Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.O.[NH:12]1[C:20](=[O:21])[C:18](=O)[C:16](=O)[NH:15][C:13]1=[O:14].B(O)(O)O>C(O)(=O)C>[CH:3]1[C:2]([Cl:1])=[C:7]([Cl:8])[CH:6]=[C:5]2[N:9]=[C:16]3[NH:15][C:13](=[O:14])[NH:12][C:20](=[O:21])[C:18]3=[N:10][C:4]=12
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Agent: OB(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2nc3cc(Cl)c(Cl)cc3nc2[nH]1
Yield: 99.9 %

Procedure:
A solution of 10 g of 4,5-dichloro-o-phenylenediamine, 9 g of alloxan hydrate, 1.5 g of boric acid and 250 ml of glacial acetic acid was stirred overnight at room temperature to obtain a brown-black solution which was filtered. The yellow-buff crystalline solid was well washed with water to obtain 15.9 g of 7,8-dichloro-alloxazine melting at >370° C. A solution of 2 g of 7,8-dichloro-alloxazine in 10 ml of concentrated sulfuric acid was slowly heated to 240° C. and held there for 10 minutes. The mixture was cooled and poured onto ice and the mixture was made alkaline with sodium hydroxide addition. The mixture was extracted several times with ether to obtain 0.73 g of 2-amino-6,7-dichloro-quinoxaline as an orange crystalline solid melting at 220° C.
Reaction SMILES: C([O-])(=O)C.[CH3:5][P:6](=[O:11])([O:9][CH3:10])[O:7][CH3:8].P(=O)([O-])[O-].C([Li])CCC.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][C:27](OC)=[O:28]>O1CCCC1.CCCCCC.C(O)(=O)C>[O:28]=[C:27]([CH2:26][C:22]1[S:21][CH:25]=[CH:24][CH:23]=1)[CH2:5][P:6](=[O:11])([O:9][CH3:10])[O:7][CH3:8]
Reactant: COC(=O)Cc1cccs1
Reactant: COP(C)(=O)OC
Agent: CC(=O)[O-]
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COP(=O)(CC(=O)Cc1cccs1)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 37.2 g (0.3 -thienyl)acetate mole) dimethyl methylphosphonate (Aldrich) in 400 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 194 ml of 1.6 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 23.4 g (0.15 mole) methyl 2-(2 -thienyl)acetate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 3.5 hours at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 6 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 75 ml water the aqueous phase extracted with 100 ml portions of chloroform (3a) the combined organic extracts were backwashed (50 ml H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 150-52° (<0.5 mm) to give 4.8 g dimethyl 2-oxo-3-(2-thienyl)propylphosphonate (2a).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O>>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Brc1ccc2c(n1)CCCC2
Reactant: OB(O)c1ccccc1F
Product: Fc1ccccc1-c1ccc2c(n1)CCCC2

Procedure:
Subsequently, Suzuki-Miyaura conditions were applied as in FIG. 8 using 2-bromo-5,6,7,8-tetrahydroquinoline and 2-fluorophenylboronic acid to obtain the 2-(2-fluorophenyl)-5,6,7,8-tetrahydroquinoline precursor as depicted in FIG. 10. After isolation and purification by flash chromatography, this viscous yellow-orange liquid solidifies at room temperature. In general, 2-(2-fluorophenyl)-pyridine derivatives wore prepared in high yields (over 92%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:26]2[CH2:27][CH2:28][CH:23]([C:20]3[CH:19]=[CH:18][C:17]([F:16])=[CH:22][CH:21]=3)[CH2:24][CH2:25]2)[N:3]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:5]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1Cl
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(Cl)nc(NCCO)nc1N1CCC(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4,6-dichloro-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 41a) was treated with 4-(4-fluoro-phenyl)-piperidine hydrochloride in dioxane in the presence of N-ethyl-diisopropyl-amine at room temperature to yield 4-chloro-6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as a white lyophilisate; MS: [M+H]+=376.
Reaction SMILES: C1(O[C:8](=[O:42])[O:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][N:29]([C:32]5[C:40]6[CH:39]=[CH:38][S:37][C:36]=6[CH:35]=[CH:34][CH:33]=5)[CH2:28][CH2:27]4)[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:41])C=CC=CC=1.[NH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1.O>C1COCC1>[S:37]1[CH:38]=[CH:39][C:40]2[C:32]([N:29]3[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:18]4[CH:19]=[C:20]5[C:15]([CH:14]=[CH:13][C:12](=[O:41])[N:11]5[CH2:10][O:9][C:8]([N:43]5[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]5)=[O:42])=[CH:16][CH:17]=4)[CH2:31][CH2:30]3)=[CH:33][CH:34]=[CH:35][C:36]1=2
Reactant: C1CCNCC1
Reactant: O=C(OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)Oc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)N1CCCCC1
Temperature: 25 °C
Reaction time: 84 h

