Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)Cl.[F:6][C:7]1[N:12]=[C:11]([C:13]2[N:14]([CH2:18][C:19]3[N:24]=[CH:23][N:22]4[CH:25]=[C:26]([C:28]([NH2:30])=O)[N:27]=[C:21]4[C:20]=3[CH2:31][CH2:32][CH3:33])[CH:15]=[CH:16][N:17]=2)[CH:10]=[CH:9][CH:8]=1>N1C=CC=CC=1>[F:6][C:7]1[N:12]=[C:11]([C:13]2[N:14]([CH2:18][C:19]3[N:24]=[CH:23][N:22]4[CH:25]=[C:26]([C:28]#[N:30])[N:27]=[C:21]4[C:20]=3[CH2:31][CH2:32][CH3:33])[CH:15]=[CH:16][N:17]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncn2cc(C(N)=O)nc12
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncn2cc(C#N)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
POCl3 (0.5 ml) is added to a solution of 128 (0.75 mmol) in pyridine (3 ml) and the mixture is stirred at room temperature overnight. The solvent is evaporated and the residue is purified by PTLC (5% MeOH in CH2Cl2) to afford the product (127); LC-MS, M+1 362.1; 1H-NMR (CDCl3) δ: 8.77 (s, 1H), 8.11 (dd, 1H), 8.03 (s, 1H), 7.82 (q, 1H), 7.19 (s, 1H), 7.18 (s, 1H), 6.82 (dd, 1H), 6.03 (s, 2H), 3.11–3.17 (m, 2H), 1.67–1.75 (m, 2H), 1.01 (t, 3H).
Reaction SMILES: C([N:4](CC)[CH:5]([CH3:7])[CH3:6])(C)C.OC(C(F)(F)F)=O.[N:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27]3([C:30]4[N:34]5[CH:35]=[C:36]([C:39]6[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=6)[C:42]([OH:44])=O)[CH:37]=[N:38][C:33]5=[N:32][CH:31]=4)[CH2:29][CH2:28]3)=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C1(N)CC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.CO>[CH:5]1([NH:4][C:42](=[O:44])[C:41]2[CH:45]=[CH:46][CH:47]=[C:39]([C:36]3[CH:37]=[N:38][C:33]4[N:34]([C:30]([C:27]5([C:23]6[CH:22]=[C:21]7[C:26](=[CH:25][CH:24]=6)[N:17]=[CH:18][CH:19]=[CH:20]7)[CH2:29][CH2:28]5)=[CH:31][N:32]=4)[CH:35]=3)[CH:40]=2)[CH2:7][CH2:6]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(NC1CC1)c1cccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N,N-Diisopropylethylamine (194 μL, 1.11 mmol) was added to a mixture of 3-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoic acid TFA salt (126.9 mg, 0.2 mmol), cyclopropylamine (17.1 mg, 0.3 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (97.3 mg, 0.22 mmol) in N,N-dimethylformamide (1.0 mL). The mixture was stirred at RT for 3 h, and was diluted with methanol (0.8 mL). The resulting solution was purified by RP-HPLC (pH=10) to give the desired product. LCMS: (M+H)=446.1.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)([CH3:9])[C:3]#[C:4][C:5]([F:8])([F:7])[F:6].FC(F)(F)C(C1C=CC(OC)=C(C=1)[CH:30]=[O:31])C(F)(F)F>>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH:11]=1)[CH:30]=[O:31])([CH3:1])[C:3]#[C:4][C:5]([F:8])([F:7])[F:6]
Reactant: COc1ccc(C(C)(C)C#CC(F)(F)F)cc1
Reactant: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1C=O
Product: COc1ccc(C(C)(C)C#CC(F)(F)F)cc1C=O

