Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:35]([O:36][CH3:37])=[CH:34][C:24]2[CH2:25][CH2:26][N:27]([CH2:30][CH:31]([OH:33])[CH3:32])[CH2:28][CH2:29][C:23]=2[CH:22]=1>>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:20][C:21]2[C:35]([O:36][CH3:37])=[CH:34][C:24]3[CH2:25][CH2:26][N:27]([CH2:30][CH:31]([OH:33])[CH3:32])[CH2:28][CH2:29][C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CC(C)O)CC2
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)CCN(CC(C)O)CC2
Yield: 53 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol. Product was isolated as a tan foam (55 mg, 53%). mp: 120° C., MS (ESI+): 513 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.22 (s, 1H), 7.91 (s, 1H), 7.42 (s, 1H), 6.66 (s, 1H), 6.57 (s, 1H), 6.51 (s, 1H), 6.33 (s, 2H), 5.60 (s, 1H), 5.35 (s, 1H), 5.32 (s, 1H), 4.47 (t, J=8 Hz, 1H), 3.88 (s, 4H), 3.09 (s, 1H), 2.89-2.87 (m, 7H), 2.63 (m, 2H), 2.53 (d, 2H), 2.28 (d, J=10 Hz, 2H), 1.67 (d, J=8 Hz, 1H), 1.17 (d, J=6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@H:18]3[N:23]([CH2:24][C:25](O)=[O:26])[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[NH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:19][O:20][C:21]([CH3:28])([CH3:29])[CH2:22][N:23]3[CH2:24][C:25](=[O:26])[NH:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC1(C)CN(CC(=O)O)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Reactant: Nc1cccnc1
Product: CC1(C)CN(CC(=O)Nc2cccnc2)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Yield: 55 %

Procedure:
The desired compound was prepared according to Method F from [(S)-5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and 3-aminopyridine. The product was isolated as hydrochloride salt in 55% yield. 1HNMR (300 MHz, D2O): δ 1.34 (s, 3H), 1.54 (s, 3H), 2.60 (d,1H), 3.4 (d, 1H), 3.50 (d, 1H), 3.70 (t, 1H), 3.81 (d, 1H) 4.23 (d, 2H), 7.69 (d, 1H), 7.98 (d, 1H), 8.01 (d, 1H), 8.17(d, 1H), 8.42 (d, 1H), 8.48-8.55 (m, 3H), 9.09 (s,1H), 9.30 (d, 1H). Retention Time (LC, method: ammonium acetate standard): 1.56 min. MS (M+H+): 493.2.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[N:7].C[O-].[Na+].O.[NH2:12][NH2:13]>C(O)C.O>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:12][NH2:13])[NH2:7]
Reactant: N#Cc1ccc[nH]1
Reactant: NN
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NN=C(N)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1H-pyrrole-2-carbonitrile 10 g (108 mM) and sodium methoxide (1 eq) in ethanol (20 ml) and stirred for 10 min. Hydrazine hydrate (3 eq.) is then added and resulting reaction mixture is stirred at room temperature for 18 hrs. Reaction mass is then diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulphate and concentrated under vacuum to yield desired compound.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([C@@H:30]2[CH2:34][CH2:33][CH2:32][NH:31]2)[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:20]4[C@H:27]([CH3:28])[CH2:26][C@@H:25]([OH:29])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1.[CH:35](N(C(C)C)CC)([CH3:37])[CH3:36].CC(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([C@@H:30]2[CH2:34][CH2:33][CH2:32][N:31]2[CH:35]([CH3:37])[CH3:36])[C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[C:20]4[C@H:27]([CH3:28])[CH2:26][C@@H:25]([OH:29])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:17][CH2:18]2)=[O:12])=[CH:6][CH:5]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4CCCN4)CC3)c21
Reactant: CCN(C(C)C)C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCCl
Product: CC(C)N1CCC[C@H]1[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone di-hydrochloride (0.074 g, 0.1399 mmol) was dissolved in 1,2-dichloroethane (0.50 mL) and treated with diisopropylethylamine (0.04874 mL, 0.2798 mmol), propan-2-one (0.03082 mL, 0.4197 mmol) and sodium triacetoxyborohydride (0.1483 g, 0.6996 mmol). The mixture was stirred at 40° C. for 18 hours. The reaction was quenched with 3N HCl and stirred for 30 minutes. The reaction was neutralized to a pH of about 8 to about 8.5 with slow addition of saturated NaHCO3. The reaction was diluted with methylene chloride and separated. The aqueous layer was washed with methylene chloride (2×), and the combined organics were dried over Na2SO4 and concentrated in vacuo. The material was subjected to chromatography on SiO2 eluting with 5% MeOH/1% NH4OH/methylene chloride. The recovered free base (51.2 mg) was dissolved in dioxane (1 mL) and treated with 4N HCl in dioxane (1.5 mL). After stirring for 5 minutes, the mixture was concentrated in vacuo. The mixture was re-dissolved and re-concentrated in vacuo three times from MeOH. The mixture was re-dissolved in MeOH (0.5 mL+0.25 mL wash) and added dropwise to stirred Et2O (30 mL). The resultant solid was stirred for 30 minutes. The solid was then filtered, washed with Et2O and dried under a blanket of nitrogen. (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-1-isopropylpyrrolidin-2-yl)ethanone dihydrochloride was recovered as a solid (0.026 g, 59%). MS (ESI+) [M+H] 498.2/500.1. 1H NMR (CD3OD, 400 MHz) δ 8.56 (s, 1H), 7.44 (dd, 4H), 5.29 (t, J=8.1 Hz, 1H), 4.56 (d, J=10.3, 1H), 4.44-4.35 (m, 1H), 4.29-4.06 (m, 3H), 3.87-3.75 (m, 3H), 3.72-3.62 (m, 1H), 3.60-3.35 (m, 5H), 2.31-2.25 (m, 1H), 2.23-2.08 (m, 2H), 2.07-1.95 (m, 1H), 1.90-1.78 (m, 1H), 1.78-1.68 (m, 1H), 1.39 (d, 3H), 1.32 (d, 3H), 1.18 (d, 3H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N:10]1([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:10]1([CH:16]2[CH2:21][CH2:20][N:19]([C:2]3[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=3)[CH2:18][CH2:17]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1ccc(F)cc1
Reactant: C1CCN(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(N2CCC(N3CCCCC3)CC2)cc1
Temperature: 100 °C

