Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].C([O-])([O-])=O.[K+].[K+].[CH3:12][C:13]([C:15](Cl)=[O:16])=[CH2:14]>C(#N)C.CO>[OH:5][CH:3]([CH3:4])[CH2:2][NH:1][C:15](=[O:16])[C:13]([CH3:14])=[CH2:12]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(O)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: C=C(C)C(=O)NCC(C)O
Temperature: 25 °C

Procedure:
3.75 g of 1-amino-2-propanol (0.05 mol) were placed in a three-necked flask, equipped with dropping funnel and gas inlet and gas outlet pipe, together with 30 ml of acetonitrile (anhydrous) and 13.79 g of K2CO3 (0.1 mol), and cooled to 0° C. in an ice bath. 6.18 g of methacryl chloride (0.06 mol), dissolved in 30 ml of acetonitrile, were added dropwise over 30 minutes with constant stirring and gentle passage of nitrogen. After stirring for a further 60 minutes with ice cooling, the mixture was allowed to warm to room temperature and was stirred for a further 30 minutes. The batch was filtered through a glass frit and the precipitate was discarded. The filtrate was concentrated in a rotary evaporator until a viscous oil was produced. This was dissolved in 30 ml of methanol and separated from any precipitate which appeared. The filtrate was again concentrated in a rotary evaporator and the residual amounts of the solvent were removed in a high vacuum. The yield was 6.66 g.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.O=P(Cl)(Cl)[Cl:15].C(=O)(O)[O-].[Na+].Cl>C1COCC1.C(OCC)(=O)C.CN(C=O)C>[Cl:15][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=2)[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc2nc(O)ccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Oc1ccc2nc(Cl)ccc2c1

Procedure:
A solution of quinoline2,6-diol (1 eq) in THF (0.25 M) was treated with POCl3 (1.1 eq) and a drop of DMF. Crushed ice was added to the reaction mixture and EtOAc was added and neutralized with a solution of sodium bicarbonate. The mixture was brought back to pH 6-7 with 1N HCl and ethyl acetate layer was separated, washed with water and brine to provide title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O([CH2:29][C:30]([F:33])([F:32])[F:31])S(C(F)(F)F)(=O)=O.ClCCl>CO>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:29][C:30]([F:33])([F:32])[F:31])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2N(CC(F)(F)F)C1=O

Procedure:
In an analogous manner to that described in Example 53 a), the alkylation of the (S)-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester with 2,2,2-trifluoroethyl triflate, yielded, after chromatography on silica gel using a 99:1-mixture of dichloromethane and methanol as the eluent, the title compound as a white foam; MS: m/e=360 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:25][C:24]2[C:4](=[CH:5][C:6]3[N+:11]([O-:12])=[N:10][C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[N:8][C:7]=3[CH:23]=2)[CH2:3]1.C[OH:27].C(Cl)Cl>>[CH3:1][CH:2]1[CH2:25][C:24]2[C:4](=[CH:5][C:6]3[N+:11]([O-:12])=[N:10][C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[N+:8]([O-:27])[C:7]=3[CH:23]=2)[CH2:3]1
Reactant: CO
Reactant: CC1Cc2cc3nc(NCCCN4CCOCC4)n[n+]([O-])c3cc2C1
Solvent: ClCCl
Product: CC1Cc2cc3c(cc2C1)[n+]([O-])c(NCCCN1CCOCC1)n[n+]3[O-]

