Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][C:3]1([CH3:18])[CH:12]=[C:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1.[Cl-].[Zn+2:20].[Cl-]>CO.O>[Zn:20].[CH3:2][C:3]1([CH3:18])[CH:12]=[C:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1
Reactant: [Zn+2]
Agent: CC1(C)C=C(OS(C)(=O)=O)c2ccccc2N1
Agent: [Cl-]
Agent: [Na]
Solvent: CO
Solvent: O
Product: [Zn]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a solution of 13.2 g. of (2,2-dimethyl-1,2-dihydroquinoline-4-yl)-methylsulfonic acid sodium salt in 10 ml of methanol 2.7 g or zinc chloride are added. The solution is stirred at room temperature of 2 hours, whereupon it is diluted with 40 ml of water. The solution is then evaporated in vacuo on water bath. 9.9 g (87%) of (2,2-dimethyl-1,2-dihydroquinoline-4-yl)-methylsulfonic acid zinc salt are obtained, melting at 98° to 100° C.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[N:19]=[C:18]([C:20]([NH:22][CH2:23][CH2:24][CH3:25])=[O:21])[CH:17]=[CH:16][CH:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[N:19]=[C:18]([C:20]([NH:22][CH2:23][CH2:24][CH3:25])=[O:21])[CH:17]=[CH:16][CH:15]=2)=[N:13]1
Reactant: COC(=O)c1ccccc1S
Reactant: CCCNC(=O)c1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCNC(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 80.4 %

Procedure:
A mixture of methyl thiosalicylate (4.2 g, 25 mmol), 6-cyano-N-propyl-2-pyridinecarboxamide (2.5 g, 13 mmol), triethylamine (4.0 ml, 28 mmol) and toluene (8 ml) was refluxed for 8 hrs as described in Example 1. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (3.4 g, 78%) as crystals.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.[CH:15](N(CC)C(C)C)(C)C.C[C:25]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:26]=1[C:27]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[C:32]([Cl:39])[CH:31]=1)=[O:28].O>C(Cl)Cl>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:34]([C:33]3[CH:37]=[CH:38][C:30]([NH:29][C:27](=[O:28])[C:26]4[CH:25]=[CH:43][CH:42]=[C:41]([F:44])[C:40]=4[CH3:15])=[CH:31][C:32]=3[Cl:39])=[O:35])[CH2:6][C:5]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)c(Cl)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1c(F)cccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1.50 g of 10,11-dihydro-5 H-pyrrolo [2,1-c][1,4]benzodiazepine in 25 ml of methylene chloride is added 1.23 g of N,N-diisopropylethylamine. While cooling in an ice bath, a solution of 3.08 g of [4-[(2-methyl-5-fluorobenzoyl)amino]-2-chlorobenzoyl chloride in 50 ml of methylene chloride is added. The reaction mixture becomes homogeneous and is stirred at room temperature for 18 hours. Water is added and the separated organic layer washed with saturated sodium bicarbonate, dried with Na2SO4 and passed through a short pad of hydrous magnesium silicate two times. The methylene chloride is removed in vacuo to give 3.81 g of a glass. A sample is crystallized from ethyl acetate to give crystalline solid, m.p. 200-205° C.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3]1.C(N(CC)CC)C.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[S:2]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:3]1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCc1ccsc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCc1ccsc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
2-(Thiophen-3-yl)ethanamine hydrochloride (3 g, 18 mmol) was taken in THF (40 mL) and treated with triethylamine (9.92 mL, 71.2 mmol). The reaction was cooled down to 0° C. and benzoyl chloride (2.55 mL, 21.9 mmol), diluted with THF was added dropwise to the reaction. The reaction was stirred for 3 h and the volatiles removed in vacuo. The residue was dissolved in ethyl acetate and washed with an aqueous saturated solution of sodium bicarbonate, water and brine. The organic solution was dried with sodium sulfate and purified by flash chromatography using a gradient of 25 to 70% ethyl acetate in hexanes to afford an off-white solid (4 g). MS (M+H)+ 232.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:4](=[O:6])[C:3]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:2]=2[F:1])=[CH:15][CH:14]=1
Reactant: O=C(O)c1cc(F)ccc1F
Reactant: Nc1ccccc1
Product: Nc1ccc(C(=O)c2cc(F)ccc2F)cc1
Reaction time: 1 h
Yield: 209.6 %