Procedure:
To a solution (5 ml) of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester (0.44 g) synthesized in the same manner as in Example 7 in THF was added piperidine (0.76 ml), and the mixture was stirred at room temperature for 3.5 days. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by moderate-pressure basic silica gel column chromatography (hexane:ethyl acetate=1:0 to 1:1) to give the title compound (0.44 g, yield quantitative) as a colorless amorphous solid.
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([NH:14][CH2:15][C:16]([N:18]([C:20]2[C:21]([Cl:40])=[C:22]([C:36]([Cl:39])=[CH:37][CH:38]=2)[CH2:23][O:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[C:32]([CH3:35])[CH:31]=[CH:30]3)[CH3:19])=[O:17])=[O:13])=[CH:6][CH:5]=1)([OH:3])=O.[NH2:41][C:42]1[CH:47]=[N:46][CH:45]=[CH:44][N:43]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[Cl:40][C:21]1[C:20]([N:18]([CH3:19])[C:16](=[O:17])[CH2:15][NH:14][C:12](=[O:13])/[CH:11]=[CH:10]/[C:7]2[CH:8]=[N:9][C:4]([C:1](=[O:3])[NH:41][C:42]3[CH:47]=[N:46][CH:45]=[CH:44][N:43]=3)=[CH:5][CH:6]=2)=[CH:38][CH:37]=[C:36]([Cl:39])[C:22]=1[CH2:23][O:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[C:32]([CH3:35])[CH:31]=[CH:30]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(C(=O)O)nc4)c3Cl)c2n1
Reactant: Nc1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(C(=O)Nc5cnccn5)nc4)c3Cl)c2n1
Temperature: 25 °C
Reaction time: 36 h
Yield: 18.5 %

Procedure:
To a mixture of 8-[3-[N-[(E)-3-(6-carboxypyridin-3-yl)-acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (100 mg), 2-aminopyrazine (19.7 mg) and N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (43 mg) and 1-hydroxybenzotriazole (35 mg), and the mixture was stirred for 36 hours at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (methylene chloride--methanol) to give 8-[2,6-dichloro-3-[N-methyl-N-[(E)-3-[6-(2-pyrazinylcarbamoyl)-pyridin-3-yl]acryloylglycyl]amino]benzyloxy]-2-methylquinoline (21 mg) as an amorphous powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22].O>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][S:21]([CH:20]=[CH2:19])(=[O:23])=[O:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=CS(=O)(=O)NCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.4 %

Procedure:
A cold solution of 4-methoxybenzylamine (2 g) and triethylamine (2.8 ml) in dry dichloromethane (20 ml) at -78° was transferred under nitrogen to a solution of 2-chloroethanesulphonyl chloride (4.9 g) in dry dichloromethane (20 ml) at -78°. The mixture was stirred for 4 h whilst warming to room temperature and then refrigerated overnight. Water (ca 100 ml) was added and the organic layer separated. This was washed with hydrochloric acid (2N, 50 ml), water (50 ml) and brine (50 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane) to give the title compound as a powder (2 g) m.p. 68°-69°.
Reaction SMILES: [CH:1]12[O:6][CH:2]1[CH2:3][CH2:4][CH2:5]2.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[OH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccccc1
Reactant: C1CC2OC2C1
Product: OC1CCCC1Nc1ccccc1