Procedure:
H2O2 (70%, 0.72 mL, ca. 14.3 mmol) was added dropwise to a stirred solution of TFAA (2.0 mL, 14.3 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 98 (490 mg, 1.4 mmol) and TFA (0.55 mL, 7.1 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 98 (280 mg, 57%) and (ii) 1,4-dioxide 99 (88 mg, 17%) as a red solid: mp (MeOH/DCM) 161-163 DC; 1H NMR δ 8.30 (br s, 1H, NH), 8.08 (br s, 2H, H-5, H-9), 3.82 (br t, J=4.5 Hz, 4H, 2×CH2O), 3.58-3.63 (m, 2H, CH2N), 3.15-3.25 (m, 2H, CH2), 2.61-2.74 (m, 3H, CH, CH2), 2.57 (br t, J=6.1 Hz, 2H, CH2N), 2.47-2.53 (m, 4H, 2×CH2N), 1.83-1.90 (m, 2H, CH2), 1.18 (d, J=6.2 Hz, 3H, CH3); 13C NMR δ 155.2, 149.5, 145.2, 138.1, 129.5, 115.8, 111.7, 66.9 (2), 57.7, 53.8 (2), 41.6, 41.4, 40.4, 34.9, 24.5, 20.2. Anal. calcd for C18H25N5O3: C, 60.2; H, 7.0; N, 19.5. Found: C, 60.6; H, 7.0; N, 18.3%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15].C[Al](C)C.[NH:26](/[C:30](/[CH3:36])=[CH:31]\[C:32](OC)=[O:33])[C:27]([CH3:29])=O>C(Cl)Cl>[CH2:13]([O:12][CH2:11][CH2:10][N:9]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH3:21])[C:3]1[CH:4]=[CH:5][C:6]([N:8]2[C:32](=[O:33])[CH:31]=[C:30]([CH3:36])[N:26]=[C:27]2[CH3:29])=[CH:7][C:2]=1[F:1])[CH2:14][CH3:15]
Reactant: CCCOCCN(CCOCCC)c1ccc(N)cc1F
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: CCCOCCN(CCOCCC)c1ccc(-n2c(C)nc(C)cc2=O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To a solution of 2-fluoro-N1,N1-bis(2-propoxyethyl)benzene-1,4-diamine (0.50 g, 1.68 mmol) in CH2Cl2 (10 mL) was added trimethylaluminum (3.4 mL, 6.8 mmol, 2 M in toluene) slowly. The reaction mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (0.32 g, 2.02 mmol) in CH2Cl2 (2 mL). The reaction mixture was stirred at rt for 72 h, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as pale yellow oil (0.53 g, 78%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: OO.N.[CH2:4]([N:8]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([CH:17]([C:19]#[N:20])[OH:18])[N:10]=[C:9]1[N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)[C:5]#[C:6][CH3:7].S([O-])(O)=[O:35].[Na+]>CO>[CH2:4]([N:8]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([CH:17]([C:19](=[O:35])[NH2:20])[OH:18])[N:10]=[C:9]1[N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)[C:5]#[C:6][CH3:7]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(O)C#N)c1C(=O)OC
Reactant: O=S([O-])O
Agent: N
Agent: OO
Agent: [Na+]
Solvent: CO
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C(O)C(N)=O)c1C(=O)OC
Reaction time: 15 h

Procedure:
3.2 ml of 30% aqueous hydrogen peroxide and 3.2 ml of 28% aqueous ammonia solution were added to an 8 ml methanol solution of 0.274 g of t-butyl 4-[1-(2-butynyl)-4-(cyano-hydroxymethyl)-5-methoxycarbonyl-1H-imidazol-2-yl]piperazine-1-carboxylate at 5° C., and the mixture was stirred for 15 hours. 100 ml of a saturated sodium hydrogen sulfite solution was added to the solution, and the mixture was extracted twice with 100 ml of ethyl acetate. The organic layers were combined together. The combined organic layers were dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.039 g of the title compound was obtained from the fraction eluted with methanol-ethyl acetate (1:9).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:34][O:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[NH:2]=[C:1]([N:41]1[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][O:35][CH3:34])[CH2:39][CH2:40]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: COCCN1CCNCC1
Product: COCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 41.5 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2.2 equivalent of 1-(2-methoxyethyl)piperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:26][C@@H:27]1[C@@H:68]([O:69][C:70](=[O:72])[CH3:71])[C@H:67]([O:73][C:74](=[O:76])[CH3:75])[C@@H:66]([C:77]([O:79][CH3:80])=[O:78])[O:65][C@H:28]1[O:29][C:30]1[CH:35]=[CH:34][C:33]([C@@H:36]2[C@@H:39]([CH2:40][CH2:41][C@H:42]([O:50][C:51](=[O:53])[CH3:52])[C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)[C:38](=[O:54])[N:37]2[C:55]2[CH:60]=[CH:59][C:58]([C:61]#[C:62][CH2:63][OH:64])=[CH:57][CH:56]=2)=[CH:32][CH:31]=1)(=[O:25])[CH3:24].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:23]([O:26][C@@H:27]1[C@@H:68]([O:69][C:70](=[O:72])[CH3:71])[C@H:67]([O:73][C:74](=[O:76])[CH3:75])[C@@H:66]([C:77]([O:79][CH3:80])=[O:78])[O:65][C@H:28]1[O:29][C:30]1[CH:35]=[CH:34][C:33]([C@@H:36]2[C@@H:39]([CH2:40][CH2:41][C@H:42]([O:50][C:51](=[O:53])[CH3:52])[C:43]3[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=3)[C:38](=[O:54])[N:37]2[C:55]2[CH:60]=[CH:59][C:58]([C:61]#[C:62][CH:63]=[O:64])=[CH:57][CH:56]=2)=[CH:32][CH:31]=1)(=[O:25])[CH3:24]
Reactant: COC(=O)[C@H]1O[C@@H](Oc2ccc([C@@H]3[C@@H](CC[C@H](OC(C)=O)c4ccc(F)cc4)C(=O)N3c3ccc(C#CCO)cc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H]1O[C@@H](Oc2ccc([C@@H]3[C@@H](CC[C@H](OC(C)=O)c4ccc(F)cc4)C(=O)N3c3ccc(C#CC=O)cc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.5 h

