Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:21]/[NH:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)/[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: NNC(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1ccccc1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 53.2 %

Procedure:
1-(5-Chloro-2-hydroxyphenyl)ethanone (100 mg, 0.586 mmol) and benzohydrazide (80 mg, 0.586 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound (90 mg) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 7.95 (m, 2H), 7.67-7.62 (m, 2H), 7.56 (m, 2H), 7.35 (dd, 1H, J=2.4 & 8.8 Hz), 6.95 (d, 1H, J=8.4 Hz), 3.35 (s, 3H). ESI-MS: 289.0 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([N+:22]([O-])=O)=[C:11]([CH:21]=2)[O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1>CO.[Pd]>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:8]=[CH:9][C:10]([NH2:22])=[C:11]([O:12][CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[CH:21]=2)[CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1OCCN1CCOCC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCOCC2)cc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.9 %

Procedure:
A solution of 106B (50 mg, 0.15mmol) in MeOH (10 mL) was degassed for 10 minutes and then treated with 10% Pd on activated carbon (15 mg). The reaction mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. The catalyst was removed by filtration and the filtrate was concentrated to give 4-morpholino-2-(2-morpholinoethoxy)aniline (35 mg, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH2:15][CH:14]([C:16]([NH2:18])=[O:17])[O:13][N:12]=2)[CH2:7][CH2:6]1.C([O-])(=O)C.[Na+].II.[O-]S([O-])(=S)=O.[Na+].[Na+]>ClC1C=CC=CC=1.CCOC(C)=O.O>[Br:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:15]=[C:14]([C:16]([NH2:18])=[O:17])[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: NC(=O)C1CC(N2CCC(Oc3cc(F)ccc3Br)CC2)=NO1
Agent: CC(=O)[O-]
Agent: II
Agent: O=S([O-])([O-])=S
Solvent: Clc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(N2CCC(Oc3cc(F)ccc3Br)CC2)no1
Reaction time: 0.08 h

Procedure:
To a stirred suspension of 3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-4,5-dihydroisoxazole-5-carboxamide (2.3 g, 5.96 mmol) and sodium acetate (1.3 g, 15.85 mmol) in chlorobenzene (15 mL) was added iodine (2 g, 7.88 mmol). The mixture was heated at reflux temperature for 3 h. After cooling, a solution of Na2S2O3, water and EtOAc were added. The mixture was stirred for 5 min and filtered through celite to remove the insoluble material. The organic layer was then separated, washed with brine, dried (Na2SO4) and concentrated. The residue was triturated with Et2O to give the title compound as light brown powder.
Reaction SMILES: N1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=C[CH:12]=1>B(F)(F)F>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:12]=[CH:2][CH:3]=1
Reactant: c1ccc2ncccc2c1
Reactant: c1ccncc1
Agent: FB(F)F
Product: c1ccc2ccccc2c1

