactant: ClCC(CCl)OC(CCl)CCl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: N#N
Solvent: O
Solvent: Clc1ccccc1Cl
Product: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Reaction time: 4 h

Procedure:
A 5 L 3-neck flask fitted with overhead mechanical stirrer, thermometer, condenser and N2 line was charged with chrysene (Eastman Kodak Co., Rochester, NY, 14650, 100 g, 0.438 mol) and o-dichlorobenzene (2.5 L). The liquid was warmed until all the large chunks of solid dissolved (80°) and then cooled quickly to give finely divided crystals. After further cooling with a salt-ice bath to 5°, SnCl4 (Aldrich Chemical Co., Milwaukee, WI, 53201, 98%, 228.2 g, 0.876 mol, 102.4 mL) was added in one portion. No temperature change occurred. The reaction mixture was kept below 5°, and 1,1-dichloromethylmethylether (Aldrich, 70.48 g, 0.613 mol, 55.45 mL) was added dropwise over 1 h. The resulting suspension was warmed slowly to 40°. The reaction mixture was then cooled to 10° and hydrolysed by careful addition of 1 L of cold H2O. After 4 h, the layers were separated and the organic layer filtered, dried with anhydrous Na2SO4 (Mallinckrodt Co., St. Louis, MO, 63147, 100 g) and filtered again. The clear yellow solution was split into 2 portions and each passed through a 500 g plug of SiO2 using PhCH3 as the eluting solvent with 500 mL fractions. This chromatography separated unreacted chrysene (3 g) from the aldehyde and a more polar product. Fractions containing the aldehyde were combined and the PhCH3 removed. Crystals formed during this process and were removed periodically by filtration. After drying (at 60°) the yield of 6-chrysenecarbaldehyde was 89.46 g (79.7%) mp 167°-169°, (C, H), (lit. 168°, N. P. Buu Hoi, J.-P. Hoffinger, and P. Jacquigon, Bull. Soc. Chim. Fr. 3808 (1968)).
Reaction SMILES: [CH2:1]([C@:8]1([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:15](=[O:16])[N:14]2[C@@H:10]([S:11][CH2:12][C@H:13]2[C:17]([NH2:19])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(Cl)=NC(Cl)=NC=1Cl>CN(C)C=O>[CH2:1]([C@:8]1([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:15](=[O:16])[N:14]2[C@@H:10]([S:11][CH2:12][C@H:13]2[C:17]#[N:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@]1(Cc2ccccc2)C[C@@H]2SC[C@@H](C(N)=O)N2C1=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@]1(Cc2ccccc2)C[C@@H]2SC[C@@H](C#N)N2C1=O
Reaction time: 2 h

Procedure:
100 mg of (3R,6R,7aS)-6-benzyl-6-tert-butoxycarbonylamino-5-oxohexahydropyrrolo[2,1-b]thiazole-3-carboxamide are dissolved in 3 ml of dimethylformamide and reacted with 28.25 mg of cyanuric chloride at room temperature. After 2 hours, the volatile constituents are stripped off in vacuo at 40° C., and the residue is purified on a column (silica gel, mobile phase: diisopropyl ether:methylene chloride=100:10).
Reaction SMILES: CC(C)(C)C([N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:21](=O)[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([S:28][CH3:29])[CH:23]=4)[CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[N:6]1)=O.CSC>C1COCC1>[CH3:29][S:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][N:17]1[CH2:18][CH2:19][CH2:20][CH:15]([NH:14][C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[NH:5][N:6]=[CH:7]3)[CH2:16]1
Reactant: CSc1cccc(C(=O)N2CCCC(Nc3ccc4c(cnn4C(=O)C(C)(C)C)c3)C2)c1
Solvent: CSC
Solvent: C1CCOC1
Product: CSc1cccc(CN2CCCC(Nc3ccc4[nH]ncc4c3)C2)c1
Temperature: 60 °C
Yield: 41.1 %