Procedure:
A mixture of 4-fluorobenzaldehyde (1 mL), {1,4′}bipiperidinyl (829.6 mg), and potassium carbonate (0.72 g) in DMF (3 mL) was heated to 100° C. for 6 h. The cooled reaction mixture was poured into water (200 mL) and then extracted with DCM. Removal of the solvent and chromatography of the residue on silica gel (1-7% 2 M methanolic ammonia/DCM) gave the title compound (838.3 mg).
Reaction SMILES: CS(O[C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=[C:15]3[CH:22]=[CH:23][S:24][C:14]=23)[CH2:8][CH2:7]1)(=O)=O.[C-:25]#[N:26].[Na+]>CS(C)=O>[N+:19]([C:18]1[C:13]([NH:12][C@@H:9]2[CH2:10][CH2:11][C@H:6]([C:25]#[N:26])[CH2:7][CH2:8]2)=[C:14]2[S:24][CH:23]=[CH:22][C:15]2=[N:16][CH:17]=1)([O-:21])=[O:20]
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#C[C@H]1CC[C@@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 90 °C
Reaction time: 6 h
Yield: 33.1 %

Procedure:
A mixture of trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl methanesulfonate (0.12 g, 0.32 mmol) and sodium cyanide (0.061 g, 1.2 mmol) in dimethyl sulfoxide (1 mL) was stirred at 90° C. for 6 h. After dilution with EtOAc, the resulting mixture was washed with sat. NaHCO3 solution, water and brine, and then concentrated. The residue was purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (32 mg). LCMS calculated for C14H15N4O2S (M+H)+: m/z=303.1. Found: 303.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=3)[C:3]=12.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33]O)[CH2:28][CH2:27]1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:33][CH2:32][N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=3)[C:3]=12
Reactant: Fc1ccc(-c2n[nH]c3nnc(-c4ccccc4)c(Cl)c23)cc1F
Reactant: CN1CCN(CCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CN1CCN(CCn2nc(-c3ccc(F)c(F)c3)c3c(Cl)c(-c4ccccc4)nnc32)CC1

