Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][C:8]([CH2:18][NH:19][C:20](=[O:30])[CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=3)([C:11]3[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32].C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1.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>[C:31]([C:33]1[CH:38]=[C:37]([C:14]2[CH:15]=[CH:16][C:11]([C:8]3([CH2:18][NH:19][C:20](=[O:30])[CH2:21][C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=4)[CH2:9][CH2:10][N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[CH:12][CH:13]=2)[CH:36]=[CH:35][CH:34]=1)#[N:32]
Reactant: O=C(Cc1cc(F)cc(F)c1)NCC1(c2ccc(I)cc2)CCN(CC2CC2)CC1
Reactant: N#Cc1cccc(B(O)O)c1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: N#Cc1cccc(-c2ccc(C3(CNC(=O)Cc4cc(F)cc(F)c4)CCN(CC4CC4)CC3)cc2)c1
Temperature: 25 °C
Yield: 60 %

Procedure:
To a flask containing 1 N-[1-cyclopropylmethyl-4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-2-(3,5-difluoro-phenyl)-acetamide (0.040 g, 0.76 mmol) was added Pd(PPh3)4 (0.01 g, 0.008 mmol, 10 mol %), 3-cyanophenylboronic acid (0.020 g, 0.12 mmol, 1.5 eq.) and Na2CO3 (0.106 g, 1 mmol). The mixture was suspended in toluene (1.5 mL), EtOH (0.75 mL) and H2O (0.5 mL) and heated to 80° C. for 18 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (5 mL) and saturated Na2CO3 (5 mL). The organic layer was washed with saturated Na2CO3 (3×5 mL), saturated brine (2×5 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a brown solid which was purified by HPLC to give the title compound N-[4-(3′-cyano-biphenyl-4-yl)-1-cyclopropylmethyl-piperidin-4-ylmethyl]-2-(3,5-difluoro-phenyl)-acetamide (0.036 g, 0.072 mmol, 10%). MS(ESI): 500.3/501.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[O:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1)[CH3:16]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:17]([O:15][CH3:16])=[CH:18][CH:19]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: COc1ccc(C(=O)O)cc1
Product: COc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline and 4-methoxylbenzoic acid to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-methoxybenzamide. MS (Q1) 341.2 (M)+.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][O:18][CH2:19][CH2:20][NH:21][C:22]([NH2:24])=[O:23])=[O:6])[CH:2]=[CH2:3].[C:25]([O-:28])(=[S:27])[CH3:26].[K+]>CN(C)C=O>[C:25]([S:27][C@@H:10]1[CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C@H:8]([CH2:17][O:18][CH2:19][CH2:20][NH:21][C:22]([NH2:24])=[O:23])[CH2:9]1)(=[O:28])[CH3:26]
Reactant: CC([O-])=S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1COCCNC(N)=O
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1COCCNC(N)=O
Temperature: 0 °C
Yield: 80.4 %