Procedure:
Into a round bottom flask was added 2,2-dimethyl-1-(5-(1-(3-(methylthio)benzoyl)-piperidin-3-ylamino)-1H-indazol-1-yl)propan-1-one (240 mg, 0.655 mmol) and THF (3 mL). The solution was heated to 60° C. and borane-dimethyl sulfide complex in THF (3.0 mL of a 2.0M solution in THF, 6.0 mmol) was added, allowing dimethyl sulfide to distill off. After the starting material was consumed, the reaction was evaporated, 5N NaOH (10 mL) was added, and the mixture was extracted with EtOAc. The organic phases were dried, evaporated, and the residue was chromatographed on silica gel, eluting with 3/1-EtOAc/Heptane to afford the title compound (95 mg, 41%).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:38])[CH2:20][NH:21][C:22](=[O:37])[NH:23][C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH:27]=[CH:28][CH:29]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:9]1[C:19](=[O:38])[CH2:20][NH:21][C:22](=[O:37])[NH:23][C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:27]=[CH:28][CH:29]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCc1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)SC[C@H]2C(=O)OC(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(CCC(=O)O)c1
Yield: 10.5 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 39, but starting from 2.5 g of ethyl (2R,4R)-3-{3-{3-[2-(4-tert-butoxycarbonyl-2-phenyl-3-thiazolidinyl)-2-oxoethyl]ureido}phenyl}propionate and 0.2 g of lithium hydroxide. The crude product is purified by chromatography on silica [eluent: ethyl acetate/methanol (90/10 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. 0.25 g of (2R,4R)-3-{3-{3-[2-(4-tert-butoxycarbonyl-2-phenyl-3-thiazolidinyl)-2-oxoethyl]ureido}phenyl}propionic acid is thus obtained in the form of an amorphous beige solid ([α]D20 =+58.4°±1.6° (C=0.61%; CHCl3)) [proton NMR (200 MHz, DMSO D6, δ in ppm), 2 rotamers at room temperature, characteristic chemical shifts at 25° C.: 1.5 (bs, 9H, (CH3)3); 2.5 (bt, 2H, CH2); 2.8 (bt, 2H, CH2); 6.8 (bd, 1H, N--C6H4 --C in position 4); 7.1 to 7.5 (m, 7H, aromatic); 7.7 (bd, 2H, aromatic). Infrared spectrum (KBr), characteristic bands in cm-1 : 3380, 2975, 2930, 2620, 1730, 1645, 1610, 1590, 1555, 1490, 1370, 1235, 1150, 785, 730, 695].
Reaction SMILES: F[C:2]1[CH:3]=[N+:4]([O-:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:12]1[C:20]2[C:15](=[CH:16][C:17]([NH2:21])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>C(O)C.CCOCC>[CH2:12]1[C:20]2[C:15](=[CH:16][C:17]([NH:21][C:2]3[CH:3]=[N+:4]([O-:11])[CH:5]=[CH:6][C:7]=3[N+:8]([O-:10])=[O:9])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Reactant: Nc1ccc2c(c1)CCC2
Solvent: CCO
Solvent: CCOCC
Product: O=[N+]([O-])c1cc[n+]([O-])cc1Nc1ccc2c(c1)CCC2
Yield: 93.3 %

Procedure:
A solution of 3-fluoro-4-nitropyridine-1-oxide (12 g) and indan-5-amine (10 g) in 200 ml ethanol was stirred at reflux for two hours, and thereafter cooled, diluted with ether and filtered to give 19 g solid, m.p. 195°. Four grams were recrystallized from ethanol to give 2.6 g crystals, m.p. 194°-195°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][NH:15][C@H:14]([C:17]([NH:19][C:20]2([C:23]#[N:24])[CH2:22][CH2:21]2)=[O:18])[CH2:13]1)(=[O:11])=[O:10].Cl.[N:26]1([C:32]2([C:35](O)=[O:36])[CH2:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:35]([C:32]2([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:33][CH2:34]2)=[O:36])[C@H:14]([C:17]([NH:19][C:20]2([C:23]#[N:24])[CH2:22][CH2:21]2)=[O:18])[CH2:13]1)(=[O:10])=[O:11]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)CN2)CC1
Reactant: O=C(O)C1(N2CCCCC2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)CN2C(=O)C2(N3CCCCC3)CC2)CC1
Yield: 49 %

Procedure:
The reaction of (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7A with 1-(piperidin-1-yl)cyclopropanecarboxylic acid hydrochloride 16A carried out according to the general procedure L yielded (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(piperidin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide as a light brown solid (49%). MS ISP (m/e): 523.4/525.3 (100/47) [(M+H)]+.