Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:7][CH2:6][C@H:4]([OH:5])[C@H:2]1[OH:3].Cl[C:9]1[N:18]=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[H-].[Na+].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN(C)C=O.C(OCC)(=O)C.O1CCOCC1>[OH:5][C@H:4]1[CH2:6][O:7][CH2:1][C@@H:2]1[O:3][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:18]=1
Reactant: C1CNCCN1
Reactant: O[C@H]1COC[C@@H]1O
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O[C@H]1COC[C@@H]1Oc1nc(N2CCNCC2)nc2ccccc12
Yield: 31.1 %

Procedure:
To a solution of 1,4-anhydro-L-threitol [manufactured by Aldrich Co., cf. J. Am. Chem. Soc., 74, 5336 (1952)] (7.34 g) and 2,4-dichloroquinazoline (5.00 g) in dimethylformamide (42 ml) is added gradually 60% sodium hydride (in oil) (1.92 g) with stirring under ice-cooling, and the mixture is stirred at room temperature for one hour and 10 minutes. The reaction mixture is diluted with ethyl acetate and washed with water 5 times. The ethyl acetate solution is dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The resulting residue is briefly purified by medium pressure liquid column chromatography [eluent, chloroform, (chloroform:methanol=200:1, v/v) ] to give an oily substance. The oily substance is dissolved in dioxane (35 ml), and the mixture is slowly added dropwise to a solution of piperazine (9.61 g) in dioxane (70 ml) with stirring at 50° C., and the mixture is stirred at the same temperature for 1.5 hour. The reaction mixture is diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The resulting solution is evaporated to dryness under reduced pressure, and the residue is purified by medium pressure column chromatography (eluent, chloroform:methanol=10:1, 5:1, v/v) to give 4-[(3S,4S)-(4-hydroxytetrahydrofuran-3-yl)oxy]-2-(1-piperazinyl)quinazoline (2.47 g) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N:11]1([CH2:16][C:17]#[N:18])[CH:15]=[N:14][CH:13]=[N:12]1.O>C1(C)C=CC=CC=1.N1CCCCC1>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[C:16]([N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[C:17]#[N:18]
Reactant: N#CCn1cncn1
Reactant: O=Cc1ccc(Cl)cc1Cl
Solvent: O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: N#CC(=Cc1ccc(Cl)cc1Cl)n1cncn1
Yield: 30 %

Procedure:
138.9 g (790 millimoles) of 2,4-dichlorobenzaldehyde, 76.7 g (710 millimoles) of 2-(1,2,4-triazol-1-yl)-acetonitrile and 1 g of piperidine in 1 l of toluene are heated at the boil under a water separator until 1 equivalent of water has been separated off. The mixture is then left to cool, and the precipitated crystals are filtered off under suction. They can be purified by recrystallization from toluene. 56.5 g (30% of theory) of 3-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-acrylonitrile of melting point 156°-160° C. are obtained.
Reaction SMILES: N#N.[C:3]1([C:9]2[CH2:10][CH2:11][CH:12](C(O)=O)[CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([N:19]([CH2:22]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:31])C=CC=CC=1>C1(C)C=CC=CC=1>[C:3]1([C:9]2[CH2:10][CH2:11][CH:12]([N:19]=[C:22]=[O:31])[CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C1C=C(c2ccccc2)CC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Agent: N#N
Solvent: Cc1ccccc1
Product: O=C=NC1C=C(c2ccccc2)CC1
Temperature: 90 °C
Yield: 74.4 %