Procedure:
A mixture of 4-chloro-3-(3,4-difluorophenyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (0.33 mmol), 2-(4-methylpiperazin-1-yl)ethanol (0.65 mmol), diethyl azodicarboxylate (114 mg, 0.65 mmol) and triphenyl phosphine (171 mg, 0.65 mmol) in 1,4-dioxane (2 mL) was heated using microwave irradiation to a temperature between 85 and 120° C. for a 30 to 90 min period. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to provide Compound 10.
Reaction SMILES: C(=O)(O)[O-].[Na+].C(O[CH2:10][C:11]1[CH2:12][S:13][C@@H:14]2[CH:21]([NH2:22])[C:20](=[O:23])[N:15]2[C:16]=1[C:17]([OH:19])=[O:18])(=O)C.[CH3:24][C:25]1[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([SH:32])[N:26]=1>O.CC(C)=O>[NH2:22][CH:21]1[C:20](=[O:23])[N:15]2[C:16]([C:17]([OH:19])=[O:18])=[C:11]([CH2:10][S:32][C:27]3[N:28]=[C:29]([CH3:31])[CH:30]=[C:25]([CH3:24])[N:26]=3)[CH2:12][S:13][C@H:14]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: Cc1cc(C)nc(S)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C)nc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)n1
Reaction time: 23 h

Procedure:
A solution of sodium bicarbonate (9.45 g.) in water (100 ml.) was added in portions to a stirred suspension of 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid (13.5 g.) in water (100 ml.) and acetone (50 ml.). The solid dissolved with effervescence. To this solution under nitrogen at 55° was added rapidly, drop by drop, a solution of 4,6-dimethyl-2-mercaptopyrimidine (10.5 g.) in water (100 ml.) and acetone (100 ml.), the pH being maintained between 7.4 and 7.8 by addition of 6 NHCl or 5% w/v aqueous NaHCO3. After 23 hours at 55°, the reaction mixture was cooled to 0° and acidified to pH 4.0. The resulting precipitate was filtered, washed with water and acetone, and dried over P2O5 to give 7-amino-3-(4,6-dimethylpyrimid-2-yl)thiomethylceph-3-em-4-carboxylic acid. A mixture of this acid (3.52 g.) and O-t-butyl-1,3-diisopropylisourea (6.0 g.) in dry CH2Cl2 (60 ml.) was stirred under nitrogen for 20 hours. The reaction mixture was filtered, the filtrate evaporated and the residue purified by chromatography on silica gel (200 g.) at -40° using CH2Cl2 /ether 6:4 v/v as eluant to give the t-butyl ester.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)(C)C.[C:21]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:21]1([C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:6]([OH:5])[C:7]=3[CH:8]=2)[CH2:25][CH2:24][CH2:23][CH:22]=1
Reactant: CC(C)[Si](Oc1cccc2[nH]ccc12)(C(C)C)C(C)C
Reactant: O=C1CCCC1
Product: Oc1cccc2[nH]c(C3=CCCC3)cc12

Procedure:
2-Cyclopent-1-enyl-1H-indol-4-ol was prepared from 4-triisopropylsilyloxy-1H-indole and cyclopentanone as described for 14c.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:18]2[CH:19]=[CH:20][N:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1)=O)(C)(C)C.[ClH:22].CO>C(Cl)Cl>[ClH:22].[ClH:22].[NH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:18]2[CH:19]=[CH:20][N:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCCNc1cccc2nccn12
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: NCCCNc1cccc2nccn12
Temperature: 25 °C
Reaction time: 20 h
Yield: 83 %

Procedure:
To a suspension of 5-[3-(tert-butoxycarbonylamino)propylamino]imidazo[1,2-a]pyridine (1.742 g, 6 mmoles) in methylene chloride (40 ml) was added hydrogen chloride-methanol (6 ml) and the mixture was stirred at room temperature for 20 hours. After the solvent was distilled off, ethanol (15 ml) and ether (30 ml) were added to the residue. Then, the crystals precipitated were filtered off and washed in turn with ether and a small amount of ethanol to obtain 1.311 g of the desired product (83.0%, pale yellow crystals).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl.[N:9]1[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=1>>[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)=[CH:11][CH:10]=1
Reactant: O=C1CCNCC1
Reactant: ClCc1ccncc1
Agent: Cl
Product: O=C1CCN(Cc2ccncc2)CC1