Procedure:
To stirred 90° C. polyphosphoric acid (125 g) was added 2,5-difluoro-benzoic acid (10.0 g, 6.32 mmol) and aniline (5.87 g 6.3 mmol) and the bath temperature raised to 180°-190° C. and held there for 1 hour. The heating bath was removed and the stirred mixture (sublimate above the solution) was treated cautiously with 50 mL of water. The mixture was stirred at 140°-155° C. for 1 hour, the heating bath removed, 45 mL of 3N HCl added, the mixture poured into 650 mL of water and filtered through a pad of Celite. The filtrate was basified with 15% sodium hydroxide and the mixture filtered through a pad of Celite. The Celite pad was washed well with methylene chloride, the methylene chloride dried (MgSO4), filtered and the solvent removed in vacuo. Purification by flash column chromatography (methylene chloride) followed by recrystallization twice from 50% ethanol (80 mL) yielded the aniline as a yellow solid (3.08 g, 21%); mp 101°-103° C. H-NMR (300 MHz, CDCl3): 4.27 (s, 2H, NH2) 6.63-6.67 (m, 2H, aromatic) 7.09-7.19 (m, 3H, aromatic) 7.68-7.71 (m, 2H, aromatic). MS (CI, CH4): 234 (M+1). Analysis for C13H9F2NO: Calculated: C, 66.95; H, 3.89; N, 6.01. Found: C, 66.86; H, 4.04; N, 5.95.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([CH2:24][S:25]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:38]([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.Cl.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:18]=[C:19]3[C:20](=[CH:21][CH:22]=2)[NH:23][N:38]=[C:24]3[S:25]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(OC2CCN(C(=O)OCc3ccccc3)C2)cc1CS(=O)(=O)c1cccc2ccccc12
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)C1
Reaction time: 0.83 h
Yield: 70.1 %

Procedure:
A suspension of 3-[4-amino-3-(naphthalene-1-sulfonylmethyl)-phenoxy]-pyrrolidine-1-carboxylic acid benzyl ester (2.36 g, 4.57 mmol) in ethanol and 1.0 N hydrochloric acid (85 mL) was heated to aid dissolution. The reaction mixture was treated slowly with sodium nitrite (0.549 g, 7.96 mmol) in water, stirred at ambient temperatures for 50 minutes, basified with solid sodium carbonate, stirred at ambient temperatures for 30 minutes and concentrated in vacuo. The resultant residue was partitioned in ethyl acetate and brine. The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. This residue was purified twice by flash chromatography with 2% methanol in chloroform and with 1.5-10% methanol in chloroform to afford 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-pyrrolidine-1-carboxylic acid benzyl ester as a buff-colored foam, 1.69 g (70.1% yield), Mass spectrum (+EI, [M+H]+) m/z 528. 1HNMR (500 MHz, DMSO-d6): δ14.09 (s, 1H), 8.72-8.75 (m, 1H), 8.55 (d, 1H, J=7.44 Hz), 8.17-8.27 (m, 1H), 7.98-8.03 (m, 1H), 7.52-7.74 (m, 4H), 7.19-7.34 (m, 6H), 7.06 (d, 1H, J=8.78 Hz), 4.99-5.09 (m, 3H), 3.61-3.70 (m, 1H), 3.34-3.55 (m, 3H), 2.11-2.28 (m, 1H), 1.99-2.07 ppm (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-])=O)[C:9]=1[Cl:10])[C:5]#[N:6].[Cl-].[NH4+]>C1COCC1.CO.O.[Fe]>[NH2:11][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([Br:1])[C:9]=1[Cl:10])[C:5]#[N:6]
Reactant: N#Cc1cc(Br)c(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: N#Cc1cc(N)c(Cl)c(Br)c1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
(I1D): A mixture of 3-bromo-4-chloro-5-nitrobenzonitrile (0.99 g, 3.79 mmol), iron (1.057 g, 18.93 mmol) and ammonium chloride (2.025 g, 37.9 mmol) in THF, MeOH and water (60 ml, 1:1:1) was heated to reflux for 1 h. More iron (0.5 g) and NH4Cl (2 g) added, heated for another 2 h and then cooled to room temperature. Filtered off solid, the filtrate was concentrated to remove the organic solvent. The residue was diluted with water, extracted with EtOAc twice, dried and concentrated to dryness. The resulting solid was trituard with EtOAc, solid was filtered off through celite pad and the filtrate was concentrated to give 0.88 g of 3-amino-5-bromo-4-chlorobenzonitrile as yellow solid which was used as such in the next reaction. Intermediate 1: To a solution of 3-amino-5-bromo-4-chlorobenzonitrile (0.88 g, 3.80 mmol) in DCM (25 mL) was added TEA (1.590 mL, 11.41 mmol), BOC2O (1.059 mL, 4.56 mmol) and DMAP (0.464 g, 3.80 mmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated, the crude product was purified using ISCO silica gel column (24 g, EtOAc/hexane=0-30%) to give 0.667 g of tert-butyl 3-bromo-2-chloro-5-cyanophenylcarbamate as white solid
Reaction SMILES: CS(C1C=CC([N:11]2C(=O)C=CC(C([O-])=O)=N2)=CC=1)(=O)=O.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([O:34][C:35]2[C:36]([C:51]([O:53]C)=O)=[N:37][N:38]([C:42]3[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[C:44]([F:50])[CH:43]=3)[C:39](=[O:41])[CH:40]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(C)(C)C>>[C:51]([C:36]1[C:35]([O:34][CH:31]2[CH2:32][CH2:33][N:28]([C:26]([O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:27])[CH2:29][CH2:30]2)=[CH:40][C:39](=[O:41])[N:38]([C:42]2[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[C:44]([F:50])[CH:43]=2)[N:37]=1)(=[O:53])[NH2:11]
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(=O)[O-])ccc2=O)cc1
Reactant: COC(=O)c1nn(-c2ccc(C#N)c(F)c2)c(=O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)c(F)c3)nc2C(N)=O)CC1
Yield: 91 %