Procedure:
Dess-Martin periodinane (33.0 mg, 0.077 mmol) was added to a solution of 10b (62.0 mg, 0.077 mmol) and pyridine (31.0 μL, 0.386 mmol) in dichloromethane (1 mL) at room temperature. After 30 min, the reaction mixture was poured into saturated aqueous sodium bicarbonate, and extracted twice with ethyl acetate. The combined organic extracts were washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 20-40% ethyl acetate/hexanes) afforded the title compound 10c.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:35])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH:29][C@H:30]([CH3:34])[C:31](O)=[O:32])=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:69]1([O:73][C:74]([N:76]2[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]2)=[O:75])[CH2:72][CH2:71][CH2:70]1>CN(C=O)C.ClCCl>[CH:69]1([O:73][C:74]([N:76]2[CH2:81][CH2:80][N:79]([C:31](=[O:32])[C@H:30]([NH:29][C:27]([C:18]3[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@H:8]4[C:6](=[O:7])[NH:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:35])[N:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:19]=3)=[O:28])[CH3:34])[CH2:78][CH2:77]2)=[O:75])[CH2:72][CH2:71][CH2:70]1
Reactant: C[C@@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reactant: O=C(OC1CCC1)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)N1CCN(C(=O)OC2CCC2)CC1
Reaction time: 1 h

Procedure:
To a solution of 100 mg (R)-2-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-propionic acid in 2 ml DMF were added 0.14 ml DIPEA, 78 mg HATU and 0.38 mg 1-cyclobutoxycarbonyl-piperazine. After stirring for 1 h it was diluted with dichloromethane and extracted with aqueous LiCl (4 w/w), aqueous NaHCO3 and 0.1 M HCl. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:5]([CH2:17][CH3:18])[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=[O:26])[CH:20]=1)[CH3:2].CO.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH2:17]([C:5]1[CH:6]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][OH:26])[CH:20]=1)[CH3:18]
Reactant: CCc1cc(OCCCS(C)(=O)=O)cc(CC)c1-c1cccc(C=O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(OCCCS(C)(=O)=O)cc(CC)c1-c1cccc(CO)c1
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A solution of 2′,6′-diethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-carbaldehyde (2.86 g, 7.64 mmol) in a mixed solvent of methanol (8 mL) and tetrahydrofuran (16 mL) was ice-cooled, sodium borohydride (90%, 0.161 g, 3.82 mmol) was added, and the mixture was stirred for 2 hr under nitrogen atmosphere. The reaction mixture was treated with 10% aqueous citric acid solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=40:80-80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (2.41 g, yield 84%) as colorless crystals.
Reaction SMILES: C(OCC[C:7]1([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH2:8]1)(=O)C.[CH2:18]1COC[CH2:19]1>>[CH2:7]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[CH2:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:19][CH:18]=1
Reactant: CC(=O)OCCC1(c2ccsc2)C=CC=CC1
Reactant: C1CCOC1
Product: c1ccc(CCc2ccsc2)cc1
Reaction time: 0.5 h
Yield: 34 %

Procedure:
1-(3-thienyl)phenylethyl acetate dissolved in THF (20 ml) was added carefully to dry liquid ammonia (300 ml). Lithium metal was added in small portions until the blue color persisted. The resulting reaction mixture was stirred for 30 min and the reaction was quenched by addition of solid ammonium chloride. The residue, after the complete evaporation of liquid ammonia, was dissolved in water (100 ml) and was extracted with methylene chloride (4×50 ml). The combined organic layers was dried over MgSO4 and filtered. Removal of the solvent gave a crude product, which was purified by column chromatography using hexane followed by mixture of ethyl acetate in hexane as eluent to give 3-phenethylthiophene (3.2 g, 34% yield) and 1-(3-thienyl)phenethyl acetate (starting material, 7g).
Reaction SMILES: [OH:1][CH:2]([CH:14]=[CH2:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].C(OC=C)(=O)C>C(OC(C)C)(C)C>[OH:1][C@@H:2]([CH:14]=[CH2:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: C=CC(O)CCCCCCCC(=O)OC
Solvent: C=COC(C)=O
Solvent: CC(C)OC(C)C
Product: C=C[C@H](O)CCCCCCCC(=O)OC
Temperature: 30 °C
Reaction time: 62 h
Yield: 30.4 %