Procedure:
1-(4-Pyridinylmethyl)-4-piperidone is prepared from 4-piperidone and 4-picolyl chloride hydrochloride essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[NH:10][C:9]2=[O:22])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:26][CH2:27][CH2:28][Cl:29].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[N:10]([CH2:26][CH2:27][CH2:28][Cl:29])[C:9]2=[O:22])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:4][CH:3]=1
Reactant: O=C1Nc2c(ccc3ccccc23)SC1c1ccc(Cl)cc1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C1C(c2ccc(Cl)cc2)Sc2ccc3ccccc3c2N1CCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of 3-(4-chlorophenyl)-1H-naphtho-[2,1-b][1,4]thiazin-2(3H)-one (10.0 g) and 96% sodium hydroxide (1.96 g) in dimethylsulfoxide (150 ml) is added 1-bromo-3-chloropropane (6.78 g) under ice cooling, and the mixture is stirred at room temperature overnight. The reaction mixture is poured into water, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed and distilled to remove the solvent. The residue is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=5:1) and further is recrystallized from methanol to give 3-(4-chlorophenyl)-1-(3-chloropropyl)-1H-naphtho[2,1-b][1,4]thiazin-2(3-H)-one (8.04 g). M.p. 110°-112.5° C.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[C:11]([N+:20]([O-])=O)[CH:12]=[CH:13][C:14]=3[OH:19])[C:9](=[O:23])[C:8]=2[C:7]([OH:24])=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+].[H][H]>[C].[Pd]>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[C:11]([NH2:20])[CH:12]=[CH:13][C:14]=3[OH:19])[C:9](=[O:23])[C:8]=2[C:7]([OH:24])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C1c2c(O)ccc([N+](=O)[O-])c2C(=O)c2c(O)ccc([N+](=O)[O-])c21
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(O)c2c1C(=O)c1c(O)ccc(N)c1C2=O
Reaction time: 5 h
Yield: 98 %

Procedure:
A 500 ml. electromagnetically stirred glass reactor was charged with 5.0 g (0.0151 mole) of 1,5-dinitro-4,8-dihydroxyanthraquinone, 100 g of a 4% aqueous solution of sodium hydroxide and 0.25 g of 5% palladium-carbon. The inside of the reactor was purged with hydrogen, and the 1,5-dinitro-4,8-dihydroxyanthraquinone was hydrogenated at 50° C. with stirring. In 5 hours, 0.0906 mole of hydrogen was absorbed, whereupon the reaction was stopped. The reaction mixture was filtered to separate the catalyst. The filtrate was oxidized with air with stirring at 20° to 30° C. for 2 hours, and then neutralized with 20% sulfuric acid to a pH of 2-3. The crystals precipitated were filtered, washed with water, and dried to afford 4.0 g of 1,5-diamino-4,8-dihydroxyanthraquinone in a yield of 97.8%.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(O[CH2:21][CH2:22][F:23])(=O)=O>CN(C)C=O>[F:23][CH2:22][CH2:21][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)OCCF
Reactant: Oc1ccccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FCCOc1ccccc1-c1ccccc1
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
To a suspension of sodium hydride (60 % oil dispersion; 4.0 g) in N,N-dimethylformamide (100 ml), 2-phenylphenol (17.0 g) was added at a temperature of 0 to 5° C., and the resultant mixture was stirred at room temperature for 1 hour. 2-Fluoroethyl methanesulfonate (14.2 g) was added thereto. The resulting mixture was heated to 90° C., followed by stirring for 5 minutes. The reaction mixture was poured onto ice-water and extracted with ethyl acetate. The extract was washed with aqueous potassium carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent, toluene) to give 1-(2-fluoroethoxy)-2-phenylbenzene (Compound No. 20) (16.4 g). nD24.8 1.5796.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:11][CH2:10][C:9]2=[O:12])=[CH:4][CH:3]=1.FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][CH2:11][CH2:10][C:9]2=[O:12]
Reactant: O=C1CCN1c1ccc(F)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCNc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
500 mg of 1-(4-fluorophenyl)azetidin-2-one (Example 154A, 3.03 mmol, 1 equivalent) were initially charged in 24 ml of dichloromethane, 0.5 ml of trifluoromethanesulphonic acid (909 mg, 6.05 mmol, 2 equivalents) were added at 0° C. and the mixture was stirred at RT for 45 min. Two more times, 0.3 equivalents of trifluoromethanesulphonic acid were added, and after each addition the mixture was stirred for 30 min. With ice cooling, saturated aqueous sodium bicarbonate solution was added carefully, and the reaction mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and concentrated. This gave 284 mg (57% of theory) of the title compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:4][CH2:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:26]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:27][C:28](ON1C(=O)CCC1=O)=[O:29]>CN(C=O)C.CCN(CC)CC>[NH:26]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:27][C:28]([NH:2][C@H:3]([C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[CH2:4][CH2:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution at 0° C, of HCl.H-Glu(OBzl)-OBzl (1.82 g, 5 mmol) in DMF (35 ml), Et3N (0.7 ml) was added dropwise followed by Boc-Gly-OSu (1.5 g, 5.5 mmol). The mixture was stirrred at 0° C for 2 hr and at room temperature overnight; pH 8 was maintained by addition of a few drops of Et3N. The reaction mixture was then evaporated to a small volume and H2O was added. The precipitated oil was extracted with EtOAc and the organic phase was washed with 1 M AcOH, water, and dried (Na2SO4). Evaporation provided an oil which was purified on a Silica gel 60 column using CHCl3 :MeOH (5:1) as eluant. The pooled fractions containing (XVIII) were evaporated yielding colorless oil which failed to crystallize, 1.62 g (67%) homogeneous on tlc [α]D25 -15.0° (c 2, MeOH). Anal. Calcd for C26H32N2O7 (484.558): C, 64.45; H, 6.66; N, 5.78. Found: C, 64.23; H, 6.72; N, 5.66. Compound XVIII was also prepared from Boc-Gly-Glu(OBzl)-OH via the cesium salt procedure of Wang et al, supra.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[C:24]([OH:32])=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[C:24]([OH:32])=[C:25]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=4[OH:21])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1ccc(-c2cccc(-c3cccc(Br)n3)n2)c(O)c1
Reactant: OB(O)c1cccc(F)c1O
Product: Cc1ccc(-c2cccc(-c3cccc(-c4cccc(F)c4O)n3)n2)c(O)c1
Yield: 17 %