Procedure:
To a N2 covered solution of 2.0 g (10.6 mmol) of the product from Step 2 in 40 ml of toluene was added 2.2 ml (15.9 mmol) of triethylamine followed by 3.4 ml (15.9 mmol) of diphenylphosphorylazide. After heating in an oil bath at 90° C. for 55 minutes. The reaction was allowed to cool and concentrated in vacuo. The residue was partitioned between 150 ml of 1:1 Et2O: hexane and 20 ml of pH 7 phosphate buffer. The aqueous layer was separated and washed once with 1:1 Et2O: hexane. The combined organic fractions were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed over 50 ml of silica gel (1% EtOAc: hexane) to yield 1.46 g (74.3%) of the titled product.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[CH:19][C:18]4=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[N:26][NH:27][CH:28]=5)[N:17]4[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>>[CH3:43][S:44]([N:26]1[CH:25]=[C:24]([C:23]2[N:17]3[C:18]([CH:19]=[N:20][C:15]([NH:14][C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)[CH:9]=4)=[N:16]3)=[CH:21][CH:22]=2)[CH:28]=[N:27]1)(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCN(c2cccc(Nc3ncc4ccc(-c5cn[nH]c5)n4n3)c2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc(Nc3ncc4ccc(-c5cnn(S(C)(=O)=O)c5)n4n3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
To a solution of [3-(4-Methyl-piperazin-1-yl)-phenyl]-[7-(1H-pyrazol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine (1.00E2 mg, 0.267 mmol) and N,N-Diisopropylethylamine (48.8 uL, 0.280 mmol) in N,N-Dimethylformamide (12.1 mL, 156 mmol) was added Methanesulfonyl chloride (21.7 uL, 0.280 mmol). The reaction was stirred at rt overnight. LCMS 453.0 (M+H), HPLC rt=2.180 min, 97% purity. The reaction mixture was concentrated to remove DMF, diluted with CH2Cl2, and washed with sat'd aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated. Product was isolated as a yellow solid (29 mg, 24%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.30 (s, 1H), 9.03 (s, 1H0, 8.97 (s, 1H), 8.71 (s, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.29 (d, J=4.6 Hz, 1H0, 7.22 (dd, J=8.3 Hz, 8.3 Hz, 1H), 7.05 (bm, 1H), 6.95 (d, J=4.6 Hz, 1H), 6.63 (dd, J=8.4 Hz, 1.4 Hz, 1H0, 3.62 (s, 3H), 3.12-3.10 (m, 4H), 2.45-2.43 (m, 4H), 2.21 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[C:14]([O:24][CH3:25])=[C:15]([CH:21]=[CH:22][CH:23]=3)[O:16][CH2:17][C:18](O)=[O:19])[N:10]([C:26](=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[OH:33])[N:9]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:68][CH:69]([CH3:72])[CH2:70][OH:71]>CN(C=O)C.CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[C:14]([O:24][CH3:25])=[C:15]([CH:21]=[CH:22][CH:23]=3)[O:16][CH2:17][C:18]([NH:68][CH:69]([CH3:72])[CH2:70][OH:71])=[O:19])[N:10]([C:26](=[O:34])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[OH:33])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1c(OCC(=O)O)cccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1ccccc1O
Reactant: CC(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1c(OCC(=O)NC(C)CO)cccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1ccccc1O
Reaction time: 16 h

Procedure:
To {3-[5-(4-Fluoro-phenyl)-3-(2-hydroxy-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-acetic acid (0.27 mmol) in dry DMF (0.5 mL) is added HATU (1.35 mmol), DIEA (0.45 mL, 2.7 mmol) and 2-amino-propan-1-ol. The mixture is kept at ambient temperature for 16 hours. The residue is diluted with EtOH (1 mL). Purification of the mixture by preparative LC/MS (30-100% MeCN/H2O) gives 2-{3-[5-(4-fluoro-phenyl)-3-(2-hydroxy-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-N-(2-hydroxy-1-methyl-ethyl)-acetamide. 1H NMR (400 MHz, CDCl3) δ 11.2 (s, 1H), 8.53 (m, 1H), 7.73 (m, 2H), 7.6 (s, 1H), 7.44 (t, J=8.4 Hz, 1H), 7.15 (t, J=8 Hz, 2H), 6.9-7.1 (m, 5H), 4.58 (s, 2H), 4.14 (m, 1H), 4.06 (s, 3H), 3.69 (m, 1H), 3.59 (m, 1H), 2.1 (bs, 2H), 1.23 (m, 3H); LC/MS (ES+): 540.1 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:5]([NH:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1)=[O:10])=[O:6].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:5]([NH:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([O:16][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:12]1)=[O:10])=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCC(=O)N1CCC(O)C1)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CCN(C(=O)CNC(=O)c2ccc(Cl)c(Cl)c2)C1
Temperature: 50 °C
Yield: 0.1 %