Procedure:
To a solution of methyl 9-hydroxy-10-undecenate (500 mg) in diisopropyl ether (12 ml) was added vinyl acetate (323 μl) and Lipase PS (AMANO SEIYAKU Co., Ltd.) (500 mg) and then shaken for 62 hours at 30° C. The reaction mixture was filtrated and the filtrate was poured into ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate anhydride, and then evaporated under reduced pressure. The resulting product was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give (R)-methyl 9-hydroxy-10-undecenate (152 mg, 30.4%).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH2:6]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25](Cl)[C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][N:22]=2)=[CH:17][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[H][H]>O1CCOCC1.[Pd]>[CH2:6]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[CH:23][C:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][N:26]=2)=[CH:17][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: [H][H]
Reactant: CCCCCCCCOc1ccc(-c2ncc(C(=O)OCC)c(Cl)n2)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCCCCCOc1ccc(-c2ncc(C(=O)OCC)cn2)cc1
Yield: 111.5 %

Procedure:
Six (6) g of hydrogenation catalyst in which 5 % of Pd was carried on activated carbon and a small amount of sodium acetate were placed in an eggplant-shaped flask. After replacing the atmosphere inside the flask with nitrogen, 6 g of the above Compound D dissolved in 90 ml of dioxane was slowly dropped into the flask through a dropping funnel. After replacing the inside atmosphere with hydrogen with stirring, hydrogen was supplied from a gas reservoir. The reaction was continued until hydrogen absorption ceased. Thereafter the atmosphere was replaced with nitrogen, and the catalyst was removed by filtration. The solvent was recovered from the filtrate. Thus obtained crude product was purified by column chromatography and recrystallization to provide 6.1 g of purified 2-(4-octyloxyphenyl)-5- ethoxycarbonylpyrimidine (Compound E).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C@@H:9]([CH2:21][CH2:22][CH3:23])[C@@H:10]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:11]([OH:13])=[O:12].[C:24](OC=O)(=[O:26])C.Cl>N1C=CC=CC=1>[CH:24]([N:8]([O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[C@@H:9]([CH2:21][CH2:22][CH3:23])[C@@H:10]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:11]([OH:13])=[O:12])=[O:26]
Reactant: CC(=O)OC=O
Reactant: CCC[C@H](NOC1CCCCO1)[C@@H](CC1CCCCC1)C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: CCC[C@@H]([C@@H](CC1CCCCC1)C(=O)O)N(C=O)OC1CCCCO1
Reaction time: 6 h
Yield: 99.9 %

Procedure:
(2R,3S)-3-(2-Tetrahydropyranyloxyamino)-2-(cyclohexylmethyl)hexanoic acid (2.00 g, 6.11 mmol) is dissolved in 15 mL of pyridine. Formic acetic anhydride (1.08 mL, 12.2 mmol) is added at 25° C. The reaction is stirred for an additional 6 h and then is poured into 50 mL of cold 1 M hydrochloric acid. The organics are extracted with two 250-mL portions of dichloromethane. The combined organic phases are then washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated in vacuo to afford (2R,3S)-3-(formyl-2-tetrahydropyranyloxyamino)-2-(cyclohexylmethyl)hexanoic acid (2.17 g, 100% yield). APCI-MS m/z 378 (M+Na)+, 354 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:26])[C:11]2[C:16]([CH:17]=[CH2:18])=[CH:15][C:14]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:13][C:12]=2[CH3:25])=[CH:4][CH:3]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:26])[C:11]2[C:12]([CH3:25])=[CH:13][C:14]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:15][C:16]=2[CH2:17][CH3:18])=[CH:4][CH:3]=1
Reactant: C=Cc1cc(N2CCOCC2)cc(C)c1C(=O)NCc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: CCc1cc(N2CCOCC2)cc(C)c1C(=O)NCc1ccc(Cl)cc1
Reaction time: 2 h
Yield: 58.3 %