Procedure:
tert-Butyl 4-(3-carbamoyl-1-(4-cyano-3-fluorophenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate was prepared in 91% yield according to procedures described in Example 31 (Step A) substituting methyl 441-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate for methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyano-3-fluorophenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (example 29). MS (ESI) 402 (M+H-tBu).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[F:14][C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][C:23](O)=O)[CH:18]=[CH:19][CH:20]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:23]([CH2:22][CH2:21][C:17]4[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=4)=[N:13][N:12]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)CCc1cccc(F)c1
Reactant: NNC(=O)c1ccc2c(c1)CCO2
Product: Fc1cccc(CCc2nnc(-c3ccc4c(c3)CCO4)o2)c1
Yield: 59 %

Procedure:
In the same manner as in Example 14 and using 2,3-dihydro-1-benzofuran-5-carbohydrazide instead of 1H-benzotriazole-5-carbohydrazide and 3-(3-fluorophenyl)propionic acid instead of 3-(3-cyanophenyl)propionic acid, the title compound (yield 59%) was obtained as colorless crystals.
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[C:16](=[O:29])[C:17]4[N:18]=[CH:19][N:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:21]=4[N:22]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N([O-])=[O:38].[Na+].OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([N:15]2[C:16](=[O:29])[C:17]3[N:18]=[CH:19][N:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:21]=3[N:22]=[C:14]2[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2](=[O:38])[NH:7][CH:6]=3)=[CH:9][CH:10]=2)=[CH:31][CH:32]=1
Reactant: Nc1ccc(-c2ccc(-c3nc4c(ncn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)cn1
Reactant: O=N[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=c1ccc(-c2ccc(-c3nc4c(ncn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)c[nH]1
Temperature: 100 °C