Procedure:
A suspension of 3,4-dichloro-N-[2-(3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-benzamide (2.00 g, 6.30 mol) in pyridine (40 mL) was heated at about 50° C. until the solution became homogenous and then cooled to about 0° C. Methanesulfonyl chloride (1.46 mL, 18.9 mol) was added to the reaction mixture dropwise. The reaction mixture was allowed to warm to room temperature and then concentrated in vacuo. The residue was dissolved in DCM (50 mL), washed with brine (2×50 mL), and the organic portion was separated, dried over MgSO4, filtered, and concentrated in vacuo to give methanesulfonic acid 1-[2-(3,4-dichloro-benzoylamino)-acetyl]-pyrrolidin-3-yl ester (2.46 g, 98%) as a brown oil which was used in subsequent reactions without further purification. RP-HPLC (Table 1, Method n) Rt 1.76 min; m/z: (M+H)+ 395.
Reaction SMILES: S(Cl)(Cl)=O.COC1C=CC=CC=1CCC(O)=O.COC1C=CC=CC=1CCC(Cl)=O.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][C:41]([N:43]=[C:44]=[S:45])=[O:42].[CH3:46][O:47][C:48]1[CH:49]=[C:50]2[C:55](=[CH:56][C:57]=1[O:58][CH3:59])[N:54]=[CH:53][CH:52]=[C:51]2[O:60][C:61]1[CH:67]=[CH:66][C:64]([NH2:65])=[CH:63][CH:62]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:46][O:47][C:48]1[CH:49]=[C:50]2[C:55](=[CH:56][C:57]=1[O:58][CH3:59])[N:54]=[CH:53][CH:52]=[C:51]2[O:60][C:61]1[CH:62]=[CH:63][C:64]([NH:65][C:44]([NH:43][C:41](=[O:42])[CH2:40][CH2:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[O:32][CH3:31])=[S:45])=[CH:66][CH:67]=1
Reactant: COc1ccccc1CCC(=O)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: COc1ccccc1CCC(=O)Cl
Agent: COc1ccccc1CCC(=O)O
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1ccccc1CCC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3-(2-methoxyphenyl)propanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3-(2-methoxyphenyl)propanoyl isothiocyanate was prepared using the resultant 3-(2-methoxyphenyl)propanoyl chloride as a starting compound according to the description of the literature. 3-(2-Methoxyphenyl)propanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (60 mg, yield 74%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:3]=1.[NH2:21][C@H:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][O:12][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[CH:10]=[CH:11][C:2]([NH:21][C@H:22]2[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23]2)=[N:3]3)=[CH:15][CH:16]=1
Reactant: Fc1ccc(COc2cccc3nc(Cl)ccc23)cc1
Reactant: N[C@@H]1CCc2ccccc21
Product: Fc1ccc(COc2cccc3nc(N[C@@H]4CCc5ccccc54)ccc23)cc1