Procedure:
Naphthalene was polymerized at a temperature of from 200° to 400° C. in the presence of a HF.BF3 catalyst to obtain a pitch which has an optical anisotropy of 100 volume % as observed under a polarization microscope, an optically anisotropic structure of a "rough flow type", a glass transition temperature width (ΔTg) of 52° C., a quinoline-insoluble content of 18.5% by weight, a Mettler softening point of 250° C. and an elemental composition as analyzed of C: 94.8 wt % and H: 5.2 wt %. This pitch was finely pulverized. Then, 200 ml of pyridine was added to 5 g of this pitch, and extraction was conducted at 100° C., followed by filtration with a 0.05 μm membrane filter to remove the pyridine-insoluble matter. Then, from the soluble matter, pyridine was removed to obtain a pyridine-soluble pitch.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:15][C:14]2[C:13](=O)[C:12]3[C:11]([C:17]([O-])=[O:18])=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.O.[NH2:22][NH2:23].C(O)(=O)C.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[CH3:1][C:2]1([CH3:20])[CH2:3][CH2:4][C:5]2[NH:6][C:7]3[C:12]4=[C:11]([C:17](=[O:18])[NH:22][N:23]=[C:13]4[C:14]=2[CH2:15]1)[CH:10]=[CH:9][CH:8]=3
Reactant: NN
Reactant: CC1(C)CCc2[nH]c3cccc(C(=O)[O-])c3c(=O)c2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: CC1(C)CCC2=C(C1)c1n[nH]c(=O)c3cccc(c13)N2
Temperature: 130 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
A solution of 7,7-dimethyl-9-oxo-5,6,7,8,9,10-hexahydroacridine-1-carboxylate (3.3 g, 11.6 mmol) and hydrazine hydrate (15 mL) in DMA (22 mL) was heated at 110° C. for 1.5 h, acetic acid (30 mL) was added and the mixture was stirred at 130° C. for another 4 hours. The reaction mixture was cooled to room temperature, and aqueous NaHCO3 (80 ml) was added to the mixture, filtered. And the filtered cake was washed with water (50 mL) and methanol (30 mL) alternatively multiple times. The solvent was removed in vacuo to give 10,10-Dimethyl-8,9,10,11-tetrahydro-2H-pyridazino[5,4,3-kl]acridin-3(7H)-one as a yellow solid (1.50 g, 49%). 1H NMR (DMSO-d6) δ 11.71 (s, 1H), 10.36 (s, 1H), 7.59-7.63 (m, 1H), 7.42-7.44 (m, 1H), 7.25-7.27 (m, 1H), 2.49-2.52 (m, 2H), 2.10 (s, 2H), 1.55 (m, 2H), and 1.00 (s, 6H). MS (ESI) m/e [M+1]+268.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH3:24][CH:25]([NH:28][C:29]1[CH2:33][S:32][C:31](=[O:34])[N:30]=1)[C:26]#[CH:27].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:33]2/[C:29]([NH:28][CH:25]([CH3:24])[C:26]#[CH:27])=[N:30][C:31](=[O:34])[S:32]/2)[CH2:8][CH2:7]1
Reactant: C#CC(C)NC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C#CC(C)NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 75 °C
Reaction time: 6 h
Yield: 36.3 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.91 g) in 2-propanol (20 mL) were added 4-(but-3-yn-2-ylamino)-1,3-thiazol-2(5H)-one (1.42 g) and piperidinium acetate (834 mg). The reaction mixture was stirred at 75° C. for 6 hr and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.0 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH:21]([N:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[CH3:22])=[C:19]([O:36][CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH:21]([N:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)[CH3:22])=[C:19]([O:36][CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1C(C)N1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2c(c1C(C)N1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of tert-butyl (Z)-4-(1-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethyl)piperazine-1-carboxylate (0.10 g, 0.21 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was azeotroped twice with toluene under reduced pressure. The residual solid was added with water, and then the mixture was adjusted to pH 9 with saturated aqueous sodium hydrogencarbonate, and extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[1-(piperazin-1-yl)ethyl]benzofuran-3(2H)-one (0.080 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[N:17]=[CH:16][CH:15]=[N:14]2)=[CH:9][CH:8]=1.CCN(CC)CC.[CH:26]1([CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=2)[CH2:28][CH2:27]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]([S:37]([C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH:26]2[CH2:27][CH2:28]2)=[CH:36][CH:35]=1)(=[O:39])=[O:38])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[N:14]=[CH:15][CH:16]=[N:17]2)=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(OCC2CC2)cc1
Reactant: COC(=O)CNCc1ccc(-n2nccn2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN(Cc1ccc(-n2nccn2)cc1)S(=O)(=O)c1ccc(OCC2CC2)cc1
Reaction time: 1 h