Procedure:
6-(3-Fluoro-2-hydroxyphenyl)-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine and 3-fluoro-2-hydroxyphenylboronic acid in 17% yield using method F; δH [2H6]-DMSO 13.37,(1H, b), 8.38,(1H, d), 8.34-8.15,(4H, m), 8.10,(1H, d), 8.01,(1H, d), 7.95,(1H, d), 7.34,(1H, t), 6.98,(1H, m), 6.81,(2H, m), 2.33,(3H, s).
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH2:23][C:24]2[S:28][C:27]3[CH:29]=[CH:30][C:31]([CH2:33][CH3:34])=[CH:32][C:26]=3[CH:25]=2)[CH:14]=1.[CH2:35]([O:42][CH:43]1[CH:48]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:47]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:46]([CH2:65][O:66][CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[O:45][C:44]1=[O:74])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Cl-].[NH4+]>C1COCC1>[CH2:35]([O:42][C@@H:43]1[C@H:48]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@@H:47]([O:57][CH2:58][C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[C@@H:46]([CH2:65][O:66][CH2:67][C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=2)[O:45][C:44]1([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH2:23][C:24]2[S:28][C:27]3[CH:29]=[CH:30][C:31]([CH2:33][CH3:34])=[CH:32][C:26]=3[CH:25]=2)[CH:14]=1)[OH:74])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCc1ccc2sc(Cc3cc(Br)c4ccccc4c3)cc2c1
Reactant: O=C1OC(COCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1ccc2sc(Cc3cc(C4(O)O[C@H](COCc5ccccc5)[C@H](OCc5ccccc5)[C@@H](OCc5ccccc5)[C@H]4OCc4ccccc4)c4ccccc4c3)cc2c1
Reaction time: 0.08 h
Yield: 0.1 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 0.83 ml, 1.33 mmol) was added dropwise to a solution of 2-(4-bromonaphtalen-2-ylmethyl)-5-ethylbenzo-[b]thiophene (460 mg, 1.21 mmol) in THF (15 ml) at −78° C. The reaction mixture was stirred at the same temperature for five minutes and to this solution, a solution of 3,4,5-trisbenzyloxy-6-benzyloxymethyltetrahydro-pyran-2-one (844 mg, 1.57 mmol) in THF (5 ml) was added dropwise. The reaction solution was stirred at −78° C. for five minutes and a saturated ammonium chloride aqueous solution was added to stop the reaction. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:9)] to obtain the title compound (1.06 mg, 100%).