Procedure:
2-Chloro-5-(4-fluoro-benzyloxy)-quinoline (100 mg, 0.347 mmol) and (R)-1-aminoindane (138 mg, 1.04 mmol) were stirred in a sealed tube at 150° C. overnight. The reaction mixture was purified by flash chromatography on silica gel (heptane/ethyl acetate 75:25). The title compound was obtained as a light brown oil (68 mg, 51%), MS: m/e=385 (M+H+).
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C@H:6]1[O:11][CH:10]=[C:9](OC(C)=O)[C@@H:8]([O:16][C:17]([CH3:19])=[O:18])[C@@H:7]1[O:20][C:21]([CH3:23])=[O:22])=[O:3].N1C=CC=CC=1.Cl.C(Cl)(Cl)Cl.[OH:35][NH2:36]>>[C:17]([O:16][C@H:8]1[C@H:7]([O:20][C:21](=[O:22])[CH3:23])[C@@H:6]([CH2:5][O:4][C:2](=[O:3])[CH3:1])[O:11][CH2:10][C:9]1=[N:36][OH:35])(=[O:18])[CH3:19]
Reactant: CC(=O)OC[C@H]1OC=C(OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1OCC(=NO)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 24 h

Procedure:
[litt=F. W. Lichtenthaler and P. Jarglis. Tetrahedron Letters 21 (1980) 1425-1428] To a solution of 2,3,4,6-tetra-O-acetyl-2-hydroxy-D-glucal (7.90 g, 23.9 mmol) in dry pyridine (40 mL, 496 mmol), HONH2, HCl (5.85 g, 84.2 mmol) was added and the mixture was stirred for 24 h. The reaction mixture was concentrated and dissolved in CHCl3 (300 mL). The organic phase was washed with 1 M HCl (aq., 75 mL), sat. aq. NaHCO3 (75 mL) and H2O (75 mL), dried (MgSO4) and evaporated to a syrup of 2, (7.19 g, 99%). By addition of a small volume of EtOH the product crystallysed (4.43 g, 61%, mp 86-89° C.). Two recrystallisations from toluene afforded an analytical sample: mp 90-92° C.; [α]D−39.4° (c 1.3, CHCl3) [Lit. mp 89-90° C., [α]D−39.0 (c 0.4, CHCl3)].
Reaction SMILES: [OH:1][CH:2]([C:5]1[C:13]2[C:8](=[N:9][C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH3:32])=[O:30])=[CH:24][CH:23]=3)=[N:11][C:12]=2[N:14]2[CH2:20][CH:19]3[O:21][CH:16]([CH2:17][CH2:18]3)[CH2:15]2)[N:7]([CH2:33][CH3:34])[N:6]=1)CO>C(Cl)Cl.C1COCC1>[CH2:33]([N:7]1[C:8]2=[N:9][C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH3:32])=[O:30])=[CH:24][CH:23]=3)=[N:11][C:12]([N:14]3[CH2:15][CH:16]4[O:21][CH:19]([CH2:18][CH2:17]4)[CH2:20]3)=[C:13]2[C:5]([CH:2]=[O:1])=[N:6]1)[CH3:34]
Reactant: CCn1nc(C(O)CO)c2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)NC)cc3)nc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCn1nc(C=O)c2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)NC)cc3)nc21
Reaction time: 1 h