Procedure:
A solution of (2S,4R)-1-allyloxycarbonyl-4-methane- sulfonyloxy-2-[(2-ureidoethyl)oxymethyl]pyrrolidine (1.00 g) and potassium thioacetate (0.48 g) in dimethylformamide (6 ml) was heated at 80°-85° C. for 30 minutes. The mixture was poured into ice-water (30 ml) and extracted with ethyl acetate (12 ml×3). The organic layer was washed with brine (18 ml×2), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (50 g) and eluted with a mixture of methanol and dichloromethane (5:95 v/v) to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-[(2-ureidoethyl)oxymethyl]pyrrolidine (0.76 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[CH:55]=[N:54][C:53]([Br:56])=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:56][C:53]1[N:54]=[CH:55][C:50]([NH:49][C:40](=[O:42])[C@@H:39]([C:31]2[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:36])=[O:37])=[C:29]([Cl:28])[CH:30]=2)[CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[N:51][CH:52]=1
Reactant: Nc1cnc(Br)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
A stirred solution of triphenylphosphine (8.57 g, 32.6 mmol) in anhydrous methylene chloride (110 mL) under nitrogen at 0° C. was treated with N-bromosuccinimide (5.80 g, 32.6 mmol). After 15 min, 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 9.00 g, 27.2 mmol) was added to the reaction. The mixture was allowed to warm to 25° C. After stirring at 25° C. for 10 min, the reaction was treated with 2-amino-5-bromopyrazine (7.92 g, 45.6 mmol) followed by pyridine (8.79 mL, 108.8 mmol). The mixture was allowed to stir at 25° C. for 1.5 h. At this time, the reaction was diluted with methylene chloride and then was washed with a 1N aqueous hydrochloric acid solution (200 mL) followed by a 10% aqueous potassium carbonate solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 3/7 ethyl acetate/hexanes) afforded N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (10.02 g, 76%) as a white foam: mp 77–82° C. (foam to gel); (ES)+-HRMS m/e calcd for C19H21BrClN3O3S (M+H)+ 486.0249, found 486.0255.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C@:13]2([CH3:18])[C@H:16]([CH3:17])[C@H:9]1[CH2:10][C:11]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][NH2:26])=[O:24])=[CH:19][C:12]=12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([CH3:37])(OCC)(OCC)OCC>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C@:13]2([CH3:18])[C@H:16]([CH3:17])[C@H:9]1[CH2:10][C:11]1[CH:22]=[CH:21][C:20]([C:23]3[O:24][C:27]([CH3:37])=[N:26][N:25]=3)=[CH:19][C:12]=12)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1[C@H]2Cc3ccc(C(=O)NN)cc3[C@]1(C)CCN2C(=O)OC(C)(C)C
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nnc(-c2ccc3c(c2)[C@]2(C)CCN(C(=O)OC(C)(C)C)[C@H](C3)[C@H]2C)o1
Temperature: 25 °C

Procedure:
(2R,6R,11S)-8-Hydrazinocarbonyl-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester (0.50 g) in (EtO)3CMe (2 mL) is heated in a microwave oven at 120° C. for 30 min. After cooling to room temperature, the mixture is concentrated under reduced pressure and the residue is purified by HPLC on reversed phase (MeCN/H2O/NH4OH) to give the title compound.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH4:10]>C(O)C>[C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:10]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:1][OH:8])([OH:9])=[O:8]
Reactant: CCCCC=CC(=O)O
Reactant: C
Solvent: CCO
Product: O=C(O)CCCCCCc1ccccc1CO

Procedure:
A solution of 2.30 g. of the above heptenoic acid in 100 ml. of ethanol is stirred with 5 g. of activated charcoal for 30 minutes and filtered. The filtrate is hydrogenated at atmospheric pressure in the presence of 143 mg. of platinum oxide. The solution is filtered, evaporated and recrystallized from toluene to yield 2-(6-carboxyhexyl)benzyl alcohol as white crystals having a melting point of 75°-77° C.
Reaction SMILES: [CH3:1][C:2]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)([C:9]([O:11]C(C)C)=[O:10])[C:3]([O:5]C(C)C)=[O:4].O1CCOCC1.O.[OH-].[Li+].Cl>C(OCC)(=O)C.O>[CH3:1][C:2]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)([C:9]([OH:11])=[O:10])[C:3]([OH:5])=[O:4]
Reactant: CC(C)OC(=O)C(C)(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(Cc1ccc([N+](=O)[O-])cc1)(C(=O)O)C(=O)O
Temperature: 50 °C
Reaction time: 22 h
Yield: 106.8 %