Procedure:
To a solution of 79.5 g (323.2 mmol) of the compound of stage 3.2, 80.9 ml (581.6 mmol) of Et3N and 1.97 g (16.1 mmol) of DMAP in 1000 ml of CH2Cl2, a solution of 99.6 g (404 mmol) of 4-cyclopropylmethoxy-benzenesulfonyl chloride in 150 ml of CH2Cl2 is added and stirred for 60 min. at 0–5° C. After stirring for additional 18 h at r.t., the reaction mixture is quenched with ice water and extracted with CH2Cl2. The combined extracts are washed with H2O, brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by CC on silica gel (n-Hexane:AcOEt=4:1˜2:1) to give the title compound as colorless solid; 1H-NMR (400 MHz, CDCl3): 0.35–0.45 (m, 2H), 0.65–0.75 (m, 2H), 1.25–1.35 (m, 1H), 3.58 (s, 3H), 3.87 (d, 2H, J=7.04 Hz), 3.94 (s, 2H), 4.52 (s, 2H), 6.99 (d, 2H, J=7.04 Hz), 7.37 (d, 2H, J=8.56 Hz), 7.81 (s, 2H), 7.82 (d, 2H, J=7.04 Hz), 8.02 (d, 2H, J=8.56 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:20]=[CH:19][C:18]3[N:17]([CH3:21])[C:16]4[CH2:22][CH:23]5[NH:27][CH:26]([C:15]=4[C:14]=3[C:13]=2C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[ClH:35]>C(OCC)C>[ClH:35].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]2[CH2:22][CH:23]4[NH:27][CH:26]([C:15]3=2)[CH2:25][CH2:24]4)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccc(C#N)cc4)ccc31)C1CCC(C2)N1
Agent: Cl
Solvent: CCOCC
Product: Cn1c2c(c3cc(S(=O)(=O)c4ccc(C#N)cc4)ccc31)C1CCC(C2)N1

Procedure:
The product of step A was subjected to Boc-deprotection with 2 M HCl in diethyl ether following the procedure of Example 28, step B. The crude material was purified by flash column chromatography (SiO2, 80:18:2 chloroform/methanol/ammonium hydroxide) and the product treated directly with 1.25 M HCl in methanol (0.5 mL). After concentration in vacuo the residue was lyophilized to give 2-(4-cyanophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (38 mg, 49%, AUC HPLC >99%) as a white solid: mp 216-218° C.; 1H NMR (D2O, 300 MHz) δ 8.23 (d, J=1.5 Hz, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.78 (dd, J=8.4, 1.8 Hz, 2H), 7.62 (dd, J=8.7 Hz, 1.5 Hz, 1H), 7.49 (d, J=8.7 Hz, 1H), 5.23 (d, J=4.8 Hz, 1H), 4.52-4.57 (m, 1H), 3.51 (s, 3H), 3.46 (dd, J=17.7, 4.5 Hz, 1H), 3.01 (d, J=17.4 Hz, 1H), 2.20-2.48 (m, 3H), 1.78-1.94 (m, 1H); APCI MS m/z 378 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.[N:25]1([CH2:31][C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[CH2:35][NH2:36])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:24][C:12]1[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:36][CH2:35][C:34]3[CH:37]=[CH:38][CH:39]=[C:32]([CH2:31][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:33]=3)=[O:23])=[CH:19][CH:20]=2)=[CH:14][C:9]([NH:8][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:7])=[CH:10][CH:11]=1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Reactant: NCc1cccc(CN2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCc2cccc(CN3CCOCC3)c2)cc1
Yield: 64.2 %

Procedure:
5′-(3-Furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (50 mg, 0.156 mmol), 3-(morpholin-4-ylmethyl)benzylamine (32 mg, 0.156 mmol), HATU (59.2 mg, 0.156 mmol), HOBT (21 mg, 0.156 mmol) and DIPEA (27 μl, 0.156 mmol) in DMF (2 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with water (2×30 ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum and the residue chromatographed on a silica flash column eluting with DCM/methanoltriethylamine (96:2:2). Concentration of the product fractions under vacuum gave N-(6-methyl-4′-{[(3-morphlin-4-ylmethylbenzyl)amino]carbonyl}-1,1′-biphenyl-3-yl)-3-furamide (51 mg, 81%). NMR; δH [2H6]-DMSO 9.92,(1H, s), 9.11,(1H, t), 8.35,(1H, s), 7.97,(2H, d), 7.78,(1H, t), 7.66,(1H, dd), 7.60,(1H, d), 7.46,(2H, d), 7.28,(3H, m), 7.22,(1H, d), 7.17,(1H, d), 6.98,(1H, m), 4.50,(2H, d), 3.54,(4H, m), 3.43,(2H, s), 2.33,(4H, m), 2.19,(3H, s). LCMS: retention time 2.40 min, MH+510.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1.CN(C)[CH:23]=[O:24]>O1CCCC1.O.C(O)(=O)C>[Cl:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([Br:13])[C:15]=1[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: Clc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Product: O=Cc1c(Cl)cccc1Br
Temperature: 0 °C