Procedure:
This compound was prepared from Compound 57 in the same manner of Compound 9.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:22][C:11]2[CH2:12][CH2:13][C:14]3[CH:15]=[N:16][C:17]([S:20][CH3:21])=[N:18][C:19]=3[C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1.CC(C)=O>[C:1]([O:5][C:6]([C:8]1[S:22][C:11]2=[CH:12][CH:13]=[C:14]3[C:19]([N:18]=[C:17]([S:20][CH3:21])[N:16]=[CH:15]3)=[C:10]2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2c(n1)-c1cc(C(=O)OC(C)(C)C)sc1CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CSc1ncc2ccc3sc(C(=O)OC(C)(C)C)cc3c2n1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
2-Methylsulfanyl-5,6-dihydro-thieno[2,3-h]quinazoline-8-carboxylic acid tert-butyl ester (9.0 g, 26.91 mmol) and DDQ (12.22 g, 53.82 mmol) were suspended/dissolved in dry dioxane (100 mL) and heated at reflux for 1 hour. Further DDQ (12.22 g, 53.82 mmol) was added and the resulting suspension was heated at reflux for 1.5 hours. After cooling to room temperature the mixture was concentrated under reduced pressure and then partitioned between EtOAc and saturated Na2CO3. The aqueous layer was further extracted with EtOAc (3×200 mL) and the combined organics were washed with saturated Na2CO3 (2×250 mL) and brine (1×200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The deep brown gum obtained was redissolved in hot acetone, silica (˜60 mL) was added and the resultant suspension was concentrated under reduced pressure. The solid obtained was subjected to column chromatography (gradient elution, 20-30% acetone in hexanes, ˜600 mL silica) giving a light brown solid (6.50 g, 73% yield)). MS (ES+) 333. δH (CDCl3) 1.7 (9H, s), 2.8 (3H, s), 7.8 (1H, d), 7.9 (1H, d), 8.8 (1H, s), 9.2 (1H, s)
Reaction SMILES: CO.C(N(CC)CC)C.[CH:10]1[C:20]2[CH:19]=[CH:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[C:15](=[O:25])[C:14]=2[CH:13]=[CH:12][C:11]=1[C:26](OC)=[O:27].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O.CCOCC>[CH:26]([C:11]1[CH:12]=[CH:13][C:14]2[C:15](=[O:25])[C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[CH:18]=[CH:19][C:20]=2[CH:10]=1)=[O:27]
Reactant: COC(=O)c1ccc2c(=O)c3ccccc3ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: O=Cc1ccc2c(=O)c3ccccc3ccc2c1
Reaction time: 16 h
Yield: 50 %

Procedure:
The acid chloride from Preparation 3A is converted to the methyl ester by reaction with methanol and triethylamine. 2.0 Gm. of methyl 5H-dibenzo[a,d]cyclohepten-5-one-2-carboxylate is dissolved in 200 ml. of ether and 0.5 gm. of lithium aluminium hydride is added. The reaction is refluxed for two hours then cooled and the excess reducing agent is decomposed by addition of water. The solution is filtered and to the filtrate is added 15.0 gm. of manganese dioxide. The mixture is stirred for 16 hours then filtered and evaporated to give a 50% yield of 2-formyl 5H-dibenzo[a,d] cyclohepten5-one, m.p. 149°-152° C.
Reaction SMILES: [CH:1](=O)[CH3:2].[NH:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][C:14]([C:16]1[NH:20][CH:19]=[N:18][C:17]=1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1)=[O:22])=[O:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>CN(C=O)C>[NH:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[NH:13][C:14]([C:16]1[NH:20][CH:19]=[N:18][C:17]=1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH2:1][CH3:2])[CH2:33][CH2:32]2)=[CH:26][CH:25]=1)=[O:22])=[O:15]
Reactant: CC=O
Reactant: O=C(Nc1ccc(OC2CCNCC2)cc1)c1nc[nH]c1C(=O)Nc1nc2ccccc2[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCC(Oc2ccc(NC(=O)c3nc[nH]c3C(=O)Nc3nc4ccccc4[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Acetaldehyde (0.088 g, 2.0 mmol) was weighed out into a dry 25 ml round bottom flask. N5-(1H-benzo[d]imidazol-2-yl)-N4-(4-(piperidin-4-yloxy)phenyl)-1H-imidazole-4,5-dicarboxamide (0.0446 g, 0.1 mmol) was added, followed by DMF (3.0 ml) of sodium triacetoxyborohydride (0.106 g, 0.5 mmol). The reaction mixture was stirred at room temperature over night (16 hours). The reaction mixture was then treated with 1 mL of 1N hydrochloric acid and concentrated under reduced pressure. The resulting crude material was purified by reverse phase HPLC (ammonium acetate/acetonitrile) to give N5-1H-benzimidazol-2-yl-N4-{4-[(1-ethylpiperidin-4-yl)oxy]phenyl}-1H-imidazole-4,5-dicarboxamide as an grey-white solid. 1H-NMR (DMSO-d6) 8.05 (s, 1H), 7.68 (d, 2H), 7.43 (s, br 2H), 7.05 (dd, 2H), 6.93 (d, 2H), 4.31 (m, 1H), 2.65 (m, 2H), 2.29 (q, 2H), 2.14 (m, 2H), 1.88 (m, 2H), 1.59 (m, 2H), 0.95 (t, 3H). MS (EI): 474 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19](=[CH2:21])[CH3:20].[I-].[K+]>CS(C)=O.O>[CH3:20][C:19]([CH2:21][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N+:9]([O-:11])=[O:10])=[CH2:18]
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=C(C)COc1cccc(C)c1[N+](=O)[O-]
Yield: 100.2 %