Procedure:
Reaction of the cyclopentene oxide IIIa with an aniline under conditions well known in the art gives the N-(2-hydroxycyclopentyl)aniline IX which, when reacted with chlorosulfonic acid in a nonpolar organic solvent, e.g., methylene chloride, at 20°-30° C. followed by heating with a selected C1 to C3 -monoalkylamine (aqueous) or ammonium hydroxide (aqueous) at 100°-150° C. for 40-55 hours at elevated pressure (2-10 atm.), gives the diamine X. Reaction of diamine X with 2,2,2-trichloroethyl chloroformate, or equivalent N-blocking compound, at 20°-30° C. for 1-5 hours proceeds in the presence of an acid scavenger, e.g., triethylamine, to give the 2-(N-blocked amino) compound XI. Acylation of the N-blocked compound XI with the selected acid anhydride, ##STR44## by heating at 90°-120° C. for 12 to 30 hours gives the N-blocked anilide XII. Deprotection of the 2-amino function of the 2-N-blocked anilide XII is then accomplished by reaction with an N-deblocking agent such as metal dust in acid, e.g., zinc in acetic acid, in a polar organic solvent, e.g., methanol, at 20°-100° C. for 2 to 6 hours. Work-up, isolation and purification procedures are those standard in the art of organic chemistry.
Reaction SMILES: [CH3:1][C:2]([CH3:33])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([O:17]C(/C=C/C=C/C=C/C=C/C(O)=O)=O)[C@H:10]1[O:31][CH3:32])[CH3:8].C1CCC(NC2CCCCC2)CC1.[OH-].[Na+].CCOCC.CC(C)=CC[C@H]1O[C@@]1([C@@H]1[C@]2(OC2)CC[C@@H](OC(/C=C/C=C/C=C/C=C/C(O)=O)=O)[C@H]1OC)C>O>[CH3:32][O:31][C@@H:10]1[CH:11]([OH:17])[CH2:12][CH2:13][C@@:14]2([O:16][CH2:15]2)[CH:9]1[C@:6]1([CH3:8])[C@@H:5]([CH2:4][CH:3]=[C:2]([CH3:33])[CH3:1])[O:7]1
Reactant: CO[C@@H]1[C@H](OC(=O)/C=C/C=C/C=C/C=C/C(=O)O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Agent: C1CCC(NC2CCCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CO[C@@H]1C(O)CC[C@]2(CO2)C1[C@@]1(C)O[C@@H]1CC=C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The mixture of fumagillin DCHA salt (10 g, 0.022 mol), 800 mL of 0.1 N NaOH solution in H2O, and 800 mL of Et2O was stirred at RT for 3 h. LC/Mass showed that the fumagillin had been consumed. The mixture was treated with 400 mL of Ether and the layers were separated. The water layer was extracted with ether (3×500 mL) and the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified on a Biotage (EtOAc/hexanes) to provide ANT-2970 (4.1 g, 6.16 g theoretical, 66%). 1H NMR (300 MHz, CDCl3,) δ 1.21 (s, 3H), 1.65 (s, 3H), 1.75 (s, 3H), 1.90-2.05 (m, 3H), 2.18-2.26 (m, 2H), 2.34-2.39 (m, 2H), 2.55 (d, 1H), 2.59 (t, 1H), 2.92 (m, 1H), 3.48 (s, 3H), 3.62 (dt, 1H), 4.38 (m, 1H), 5.21 (m, 1H); LC-MS 283 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C)[C@H:9]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:10][CH2:11][C:12](OC)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:32](Cl)(=[O:34])[CH3:33].C1C[O:39]CC1>>[C:32]([O:34][CH2:12][CH2:11][CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:16][O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20])(=[O:39])[CH3:33]
Reactant: COC(=O)CC[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reactant: C1CCOC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)OCCC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of (S)-methyl 4-(tert-butoxycarbonyl(methyl)amino)-5-(tert-butyldimethylsilyloxy)pentanoate (111 mmol) and pyridine (150 mL, 1.662 mol) in THF (500 mL) was added acetyl chloride (150 mL, 333.2 mmol) at 0° C. The resulting mixture was stirred at RT for 1 h. The solvent was removed and the remaining residue was diluted with EtOAc. The organic mixture was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel column to give (S)-4-(tert-butoxycarbonylamino)-5-(tert-butyldimethylsilyloxy)pentyl acetate (39.6 g, 95%). LRMS (M+H+-Boc) m/z 276.2.
Reaction SMILES: [CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1CC=O)[CH3:2].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=C(CC)C=[O:33])C=CC=CC=1.[C:48]1([CH3:54])[CH:53]=[CH:52]C=[CH:50][CH:49]=1>>[CH2:49]([C:48](=[CH:53][CH2:52][C:4]1[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19])=[C:6]2[C:10](=[C:11]([CH3:12])[C:3]=1[CH2:1][CH3:2])[CH2:9][O:8][C:7]2=[O:13])[CH:54]=[O:33])[CH3:50]
Reactant: CCc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=O)C(=O)OC2
Reactant: Cc1ccccc1
Reactant: CCC(C=O)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCC(C=O)=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Reaction time: 15 h
Yield: 48 %