Procedure:
An 250-mL round bottom flask was charged with diisopropyl 2-methyl-2-(4-nitrobenzyl)malonate (1.15 g, 3.55 mmol), dioxane (20 ml) and water (10 ml). To this solution was then added lithium hydroxide monohydrate (0.74 g, 17.8 mmol). The resulting mixture was stirred at 50° C. for 22 h. After this time, the reaction mixture was cooled and acidified with 2N aqueous HCl (10 mL). The mixture was diluted with ethyl acetate (100 mL) and the organic layer washed with saturated sodium chloride (2×10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (0.96 g, 100%) as a white solid. MW=253.21. 1H NMR (DMSO-d6, 300 MHz) δ 13.04 (br s, 2H), 8.20-8.12 (m, 2H), 7.49-7.42 (m, 2H), 3.21 (s, 2H), 1.17 (s, 3H).
Reaction SMILES: [C:1](OC)(=O)[C:2]1[C:3](=[CH:8][C:9](=[CH:14][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])[C:4](OC)=O.[C:19]([O:27][CH3:28])(=[O:26])[C:20]1C=CC=C[CH:21]=1>>[CH:1]1[C:2]2[C:3](=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=2)[CH:4]=[CH:21][C:20]=1[C:19]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1ccc(C(=O)OC)c(C(=O)OC)c1
Reactant: COC(=O)c1ccccc1
Product: COC(=O)c1ccc2cc(C(=O)OC)ccc2c1

Procedure:
The procedure in Example 1 was repeated to carry out esterification except that mixed solvent containing 10.0 g of trimethyl trimellitate and 2.0 g of methyl benzoate was fed into the reactor. The results of analysis for the reaction product indicated 91.2 mol % yield of-the objective dimethyl 2,6-naphthalene-dicarboxylate based on 2,6-naphthalene-dicarboxylic acid; 96.0% efficiency of equilibrium achievement; and at most 1.0 mol % by-produced dimethyl ether based on methanol that was fed into the reaction system.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.CC(C)C(O)=O.[CH3:13][N:14]([CH3:17])[CH:15]=O>>[CH3:13][N:14]([CH3:17])[CH:15]=[N:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: Nc1nccs1
Reactant: CN(C)C=O
Solvent: CC(C)C(=O)O
Product: CN(C)C=Nc1nccs1

Procedure:
prepared by reaction of 2-aminothiazole with N,N-dimethylformamide dimethyl acetate. LC-MS: tR=0.40 min; [M+H]+=156.0.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)[CH3:2].[Li+].[CH2:9]([Si:11]([CH2:21]C)([CH2:19]C)[C:12]1[O:16][CH:15]=[C:14](C=O)[CH:13]=1)C.C(OC(=O)C)(=O)C>>[CH2:1]([C:13]1[CH:14]=[CH:15][O:16][C:12]=1[Si:11]([CH3:9])([CH3:19])[CH3:21])[CH3:2]
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)OC(C)=O
Product: CCc1ccoc1[Si](C)(C)C

Procedure:
Reacting 1-N-acetyl-20-(-N',N'-dimethyl)decyl diamine (prepare from 1,10-(-N',N'-dimethyl)decyl diamine with acetyl chloride) with lithium diisopropylamide, followed by 5-triethylsilyl-3-furaldehyde and acetic anhydride gives 4-[1-acetoxy-2(N-10-N',N'-dimethyl)aminodecyl)amido]ethyl-2-trimethylsilylfuran. Treatment of this intermediate with excess iodomethane followed by singlet oxygen oxidation gives r-[1-acetoxy-2-(N-10-(N',N',N'-trimethyl)aminodecyl)amido]ethyl-5-hydroxy-2(5H)-furanone.
Reaction SMILES: CC1(C)[O:6][C@H:5]([C:7]([N:9]2[CH2:14][CH2:13][C:12]([C:15]3[C:20]([F:21])=[CH:19][C:18]([N:22]4[CH2:26][C@H:25]([CH2:27][N:28]([C:36]5[CH:41]=[N:40][CH:39]=[CH:38][N:37]=5)C(OC(C)(C)C)=O)[O:24][C:23]4=[O:42])=[CH:17][C:16]=3[F:43])=[CH:11][CH2:10]2)=[O:8])[CH2:4][O:3]1.FC(F)(F)C(O)=O.O>ClCCl>[OH:6][C@@H:5]([CH2:4][OH:3])[C:7]([N:9]1[CH2:14][CH2:13][C:12]([C:15]2[C:20]([F:21])=[CH:19][C:18]([N:22]3[CH2:26][C@H:25]([CH2:27][NH:28][C:36]4[CH:41]=[N:40][CH:39]=[CH:38][N:37]=4)[O:24][C:23]3=[O:42])=[CH:17][C:16]=2[F:43])=[CH:11][CH2:10]1)=[O:8]
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CN(c2cc(F)c(C3=CCN(C(=O)[C@@H]4COC(C)(C)O4)CC3)c(F)c2)C(=O)O1)c1cnccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C([C@@H](O)CO)N1CC=C(c2c(F)cc(N3C[C@H](CNc4cnccn4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102 %