Procedure:
A mixture of 20.0 grams (0.130 mole) of 3-methyl-2-nitrophenol and 22.5 grams (0.163 mole) of potassium carbonate in 200 mL of dimethyl sulfoxide was stirred, and 15.3 mL (0.156 mole) of methallyl chloride was added dropwise during a five minute period. Upon completion of addition, 5.4 grams (0.033 mole) of potassium iodide was added in one portion. The reaction mixture was then stirred at ambient temperature for about 18 hours. After this time the reaction mixture was poured into 500 mL of water. The mixture was then extracted with two 200 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 27.0 grams of 2-methyl-3-(3-methyl-2-nitrophenoxy)-1-propene. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][CH:3]([Cl:5])Cl.[CH3:6][CH:7]([CH3:14])[CH2:8][C:9](=[O:13])C(O)=O>>[CH3:6][CH:7]([CH3:14])[CH2:8][C:9](=[O:13])[C:3]([Cl:5])=[O:2]
Reactant: COC(Cl)Cl
Reactant: CC(C)CC(=O)C(=O)O
Product: CC(C)CC(=O)C(=O)Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
30.4 g (264 mmol) of dichloromethyl methyl ether were added slowly to 34.4 g (264 mmol) of 4-methyl-2-oxovaleric acid and the mixture was heated to 50° C. (bath temp.). After stirring for 60 min. at this temperature, the crude product was fractionated on a vigreux column to give the 4-methyl-2-oxovaleryl chloride (b.p. 41° C./14 mbar). 14.7 g (99 mmol) of 4-methyl-2-oxovaleryl chloride were dissolved in 144 ml of tetrahydrofuran and the solution was added dropwise at 0° C. to a solution of 6.66 g (45 mmol) of the polyester of Example 6 (monomer unit 2c) and 7.83 g (99 mmol) of pyridine in 514 ml of tetrahydrofuran/dimethylformamide (5:1). The reaction mixture was stirred at 0° C. for additional 3 hours, then filtered through Hyflo Cel and the filtrate was concentrated under reduced pressure. The polymeric product was precipitated by dropwise addition of the resulting solution into 1000 ml of isopropyl ether/n-hexane (1.5:1). The precipitate was stirred several times in tetrahydrofuran/diethyl ether (1:2) and the insoluble part was removed by filtration. The resulting clear solution was added dropwise into 500 ml of isopropyl ether, the precipitate was redissolved in tetrahydrofuran and precipitated from 1000 ml of n-hexane giving a polyester having the monomer unit 11c.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)([OH:3])=O.Cl.[CH3:19][O:20][C:21]([C@H:23]1[CH2:28][CH2:27][C@H:26]([NH:29][CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:25][CH2:24]1)=[O:22].ON1C2C=CC=CC=2N=N1.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[B-](F)(F)F.CN1CCOCC1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([N:7]2[CH2:8][CH2:9][CH:4]([C:1]([N:29]([C@H:26]3[CH2:27][CH2:28][C@H:23]([C:21]([O:20][CH3:19])=[O:22])[CH2:24][CH2:25]3)[CH2:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:3])[CH2:5][CH2:6]2)=[CH:11][CH:12]=1)#[N:17]
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)cc1
Reactant: COC(=O)[C@H]1CC[C@H](NCCCc2ccccc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](N(CCCc2ccccc2)C(=O)C2CCN(c3ccc(C#N)cc3)CC2)CC1

Procedure:
A solution of 1.37 g of 4-carboxy-1-(4-cyanophenyl)-piperidine, 1.85 g of N-[trans-4-(methoxycarbonyl)-cyclohexyl]-N-(3-phenylpropyl)-amine-hydrochloride, 0.88 g of 1-hydroxy-(1H)-benzotriazole, 2.1 g of 2-[(1H)-benzotriazol-1-yl]-1,1,3,3-tetramethyl-uronium-tetrafluoroborate and 1.43 ml of N-methyl-morpholine in 40 ml of dimethylformamide is heated to 60° C. for 6 hours. After cooling, the mixture is diluted with sodium bicarbonate solution and the aqueous phase is extracted with ethyl acetate. The combined ethyl acetate phases are washed with dilute citric acid solution and then with a dilute sodium bicarbonate solution and dried and the solvent is removed under reduced pressure. The residue is chromatographed with methylene chloride and methylene chloride/methanol (8:2) over silica gel. Yield: 0.55 (19% of theory), Melting point: 145°-146° C.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]([CH2:13][CH3:14])[C@H:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7].[N+](CCCC)#[C-:16]>>[ClH:1].[ClH:1].[NH2:3][C@@H:4]([CH2:13][CH3:14])[C@H:5]([OH:12])[C:6]([NH:8][CH2:9][CH2:11][CH2:10][CH3:16])=[O:7]
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: [C-]#[N+]CCCC
Agent: Cl
Product: CCCCNC(=O)[C@@H](O)[C@@H](N)CC