Procedure:
A solution of 2-[4-(6-amino-pyridin-3-yl)-phenyl]-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one (10 mg, 0.02 mmol) in acetonitrile (0.4 mL) and H2O (0.4 mL) was treated with NaNO2 and 5 μL of concentrated H2SO4. The reaction mixture was heated at 100° C. for 1 h. The reaction was allowed to cool to room temperature and neutralized with aqueous Na2CO3. The reaction was diluted with H2O and extracted with EtOAc. The combined organics were dried (MgSO4), filtered, and concentrated. The resulting crude material was purified by preparative LCMS to provide the title compound 1-(4-chloro-phenyl)-2-[4-(6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-9-phenyl-1,9-dihydro-purin-6-one_as a white solid. 1H NMR (CDCl3) δ (ppm) 8.21 (s, 1H), 8.01 (dd, 1H), 7.81 (d, 1H), 7.58 (apparent t, 2H), 7.49 (m, 1H), 7.39 (d, 2H), 7.33 (m, 3H), 7.14 (d, 2H), 6.98 (d, 1H); HPLC-MS calculated for C28H18ClN5O2 (M+H+): 492.1. Found: 492.1.
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[N:7]2[C:8]=1[C:9]([O:11]CC1C=CC([N+]([O-])=O)=CC=1)=[O:10])=[N+]=[N-].O1CCCC1.C(O)C.C(=O)(O)[O-].[Na+:40]>[Pd].O>[NH2:1][C:4]1[CH2:5][C@@H:6]2[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[N:7]2[C:8]=1[C:9]([O-:11])=[O:10].[Na+:40]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(N=[N+]=[N-])C[C@H]12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(N)C[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of p-nitrobenzyl (5R,6S)-2-azido-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate (75 mg, 0.2 mmol), tetrahydrofuran (14 ml), ethanol (14 ml), deionized water (11 ml) containing sodium bicarbonate (16.8 mg, 0.2 mmol), and 10% palladium on carbon (75 mg) is shaken under hydrogen (45 psi) at ambient temperature for 2 hours. The mixture is filtered through a celite pad to remove the catalyst which is washed with water. The combined filtrate and wash is extracted with three portions of diethyl ether, concentrated under vacuum to about 10 ml volume, and lyophilized to afford sodium (5R,6S)-2-amino-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Li].CO[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20](=[O:22])[CH3:21])[CH:14]=[CH:13]2>>[N:1]1([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C:20](=[O:22])[CH3:21])[CH:14]=[CH:13]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: COc1ccc2cc(C(C)=O)ccc2c1
Reactant: C1CNCCN1
Agent: [Li]
Product: CC(=O)c1ccc2cc(N3CCNCC3)ccc2c1
Reaction time: 65 h

Procedure:
Anhydrous piperazine (7 g, 81.3 mmol; dried in a vacuum desiccator over KOH-drierite mixture for 3 days) was dissolved in a mixture of dry, freshly distilled toluene and hexamethyl phosphoric amide (HMPA), 25 mL each. To the solution was added 556 mg (80.1 mmol) of lithium rod, cut in small pieces under argon atmosphere, and the mixture was stirred under argon for 24 hours, during which time all lithium has dissolved. Vacuum-dried 1-(6-methoxy-2-naphthyl)-1-ethanone (prepared as described in Arsenijevic et al., Org. Synth. Coll. 1988 6:34-36, the disclosure of which is incorporated herein by reference) (3.5 g, 17.5 mmol) was added and stirring was continued for additional 65 hours. After quenching with 300 mL of water, extraction with dichloromethane (3×300 ml,), drying with anhydrous magnesium sulfate, and evaporation, a mixture of white and yellow solids was obtained. Extraction with 300 mL of hot methanol gave raw product, 1-(6-piperazino-2-naphthyl)-1-ethanone, which was purified by column chromatography (70-230 mesh silica, 25×120 mm, 5% methanol in dichloromethane). The yield was 1.54 g (35%). After recrystallization from ethyl acetate, the sample melted at 170.5-172° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([CH:17]3[CH2:27][CH:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1>C(Cl)Cl.N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([CH:17]3[CH2:27][CH:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:10])=[O:9]
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2Br)ccc2c1OCC1CC21
Yield: 76.5 %

Procedure:
2-Bromobenzenesulfonyl chloride (0.559 g) was added to a solution of methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42, 0.40 g) in DCM (12 mL) and pyridine (4 mL) and the resultant mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness and the residue was dissolved in DCM and washed with 2N HCl, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-35% to give methyl (1aRS,7bSR)-5-(2-bromo-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.612 g) as a solid.
Reaction SMILES: [H-].[Na+].C([N:8]1[C:12](=[O:13])[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:10][C:9]1=[O:26])(OCC)=O.[H][H].C([O:31][C:32](=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36]Br)C>CN(C)C=O.[OH-].[Na+]>[C:32]([CH2:33][CH2:34][CH2:35][CH2:36][N:10]1[C:11]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12](=[O:13])[NH:8][C:9]1=[O:26])([OH:38])=[O:31]
Reactant: CCOC(=O)N1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H][H]
Reactant: CCOC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(O)CCCCN1C(=O)NC(=O)C1(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 15.8 %