Procedure:
To a solution of 1-{4-[3-(1,2-dihydroxyethyl)-1-ethyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}-3-methylurea (158 mg) (0.34 mmol) in DCM:THF (2:1) (6.0 mL) was added excess sodium NaIO4 on silica gel and the mixture was stirred for 1 hr. at room temperature. The insoluble material was filtered off and the organics were dried (Na2SO4) and filtered off through Magnesol and then concentrated in vacuo. to give a white solid that was collected with diethyl ether to give 110 mg. MS m/z=436.2.2 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[N+:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)([O-:33])=[O:32]>>[CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1[C:37]1[CH:38]=[CH:39][C:34]([N+:31]([O-:33])=[O:32])=[CH:35][CH:36]=1)[CH3:2]
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2ccc([N+](=O)[O-])cc2)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 4-nitrophenylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C21H19N2O5 (M+H): 379.1216. Found 379.1270
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:14]=[C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[S:12][C:4]=2[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C(N(C(C)C)CC)(C)C.[N+:31]([C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37])([O-:33])=[O:32]>O1CCCC1>[CH2:10]([O:9][C:7]([N:5]1[C:4]2[S:12][C:13]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])=[CH:14][C:3]=2[C:2]([NH:1][C:36](=[O:37])[C:35]2[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=2[N+:31]([O-:33])=[O:32])=[N:6]1)=[O:8])[CH3:11]
Reactant: CCOC(=O)n1nc(N)c2cc(C(=O)OC(C)(C)C)sc21
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1nc(NC(=O)c2ccccc2[N+](=O)[O-])c2cc(C(=O)OC(C)(C)C)sc21
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
To a solution of 5-tert-butyl 1-ethyl 3-amino-1H-thieno[2,3-c]pyrazole-1,5-dicarboxylate (500 mg, 1.606 mmol) and diisopropylethylamine (DIEA, 0.824 mL, 4.818 mmol) in tetrahydrofuran (THF, 20 mL) at 0° C., 2-nitro-benzoyl chloride (0.318 mL, 2.409 mmol) was added. The reaction mixture was kept at the same temperature for 10 minutes then allowed to reach room temperature and let react overnight. The solvent was removed under vacuum, the residue was dissolved in dichloromethane (DCM) and washed with a 10% solution of acetic acid (AcOH), water, saturated NaHCO3 and brine. The crude was purified on silica gel (eluant dichloromethane/methanol 96/4) yielding 512 mg (69%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12](=[O:21])[O:13][C@@H:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C@@H:7]1[CH2:6][CH2:5]2.Br[CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:15]1([C@H:14]2[C@@H:7]3[CH2:6][CH2:5][C:4]4[C:9]([N:8]3[C:12](=[O:21])[O:13]2)=[CH:10][CH:11]=[C:2]([O:1][CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:3]=4)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1O[C@@H](c2ccccc2)[C@@H]2CCc3cc(O)ccc3N12
Reactant: FC(F)(F)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1O[C@@H](c2ccccc2)[C@@H]2CCc3cc(OCCCC(F)(F)F)ccc3N12
Temperature: 90 °C
Yield: 66.7 %

Procedure:
To a solution of 0.65 g (2.3 mmol) of cis-(±)-7-hydroxy-3-phenyl-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one in 15 ml of dimethylformamide are added 0.66 g (3.5 mmol) of 1-bromo-4,4,4-trifluorobutane and 0.64 g (4.6 mmol) of potassium carbonate. The mixture is heated for 4 hours at 90° C. and is then diluted with ethyl acetate and washed with water. The organic phase is then dried over sodium sulphate and concentrated under reduced pressure, and the residue is chromatographed on a column of silica, with cyclohexane containing 20% of ethyl acetate. After trituration in diisopropyl ether, 0.60 g of product is obtained.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH:8]1[C:17]2[C:11]([CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:10][C:9]=1[CH2:18][C:19]1[CH:20]=[C:21]([C@@H:25]2[O:33][C@H:32]([CH2:34][OH:35])[C@@H:30]([OH:31])[C@H:28]([OH:29])[C@H:26]2[OH:27])[CH:22]=[CH:23][CH:24]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:26]([O:27][C@@H:26]1[C@@H:28]([O:29][C:28](=[O:29])[CH3:30])[C@H:30]([O:31][C:32](=[O:33])[CH3:34])[C@@H:32]([CH2:34][O:35][C:5](=[O:7])[CH3:6])[O:33][C@H:25]1[C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][C:9]2[CH:10]=[C:11]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=[CH:12]3)[CH:8]=2)[CH:20]=1)(=[O:27])[CH3:25]
Reactant: OC[C@H]1O[C@@H](c2cccc(Cc3cc4cccccc-4c3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](c2cccc(Cc3cc4cccccc-4c3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 15 h