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide dihydrochloride, Representative Procedure A, using 1-isocyanobutane in the third step (A3).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:31][CH2:32][CH:33]2[O:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[O:35][CH2:34]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:31][CH2:32][CH:33]2[O:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[O:35][CH2:34]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3O2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(CCC2COc3ccccc3O2)CC1
Reaction time: 16 h
Yield: 115.8 %

Procedure:
First 1.96 g (12.5 mmol) of piperidine-4-carboxylic acid ethyl ester and then 2.58 g (20 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 3.34 g (10 mmol) of 2-[2-(p-toluenesulphonyloxy)ethyl]-benzo-1,4-dioxan in 50 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 60° and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are washed with water and extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 3.80 g (99.2%) of crude product are obtained which are filtered over 190 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 3.7 g (96.6%) of 1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester are then obtained in the form of a yellow oil. The 1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 165°-168°.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([B:16]([OH:18])[OH:17])=[C:11]([CH3:19])[CH:10]=1)=[O:8])C.O.Cl>O1CCOCC1>[C:7]([C:9]1[CH:10]=[C:11]([CH3:19])[C:12]([B:16]([OH:17])[OH:18])=[C:13]([CH3:15])[CH:14]=1)([OH:8])=[O:6]
Reactant: CCOC(=O)c1cc(C)c(B(O)O)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C(=O)O)cc(C)c1B(O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
Lithium hydroxide monohydrate (0.089 g) was added to a mixture of 4-ethoxycarbonyl-2,6-dimethylphenylboronic acid (0.047 g), water (1 mL) and 1,4-dioxane (1 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (1.5 mL), and the solvent was evaporated under reduced pressure. The residue was washed with water to afford the title compound (0.023 g).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C@:5]12[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:46])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH2:45][C:29]4([CH2:32][C:31]([C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40])([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])[CH2:30]4)[CH:28]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1.B(F)(F)F.CCOCC.[NH:62]1[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1>C1C=CC=CC=1.[Cl-].[NH4+].Cl>[CH3:23][C@:20]12[C@@:19]3([CH3:24])[C@@H:10]([C@:11]4([CH3:46])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]3[CH2:45][C:29]5([CH2:30][C:31]([C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])([C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[O:40])[CH2:32]5)[CH:28]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:47]([C:50]([CH3:52])=[CH2:51])[CH2:48][CH2:49][C@:5]1([NH:4][CH2:3][CH2:2][N:62]1[CH2:67][CH2:66][O:65][CH2:64][CH2:63]1)[CH2:22][CH2:21]2
Reactant: C1COCCN1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCCl)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Agent: FB(F)F
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: CCOCC
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 2 h
Yield: 42.9 %

Procedure:
To a solution of diisopropyl 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-chloroethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylate (18 mg, 0.024 mmol) in a solution of borontrifluoride etherate in benzene (BF3.Et2O 2% by volume, 2 mL) at RT, was added morpholine (75 μl, 0.857 mmol) forming a cloudy mixture. The mixture was kept at 80° C. for 2 hours. The reaction was diluted with a saturated solution of ammonium chloride in 0.5 N HCl, organic materials were extracted into ethyl acetate (25 mL) three times. The organic extracts were combined and washed with a solution of sodium bicarbonate, the organic materials were concentrated, and purified by silica gel chromatography eluted with mixture of ethyl acetate and hexanes to give 8.1 mg (40%) of the desired product. MS: m/e 787.6 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 5.87 (s, 1H), 5.55-5.49 (m, 1H), 5.15-5.00 (m, 2H), 4.72 (br. s., 1H), 4.59 (br. s., 1H), 3.73 (t, J=4.4 Hz, 4H), 2.70 (s, 4H), 2.59 (d, J=2.3 Hz, 3H), 2.56-2.34 (m, 6H), 2.10 (dd, J=17.9, 6.7 Hz, 1H), 1.92-1.72 (m, 4H), 1.70 (s, 4H), 1.67-1.28 (m, 14H), 1.25 (dd, J=6.3, 5.0 Hz, 14H), 1.15 (m, 5H), 1.10 (m, 5H), 1.07 (m, 5H), 0.97 (s, 3H), 0.82 (s, 3H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[CH2:27][CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:41]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:46]=[CH:45][C:44]([CH2:47]Br)=[CH:43][CH:42]=1.C(O)(=O)CC>C1COCC1.CN1C(=O)N(C)CCC1.O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[C@H:27]([CH2:47][C:44]2[CH:45]=[CH:46][C:41]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)=[CH:42][CH:43]=2)[CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)C(=O)O1