Procedure:
[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-acetaldehyde (90 mg, 0.269 mmol) and 2-(triphenyl-phosphorylidene)-butyraldehyde (98.4 mg, 0.296 mmol) in toluene (3 mL) were heated at 100° C. After 15 hours, a second portion of 2-(triphenyl-phosphanylidene)-butyraldehyde (98.4 mg, 0.296 mmol) was added and the reaction mixture was heated for additional 33 hours. After concentration, the residue was purified by silica gel chromatography to provide 50.3 mg (48%) of the desired product as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:29]3[C:28]4[CH2:27][CH2:26][NH:25][CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:36][CH2:37][CH2:38][CH:39]=[CH:40][C:41](O)=[O:42].C(N(C(C)C)CC)(C)C>ClCCl.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:29]3[C:28]4[CH2:27][CH2:26][N:25]([C:41](=[O:42])[CH:40]=[CH:39][CH2:38][CH2:37][O:36][CH:31]5[CH2:32][CH2:33][CH2:34][CH2:35][O:30]5)[CH2:24][C:23]=4[S:22][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C(O)C=CCCOC1CCCCO1
Reactant: Clc1cc(Nc2ncnc3sc4c(c23)CCNC4)ccc1OCc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(C=CCCOC1CCCCO1)N1CCc2c(sc3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.2 %

Procedure:
In a 100 ml rb flask were placed [3-chloro-4-(pyridine-2-ylmethoxy)-phenyl]-(5,6,7,8-tetrahydro-9-thia-1,3,7-triaza-fluoren-4-yl)-amine (2.0, 4.71 mmol), 5-(tetrahydro-pyran-2-yloxy)-pent-2-enoic acid (0.94 g, 4.71 mmol) and O-(Benzotriazol-1-yl)-N,N,N′,N′-tetrafluorobonate (1.81 g, 5.66 mmol) in anhydrous dichloromethane/THF (15 ml/15 ml) and cooled at 0° C. To this cooled suspension was slowly added diisopropylethylamine (1.83 g, 14.15 mmol) (2.5 ml) during 15 minute. Then the reaction mixture was warmed to room temperature and stirred at room temperature for 12 hours. The reaction mixture was concentrated at room temperature (no heating) to remove dichloromethane. To the residue was added water and precipitated grey-white solid was filtered and washed with water. The grey-white solid was further suspended in methyl alcohol, sonicated, filtered and dried to provide 2.26 g of grey-white solid. (80.0%). It will be carried to next step reaction without any purification. 1H-NMR (DMSO-d6) δ 8.593-8.575 (m, 1H), 8.391 (s, 1H), 8.191 (s, 1H), 7.872-7.868 (m, 1H), 7.769 (s, 1H) 7.571-7.498 (m, 2H), 7.369-7.329 (m, 1H), 7.236-7.214 (d, 1H), 6.779-6.607 (m, 2H), 5.274 (s, 2H), 4.946-4.835 (d, 2H), 4.572 (s, 1H), 3.928-3.730 (m, 2H), 3.504-3.402 (m, 2H), 3.313-3.204 (m, 4H), 1.673-1.434 (m, 8H). MS m/e 605.9 (M+H), RT=3.02 min
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:15]=[CH:14][C:13]=2[NH:22][CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:29]([O-:32])([O-])=[O:30].[K+].[K+].Cl[CH2:36][C:37]#N>CC(CC)=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:15]=[CH:14][C:13]=2[NH:22][CH2:23][C:24]2[N:25]=[N:26][N:27]([CH2:36][CH2:37][O:32][CH3:29])[N:28]=2)=[O:11])=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:15]=[CH:14][C:13]=2[NH:22][CH2:23][C:24]2[N:28]([CH2:36][CH2:37][O:30][CH3:29])[N:27]=[N:26][N:25]=2)=[O:11])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: N#CCCl
Reactant: C#CCOc1ccc(NCc2nnn[nH]2)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CCOc1ccc(NCc2nnn(CCOC)n2)c(C(=O)c2ccc(C(C)C)cc2)c1
Product: C#CCOc1ccc(NCc2nnnn2CCOC)c(C(=O)c2ccc(C(C)C)cc2)c1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A mixture of 1.04 g (2.77 mmol) (4-isopropyl-phenyl)-{5-prop-2-ynyloxy-2-[(1H-tetrazol-5-ylmethyl)-amino]-phenyl}-methanone, 0.85 g K2CO3, 0.25 g KI and 0.41 g (2.95 mmol) chloroacetonitrile and 40 ml ethyl methyl ketone is stirred at 60° C. for 20 h. The reaction mixture is cooled to room temperature and poured onto water and extracted with ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane/EtOAc=2:1) to afford 0.65 g of (4-isopropyl-phenyl)-(2-{[2-(2-methoxy-ethyl)-2H-tetrazol-5-ylmethyl]-amino}-5-prop-2-ynyloxy-phenyl)-methanone (yellow oil, title compound) and 0.3 g of (4-isopropyl-phenyl)-(2-{[1-(2-methoxy-ethyl)-1H-tetrazol-5-ylmethyl]-amino}-5-prop-2-ynyloxy-phenyl)-methanone (yellow oil).
Reaction SMILES: O.[C:2]([O:6][C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]([OH:16])=O)=[O:8])([CH3:5])([CH3:4])[CH3:3].CCN=C=NCCCN(C)C.Cl.[CH3:29][N:30]([CH3:32])[NH2:31].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:29][N:30]([CH3:32])[NH:31][C:14]([C@H:10]1[CH2:11][CH2:12][CH2:13][N:9]1[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:8])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: CN(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 79 %