Procedure:
Acetic anhydride (0.3 ml) was added to a solution of (1S)-1,5-anhydro-1-[3-(azulen-2-ylmethyl)phenyl]-D-glucitol (0.24 g) in pyridine (5.0 ml) at room temperature and the mixture was stirred for 15 hours. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with 10% aqueous solution of hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate, and saturated brine in that order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-(azulen-2-ylmethyl)phenyl]-D-glucitol (0.34 g).
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])[CH2:3]1.[ClH:26].[N:27]1([C:32](N)=[NH:33])C=CC=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[ClH:26].[F:25][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:24])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:8]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:32](=[NH:27])[NH2:33])[CH2:14][CH2:13]2)=[O:9])[CH2:3]1
Reactant: N=C(N)n1cccn1
Reactant: O=C(OCC1CCNCC1)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N=C(N)N1CCC(COC(=O)[C@](O)(c2ccccc2)[C@@H]2CCC(F)(F)C2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.3 %

Procedure:
To a solution of 14 mg of piperidin-4-ylmethyl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate in 0.020 ml of anhydrous dimethylformamide, 6.3 mg of 1H-pyrazole-1-carboxamidine hydrochloride and 0.008 ml of diisopropylethylamine were added, followed by stirring at room temperature for 12 hours. The reaction liquid was condensed and dried to solid. Thus obtained crude product was purified on silica gel column chromatography (eluent: chloroform/methanol=10/1), to provide 11 mg of the title compound in the form of a colorless solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[C:22]2([CH2:27][OH:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1.CI.[CH3:31]COC(C)=O>CN(C=O)C>[F:3][C:4]1[C:5]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[C:22]2([CH2:27][O:28][CH3:31])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2cc(OC)ncc2F)c(C2(CO)CCCC2)c1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COCC1(c2cc(C(=O)OC)ccc2-c2cc(OC)ncc2F)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (20.0 mg 60% in oil, 522 μmol) in DMF (1.0 mL) was slowly added methyl 4-(5-fluoro-2-methoxypyridin-4-yl)-3-(1-(hydroxymethyl)cyclopentyl)benzoate (75.0 mg, 209.0 μmol) at 0° C. The resulting mixture was stirred at room temperature for 30 minutes and then methyl iodide (296.0 mg, 2087 μmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature overnight. EtOAc (60.0 mL) was added, and the organic layers were washed with brine (20×2 mL) and dried over MgSO4. The product was obtained after filtration and solvent removal. The product was used in the next step. MS ESI (pos.) m/e: 374.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C@H:7]2[CH2:12][CH2:11][CH2:10][C@H:9]([C:13]3[S:17][C:16]([NH:18][C:19](=[O:27])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:15][N:14]=3)[CH2:8]2)=[N:4][N:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37](O)=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C)C=O.O>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([NH:1][C:2]1[S:6][C:5]([C@H:7]2[CH2:12][CH2:11][CH2:10][C@H:9]([C:13]3[S:17][C:16]([NH:18][C:19](=[O:27])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[N:15][N:14]=3)[CH2:8]2)=[N:4][N:3]=1)=[O:38]
Reactant: COc1ccccc1CC(=O)O
Reactant: Nc1nnc([C@H]2CCC[C@H](c3nnc(NC(=O)Cc4ccccn4)s3)C2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccccc1CC(=O)Nc1nnc([C@H]2CCC[C@H](c3nnc(NC(=O)Cc4ccccn4)s3)C2)s1

Procedure:
A solution of N-(5-((1S,3S)-3-(5-amino-1,3,4-thiadiazol-2-yl)cyclohexyl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)acetamide (50 mg, 0.12 mmol), 2-(2-methoxyphenyl)acetic acid (31.0 mg, 0.19 mmol), HATU (71.0 mg, 0.19 mmol), and N-ethyl-N-isopropylpropan-2-amine (29.0 mg, 0.22 mmol) in N,N-dimethylformamide (5 ml) was stirred at 50 degree overnight. The mixture was poured into water (10 ml), the precipitate was filtered to give the crude product. The crude product was purified by a standard method to give the desired product.