Procedure:
In analogy with Example 5d), 5.55 g (13.5 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl]dihydrofuran-2-(3H)-one (preparation, see Example 1g)], dissolved in 20 ml of THF and 2.3 ml of DMPU, are deprotonated, at -70° C., with 27 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, and alkylated (1 h) with 5.0 g (20.2 mmol) of 4-biphenylylmethyl bromide (Salor, Milwaukee, U.S.A.) in 16 ml of THF. Protonating with 5 ml (67.4 mmol) of propionic acid and 5 ml of water, at -75° C., extracting and medium pressure chromatography (gradient: 30-50% ethyl acetate in toluene) results in the title compound: TLC Rf (Q)=0.15; tRet (II)=20.0 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH3:13])[CH2:11][O:10]1.[Na].[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:13])[CH2:11][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1
Reactant: c1nc[nH]n1
Reactant: CC(c1ccccn1)C1(c2ccc(F)cc2F)CO1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(c1ccccn1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 18 h

Procedure:
A mixture of the product of part (i) (2.20 g) and 1H-1,2,4-triazole sodium salt (1.53 g) in N,N-dimethylformamide (15 ml) was heated at 60° with stirring for 18 hours and then evaporated. Water (50 ml) was added and the mixture was extracted with ethyl acetate (3×50 ml). The combined extracts were dried (Na2SO4), evaporated and the residue was chromatographed on silica gel. Elution with ethyl acetate first gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair A, (0.93 g), m.p. 146°-148° (from ether).
Reaction SMILES: Cl.CCOCC.[CH2:7]([N:14]1[CH2:18][CH2:17][C:16]2([CH2:27][C:26](=[O:28])[C:25]3[C:20](=[CH:21][CH:22]=[C:23](/[CH:29]=[CH:30]/[C:31]([NH:33][O:34]C4CCCCO4)=[O:32])[CH:24]=3)[O:19]2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH2:7]([N:14]1[CH2:18][CH2:17][C:16]2([CH2:27][C:26](=[O:28])[C:25]3[C:20](=[CH:21][CH:22]=[C:23](/[CH:29]=[CH:30]/[C:31]([NH:33][OH:34])=[O:32])[CH:24]=3)[O:19]2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)C1)O2)NOC1CCCCO1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)C1)O2)NO
Reaction time: 1 h
Yield: 59.3 %

Procedure:
1 M HCl in Et2O (5 ml, 5 mmol) was added dropwise to a solution of (±)-(E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (172 mg, 0.37 mmol) in DCM (3 ml). After 1 h stirring a white solid precipitated, which was then filtered off, washed with DCM, dried under vacuum and collected to give 83 mg of (±)-(E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-N-hydroxy-acrylamide as its hydrochloride salt.
Reaction SMILES: F[C:2]1[C:11]([CH2:12][C:13]([OH:15])=[O:14])=[C:10]([F:16])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.OS(O)(=O)=O.[CH3:22]O>C(OCC)(=O)C>[CH3:22][O:15][C:13](=[O:14])[CH2:12][C:11]1[CH:2]=[C:3]2[C:8](=[CH:9][C:10]=1[F:16])[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: CO
Reactant: O=C(O)Cc1c(F)cc2ncccc2c1F
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc2cccnc2cc1F
Yield: 89.8 %

Procedure:
To a solution of (5,7-difluoro-quinolin-6-yl)-acetic acid (18.6 g, 83.4 mmol) in methanol (200 mL) was added conc. H2SO4 (4.7 mL, 87.0 mmol). The reaction mixture was concentrated to give a brown residue, which was diluted with 200 ml of ethyl acetate, washed with sat. aq. NaHCO3 and brine, then the organic layer was dried over anhydrous Na2SO4, and concentrated to give (7-fluoro-quinolin-6-yl)-acetic acid methyl ester as yellow solid (17.7 g, yield: 89.8%).