Procedure:
Under an argon atmosphere, 4.32 g (0.09 mol) of sodium hydride (50% dispersion in mineral oil) was placed in a dry, 1 liter, 3-necked round bottom flask equipped with a mechanical stirrer and thermometer. The sodium hydride was rinsed with 250 ml of dry hexane. To the washed material was added 29 g (0.09 mol) of 3-carbethoxy-5,5-diphenylhydantoin (1) [L. Call, Monat. Chem. 101:228 (1970)] dissolved in 250 ml of dry dimethylformamide (DMF). After stirring for one hour, hydrogen gas evolution ceased. Then 20.9 g (0.1 mol) of ethyl-5-bromovalerate was added and the reaction stirred overnight at room temperature. The DMF was removed under high vacuum and the residue partitioned between 500 ml of ether and 300 ml of water (H2O). The ether phase was separated, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and evaporated to give an oil. This oil was stirred at 5° C. for 3 hours in 500 ml of 2 N sodium hydroxide. Acidification with dilute hydrochloric acid precipitated an oil that was crystallized from ether and recrystallized from aqueous methanol to give 5 g of 1-(4-carboxybutyl)-5,5-diphenylhydantoin (4) as white crystals, mp 207° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH2:13][C:14](O)=[O:15])[N:11]=[C:10]([CH2:17][N:18]2[C:22](=[O:23])[N:21]([CH2:24][C@H:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[C:20]([C:31]3[CH:36]=CC(Cl)=[CH:33][CH:32]=3)=[N:19]2)[N:9]=1.C1C=CC2N(O)N=[N:44]C=2C=1.[CH2:48]([Cl:51])[CH2:49]Cl.N>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH2:13][C:14]([NH2:44])=[O:15])[N:11]=[C:10]([CH2:17][N:18]2[C:22](=[O:23])[N:21]([CH2:24][C@H:25]([OH:30])[C:26]([F:27])([F:28])[F:29])[C:20]([C:31]3[CH:36]=[CH:49][C:48]([Cl:51])=[CH:33][CH:32]=3)=[N:19]2)[N:9]=1
Reactant: On1nnc2ccccc21
Reactant: ClCCCl
Reactant: O=C(O)Cn1nc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)nc1-c1ccccc1Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)Cn1nc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)nc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
54 mg (0.10 mmol) of the compound from Example 60 were initially charged in 4 ml of DMF, and 19 mg (0.13 mmol) of HOBt and 24 mg (0.03 mmol) of EDC were added. After 10 min of stirring at RT, 0.1 ml (1.93 mmol) of ammonia solution (32% strength in water) were added and the mixture was stirred at room temperature for 16 h. The reaction solution was then freed from excess ammonia under reduced pressure, about 3 ml of water were added and the mixture was extracted three times with in each case 5 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 27 mg (46% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[F:43][C:44]1[CH:49]=[CH:48][C:47]([C@H:50]([NH2:52])[CH3:51])=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:52][C@@H:50]([C:47]2[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=2)[CH3:51])=[O:41])=[CH:18][C:17]=1[F:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@@H](N)c1ccc(F)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4ccc(F)cc4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (30 is mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (30 mg, yield 66%).
Reaction SMILES: [NH:1]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C@H:2]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][OH:4].[C:18](=O)([O:23]C1C2N=NNC=2C=CC=1)[O:19][CH2:20][CH:21]=[CH2:22]>>[NH:1]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C@H:2]([C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])[CH2:3][O:4][C:18]([O:19][CH2:20][CH:21]=[CH2:22])=[O:23]
Reactant: CC(C)(C)OC(=O)[C@H](CO)NN1CCOCC1
Reactant: C=CCOC(=O)Oc1cccc2[nH]nnc12
Product: C=CCOC(=O)OC[C@H](NN1CCOCC1)C(=O)OC(C)(C)C

Procedure:
Morpholino-Ser(OAloc) was prepared from Ser(OtBu)-OtBu. Reaction of Ser(OtBu)-OtBu with 4-morpholinecarbonyl chloride in pyridine yielded morpholino-Ser(OtBu)-OtBu. Morpholino-Ser(OtBu)-OtBu was hydrolyzed with TFA to yield morpholino-Ser. Esterification of morpholino-Ser with isobutylene in the presence of a catalytic amount of H2SO4 afforded morpholino-Ser-OtBu. Reaction of morpholino-Ser-OtBu with allyl 1-benzotriazolyl carbonate yielded morpholino-Ser(OAloc)-OtBu. Morpholino-Ser(OAloc)-OtBu was hydrolyzed with TFA in CHCl3 (1:1) to yield morpholino-Ser(OAloc).