Procedure:
A solution of N-[(4-chlorophenyl)-methyl]-2-methyl-4-morpholin-4-yl-6-vinyl-benzamide (0.18 g, 0.48 mmol) in ethyl acetate is degassed and flushed with argon for 10 min followed by the addition of Pearlman's catalyst (20% Pd(OH)2/C, 0.08 g). The resulting mixture is stirred under an atmosphere of hydrogen for 2 h. After completion of reaction (monitored by NMR), the reaction mixture is filtered through a pad of celite. The filtrate is concentrated and the residue is purified by preparative HPLC affording N-[(4-chlorophenyl)-methyl]-2-ethyl-6-methyl-4-morpholin-4-yl-benzamide (example 12) (0.105 g, 0.28 mmol, 59%). [M+H]+ 373.2.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[C:18]3[N:19]=[C:20](Cl)[N:21]=[CH:22][C:17]=3[S:16][CH:15]=2)=[O:13])[CH:4]=[CH:3][CH:2]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[NH:34]C(C2C3N=C(ON4C5C=CC=CC=5N=N4)N=CC=3SC=2)=O)C=CC=1.N[C@@H]1CCCC[C@@H]1N>O1CCOCC1.C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[C:18]3[N:19]=[C:20]([NH:24][C@@H:33]4[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:32]4[NH2:34])[N:21]=[CH:22][C:17]=3[S:16][CH:15]=2)=[O:13])[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1cccc2cccnc12)c1csc2cnc(Cl)nc12
Reactant: O=C(Nc1cccc2cccnc12)c1csc2cnc(On3nnc4ccccc43)nc12
Agent: N[C@@H]1CCCC[C@@H]1N
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@H]1CCCC[C@H]1Nc1ncc2scc(C(=O)Nc3cccc4cccnc34)c2n1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of the mixture of 80 mg of 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid quinolin-8-ylamide and 2-(benzotriazol-1-yloxy)-thieno[3,2-d]pyrimidine-7-carboxylic acid quinolin-8-ylamide and 0.17 g (1.41 mmole) of cis-1,2-diaminocyclohexane (from step a) in Dioxane (3 mL) was stirred at 60° C. for overnight. The reaction were cooled down and diluted with CH2Cl2, washed with aqueous Na2CO3, brine, dried over anhydrous Na2SO4, concentrated and purified by flash chromatography (silica gel, 40 g, 0% to 30% MeOH (0.7 N) in CH2Cl2) to 40 mg of 2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid quinolin-8-ylamide as light yellow solid. MH+/Z=419.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([S:19][C:20]2[N:24]4[CH:25]=[C:26]([C:29](=O)[CH3:30])[CH:27]=[CH:28][C:23]4=[N:22][N:21]=2)=[CH:14][CH:13]=3)[CH2:4][CH2:3]1.[NH2:32][O:33][CH2:34][CH2:35][OH:36]>CO.Cl>[OH:36][CH2:35][CH2:34][O:33]/[N:32]=[C:29](/[C:26]1[CH:27]=[CH:28][C:23]2[N:24]([C:20]([S:19][C:15]3[CH:16]=[C:17]4[C:12](=[CH:13][CH:14]=3)[N:11]=[CH:10][C:9]([CH2:8][N:5]3[CH2:6][CH2:7][O:2][CH2:3][CH2:4]3)=[CH:18]4)=[N:21][N:22]=2)[CH:25]=1)\[CH3:30]
Reactant: CC(=O)c1ccc2nnc(Sc3ccc4ncc(CN5CCOCC5)cc4c3)n2c1
Reactant: NOCCO
Agent: Cl
Solvent: CO
Product: C/C(=N\OCCO)c1ccc2nnc(Sc3ccc4ncc(CN5CCOCC5)cc4c3)n2c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
To a solution of 1-(3-(3-(morpholinomethyl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone hydrochloride (79.3) (23 mg, 0.047 mmol) and 2-(aminooxy)ethanol (10.80 mg, 0.140 mmol) in MeOH (5 ml) was added 2 drops of HCl (2 N) by a 1-ml syringe to reach pH about 3 and the mixture was stirred in a sealed tube at 85° C. for 3 h. The mixture was evaporated to dryness and the residue was dissolved in water. The solution was neutralized by adding solid NaHCO3 until pH reached 9, then extracted by DCM (3×). The combined organic layers were washed by water again, dried over Na2SO4, filtered and evaporated. The residue was purified by preparative base HPLC (gradient eluent NB from 20/80 to 95/5. mobile phase A: NH4OH/CH3CN 0.04%; mobile phase B: NH4OH/H2O 0.04%). The desired fractions were collected, evaporated by BUCHI under 30 mbar at 35° C. to remove CH3CN. The remained solution was lyophilized to afford the title compound (12.2 mg, yield 54.2%).