Procedure:
3-(4-(1-(2,2-Dimethyl-1,3-dioxolan-4(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)-(N-(t-butoxycarbonyl)pyrazin-2-ylaminomethyl)oxazolidin-2-one (400 mg, 0.65 mM) was dissolved in dichloromethane (4 ml) and treated with trifluoroacetic acid (4 ml) at ambient temperature. After stirring for 30 minutes at ambient temperature, water (0.8 ml) was added, and stirring continued for 2 hours. Solvent was removed, the residue dissolved in methanol (20 ml), and treated with aqueous ammonia to bring the pH to 8; solvent was removed, and the residue chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 5 to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (315 mg ). NMR (DMSO-d6) δ: 2.28 (br, 1H); 2.37 (br, 1H); 3.46 (m, 1H); 3.54 (m, 1H); 3.64 (t, 2H); 3.71 (m, 1H); 3.81 (dd, 1H); 4.10 (overlapping m, 4H); 4.36 (m, 1H); 4.71 (t, 1H); 4.89 (m, 1H); 5.01 (t, 1H); 5.85 (s, 1H); 7.32 (d, 2H); 7.43 (t, 1H); 7.70 (d, 1H); 1H); 7.99 (s, 1H). MS (ESP): 476 (MH+) for C22H23F2N5O5
Reaction SMILES: C(O)(=O)C.[C:5]([O:9][C:10]([N:12]1[CH2:24][CH2:23][C:15]2([N:19]=[C:18](SC)[NH:17][C:16]2=[O:22])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[F:25][C:26]([F:35])([F:34])[C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30].C(=O)(O)[O-].[Na+]>CC(N(C)C)=O>[C:5]([O:9][C:10]([N:12]1[CH2:24][CH2:23][C:15]2([N:19]=[C:18]([NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:27]([C:26]([F:25])([F:34])[F:35])[CH:28]=3)[NH:17][C:16]2=[O:22])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CSC1=NC2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(Nc1cccc(C(F)(F)F)c1)NC2=O
Yield: 50.5 %