Procedure:
H2O (0.0953 g, 0.71 mmol, 1.1 eq) was added to a stirred solution of (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.1615 g, 0.64 mmol, 1 eq) in 5 ml anhydrous CH2Cl2 at 0° C. under Ar. After 30 min EDCI.HCl (0.135 g, 0.71 mmol, 1.1 eq) was added. After 1 h 1,1-Dimethylhydrazine (0.058 ml, 0.046 g, 0.77 mmol, 1.2 eq) and DIPEA (0.33 ml, 0.25 g, 1.92 mmol, 3 eq) were added sequentially. The reaction was stirred at 0° C. to room temperature overnight. The solvent was removed in vacuo and the residue partitioned between EtOAc/water. The layers were separated. The aqueous layer was saturated with NaCl and extracted with EtOAc (×2). The combined EtOAc fractions were dried over Na2SO4. The inorganics were filtered off, and the solvent removed in vacuo. Purification via flash chromatography yielded 0.1489 g, 0.51 mmol, 79% yield) of (R)-tert-butyl 2-(2,2-dimethylhydrazinecarbonyl)pyrrolidine-1-carboxylate with some impurity. TFA (0.5 ml, 0.74 g, 6.49 mmol) was added to a stirred solution of (R)-tert-butyl 2-(2,2-dimethylhydrazinecarbonyl)pyrrolidine-1-carboxylate (0.045 g, 0.155 mmol, 1 eq) in anhydrous CH2Cl2 under Ar. After 1 h the solvent was removed in vacuo to generate (R)—N′,N′-dimethylpyrrolidine-2-carbohydrazide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH:10]=[C:11]([C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]3)=[CH:18][CH:17]=1)[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>COC(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][CH:11]([C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:26][CH2:27]3)=[CH:18][CH:17]=1)[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C2C=C(c3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)CC1CC2
Reactant: [H][H]
Agent: [Pd]
Agent: COC(C)O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(c1ccc(N3CCN(S(C)(=O)=O)CC3)cc1)C2
Yield: 91.4 %

Procedure:
3-[4-(4-Methanesulfonylpiperazin-1-yl)phenyl]-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester (0.83 g, 1.85 mmol) is solubilized in 93 ml of methoxyethanol. Palladium-on-carbon at 10% (0.395 g) is then added. The reaction medium is stirred for 5 h under 30 psi of hydrogen at 25° C. After filtration on Celite® and concentration, 0.76 g of expected 3-[4-(4-methanesulfonylpiperazin-1-yl)phenyl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester is obtained.
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][N:26]3[N:30]=[CH:31][CH:32]=[C:25]23)[CH2:6]1)(=O)C.C[O-].[Na+].C(O)(=O)C>CO.O1CCCC1>[SH:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[C@H:7]([CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][N:26]3[N:30]=[CH:31][CH:32]=[C:25]23)[CH2:6]1
Reactant: CC(=O)S[C@H]1C[C@@H](CN2CCCn3nccc32)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](S)C[C@H]1CN1CCCn2nccc21
Reaction time: 0.25 h
Yield: 89.2 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl) -2-{4,5,6,7-tetrahydropyrazolo [1,5-a]pyrimidin-4-yl}methylpyrrolidine (2.22 g) in a mixture of methanol (40 ml) and tetrahydrofuran (20 ml) was added 28% sodium methoxide in methanol solution (0.98 ml) under ice-cooling and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added acetic acid (0.29 ml) at the same temperature and the mixture was evaporated in vacuo. The resulting residue was dissolved in a mixture of ethyl acetate (100 ml) and water (30 ml). The organic layer was separated and washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and concentrated in vacuo to give (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl) -2-{4,5,6,7-tetrahydropyrazolo[ 1,5-a]pyrimidin-4-yl}methylpyrrolidine (1.80 g).