Procedure:
Acetic acid (0.275 ml, 4.8 mmol) was added to a solution of 2-methylsulfanyl-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester (72 mg, 0.24 mmol) and m-trifluoromethylaniline (0.150 ml, 1.2 mmol) in DMA (1.0 ml), and the mixture was irradiated with microwaves at 150° C. for 20 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layers were combined, washed with saturated brine and dried over magnesium sulfate, and the solvent was then distilled off. The residue was purified by silica gel column chromatography to give 4-oxo-2-(3-trifluoromethyl-phenylamino)-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester (50 mg, 51%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1O)#[N:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:15]#[N:16])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: N#Cc1ccccc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccccc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-Boc-4-hydroxypiperidine (20 g, 99.35 mmol) and 2-cyanophenol (11.82 g, 99.35 mmol) were added to mixture of triphenylphosphine (26.06 g, 99.35 mmol) and di-tert-butyl azodicarboxylate (19.56 mL, 99.35 mmol) in tetrahydrofuran (800 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was taken up in hydrochloric acid (4M in dioxane, 300 mL). The reaction mixture was stirred at room temperature for 18 hours and was then concentrated in vacuo. The residue was partitioned between water and ethyl acetate and the aqueous layer was separated and washed with ethyl acetate (2×100 mL). The aqueous solution was then basified with 2M sodium hydroxide solution and then extracted with diethyl ether (3×100 mL). The combined organic solution was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a white solid in quantitative yield. LRMS ESI m/z 203 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9][CH:8]=2)=[CH:4][CH:3]=1.[Li]C(C)(C)C.CCCCC.CN([CH:33]=[O:34])C.C(=O)=O>C1COCC1.CCOCC>[CH3:1][C:2]1[S:6][C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:33]=[O:34])[CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(Br)cc32)s1
Reactant: CN(C)C=O
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C=O)cc32)s1
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.) solution of 1-(5-methyl-thien-2-yl)-3,4-dihydro-4,4-dimethyl-7-bromo-naphthalene (Compound F, 1.35 g, 4.1 mmol), in THF (20 mL) was added t-BuLi in pentane (1.7M solution, 3.5 mL, 5.95 mmol). The reaction was stirred for 15 minutes. and DMF (600 mg, 5.8 mmol) was added and dry-ice cooling was replaced with ice-water bath. The mixture was stirred at ambient temperature for 4 hours. The reaction mixture was diluted with ether (70 mL) and washed with water (5 mL), brine (5 mL) and dried with MgSO4. Solvent was removed by distillation. The product was purified by silicagel chromatography to afford the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]([CH2:4][C:5]1[C:6](=[O:17])[CH2:7][C@@H:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:9]=1)=[O:3].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:25]=1[O:3][C:2]([CH2:4][C:5]1[C:6](=[O:17])[CH2:7][C@@H:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:9]=1)=[O:1]
Reactant: O=C(O)CC1=C[C@H](OC2CCCCO2)CC1=O
Reactant: Oc1ccc2ccccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CC1=C[C@H](OC2CCCCO2)CC1=O)Oc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.4 %

Procedure:
5 g of 2-hydroxycarbonylmethyl-4(R)-tetrahydropyranyloxy-2-cyclopenten-1-one (21 mmol) obtained from Example 44, 2-naphthol (4.7 g, 32 mmol), dichloromethane (50 ml), and 0.2 g 4-(dimethylamine)pyridine were added together to a 50 ml dichloromethane solution containing 1,3-dicyclohexylcarbodiimide (7 g, 34 mmol). The reaction mixture was stirred at room temperature for about 4 hours. The precipitate was filtered off. The filtrate was washed with 20 ml of diluted hydrochloride solution, water, dried over anhydrous magnesium sulfate, filtered, and evaporated under vacuum. The residue was purified by flash chromatography on silica gel to give the titled compound as white solid (3.8g, 64%). MP: 75° C.; [α]D+29.3° (c 1.0, CH3CN); 1H-NMR (CDCl3/TMS): δ 7.10˜7.90 (m, 8H), 4.72˜5.11 (m, 2H), 3.90 (m, 1H), 3.60 (m, 3H), 2.89 (m, 1H), 2.35˜2.60 (m, 1H), 1.40˜1.92 (m, 6H).
Reaction SMILES: [N+:1]([O:4][CH2:5][C:6]([CH2:16][O:17][N+:18]([O-:20])=[O:19])([CH2:11][O:12][N+:13]([O-:15])=[O:14])[C:7](OC)=[O:8])([O-:3])=[O:2].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>C(Cl)(Cl)Cl>[CH2:21]([NH:28][C:7](=[O:8])[C:6]([CH2:16][O:17][N+:18]([O-:20])=[O:19])([CH2:11][O:12][N+:13]([O-:15])=[O:14])[CH2:5][O:4][N+:1]([O-:3])=[O:2])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)C(CO[N+](=O)[O-])(CO[N+](=O)[O-])CO[N+](=O)[O-]
Reactant: NCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccccc1)C(CO[N+](=O)[O-])(CO[N+](=O)[O-])CO[N+](=O)[O-]
Yield: 73 %

Procedure:
1 g (3.5 mmol) of methyl 3-nitryloxy-2,2-bis(nitryloxymethyl)propionate is heated for 3 hours at 130° C. with 3 ml of benzylamine and 100 mg of ammonium chloride and the mixture is cooled, taken up in 50 ml of chloroform and washed successively with water, with dilute hydrochloric acid, with aqueous bicarbonate solution and again with water. The crude product obtained after evaporation of the solvent is purified by column chromatography to give 3-nitryloxy-2,2-bis(nitryloxymethyl)propionic acid N-benzylamide (Tri-PA-NBzl amide) as a colourless oil. Yield: 73%. Elemental analysis: (C: conforms, H: conforms, N: conforms).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:12])[CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[CH2:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>C1C=CC=CC=1>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][NH:11][C:13]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[O:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NCC(O)c1cccc(O)c1
Reactant: C1CCCCC1
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: Oc1cccc(C2CNC3(CCCCC3)O2)c1

Procedure:
A suspension of 20 g. of 1-(3'-hydroxyphenyl)-2-amino-ethanol hydrochloride in 100 ml. of cyclohexane is heated, while stirring vigorously, in a three-necked flask equipped with a dropping funnel, water separator, and thermometer. Above a temperature of 80° C., up to 100 ml. of benzene are added dropwise in such a manner so that the water of reaction formed together with the benzene is distilled of azeotropically. The temperature of the flask contents is, at the finish, about 130° C. After cooling, the crystalline reaction product is separated off, digested with benzene, and collected on a frit. There is obtained 20.3 g. (71.5% of theory) of 2-(3'-hydroxyphenyl)-1-oxa-4-azospiro[4,5]decane hydrochloride. After recrystallization from isopropanol/ethyl acetate, the product is obtained in the form of colorless crystals with a melting point of 138° - 139° C.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH2:13]([O:15][C:16](=[O:39])[CH2:17][S:18][C:19]1[N:24]=[C:23]([NH:25][CH2:26][CH2:27][NH2:28])[C:22]([C:29](=[O:38])[NH:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:21][N:20]=1)[CH3:14].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:13]([O:15][C:16](=[O:39])[CH2:17][S:18][C:19]1[N:24]=[C:23]([NH:25][CH2:26][CH2:27][NH:28][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([N:1]=[N+:2]=[N-:3])=[CH:5][CH:6]=2)[C:22]([C:29](=[O:38])[NH:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)=[CH:21][N:20]=1)[CH3:14]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NCCN)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NCCNC(=O)c2ccc(N=[N+]=[N-])cc2)n1
Reaction time: 8 h
Yield: 15.6 %

Procedure:
4-Azidobenzoyl chloride (67 mg, 0.37 mmol) was added to a solution of [4-(2-aminoethylamino)-5-(4-fluorophenylcarbamoyl)pyrimidin-2-ylsulfanyl]acetic acid ethyl ester (145 mg, 0.37 mmol) in DMF (2.0 mL). DIPEA (100 μL, 0.55 mmol, 1.5 eq) was then added to the reaction mixture and the acylation was allowed to proceed overnight at ambient temperature. The reaction mixture was concentrated by rotary evaporation and purified using flash chromatography (4 g silica gel, 10 mL/min flow rate) to yield the titled product (31 mg, 16%) as a clear glass. 1H NMR: (d6-DMSO) δ 10.23 (s, 1H), 8.67 (m, 1H), 8.55 (s, 1H), 7.81 (d, 2H), 7.62 (m, 2H), 7.13 (m, 3H), 4.07 (q, 2H), 3.97 (s, 2H), 3.60 (m, 2H), 3.42 (m, 2H), 1.14 (t, 3H); HPLC: Rt=4.36 min; MS (ESI): m/z 537.31 (M−H)−; IR (KBr): 2126 cm−1.