Procedure:
A 1.6 molar solution of butyllithium in hexanes was placed in a three-neck flask equipped with a stirrer, addition funnel, low-temperature thermometer and nitrogen inlet tube at 0° C. A solution of diisopropyl amine in anhydrous tetrahydrofuran was added dropwise. The resulting solution was stirred at 0° C. for ten minutes, then cooled to −78° C. Upon cooling, a solution of 1-bromo-3-chlorobenzene in anhydrous tetrahydrofuran was added dropwise. The reaction was stirred at −78° C. for one hour. Anhydrous dimethylformamide was added. The solution was allowed to slowly warm to room temperature, followed by the addition of acetic acid and water. The aqueous mixture was extracted with ether twice and the ether layers were separated. The combined ether layers were successively washed with aqueous hydrochloric acid and brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with hexanes-ethyl acetate to yield 2-chloro-6-bromobenzaldehyde.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:34]3[N:33]=[CH:32][N:31]=[C:29]([NH2:30])[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:35][CH2:36][CH2:37][OH:38])[C@@H:21]1[OH:39])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)Cl.[C:45](Cl)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[NH4+].[OH-]>N1C=CC=CC=1.CCOC(C)=O.O>[Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:34]3[N:33]=[CH:32][N:31]=[C:29]([NH:30][C:45](=[O:52])[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:35][CH2:36][CH2:37][OH:38])[C@@H:21]1[OH:39])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](OCCO)[C@@H]1O)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](OCCO)[C@@H]1O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
Dried 5′-O-t-butyldiphenylsilyl-2′-O-(hydroxyethyl)-adenosine (24 g, 43.7 mmol) was dissolved in anhydrous pyridine (500 mL) under inert atmosphere, and trimethylchlorosilane (27.7 mL, 218 mmol) was added at 0° C. The reaction was allowed to warm to ambient temperature, stirred for 1 hour, then cooled to 0° C. Benzoyl chloride (25.3 mL, 218 mmol) was added dropwise, then the reaction was allowed to warm to ambient temperature and stirred for 4 hours after which it was cooled to 0° C. and water (100 mL) was added. After stirring for 10 minutes aqueous 30% NH4OH (100 mL) was added, and the reaction was stirred at 0° C. for 1 hour. The solvent was evaporated in vacuo to give a residue which was dissolved in EtOAc (1 L), and the resulting solution was washed with water (200 mL) twice, then with brine (100 mL). The organic solution was dried with MgSO4, and the solvent was evaporated in vacuo to give a residue. The residue was purified by column chromatography using CH2Cl2—EtOAc—MeOH, 70:27:3, to give the title compound as a solid (23.77 g, 83%).
Reaction SMILES: C[N:2](C)CCCN=C=NCC.[F:12][C:13]([F:24])([F:23])[CH:14]1[CH2:19][CH2:18][CH:17]([C:20](O)=[O:21])[CH2:16][CH2:15]1.ON1C2C=CC=CC=2N=N1.N>CN(C=O)C.C(Cl)Cl.CO.C(OCC)(=O)C>[F:12][C:13]([F:24])([F:23])[CH:14]1[CH2:19][CH2:18][CH:17]([C:20]([NH2:2])=[O:21])[CH2:16][CH2:15]1
Reactant: O=C(O)C1CCC(C(F)(F)F)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: N
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)C1CCC(C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 66.7 %

Procedure:
At 0° C. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.90 g, 15.29 mmol) was added to a solution of 4-(trifluoromethyl)cyclohexanecarboxylic acid (3.0 g, 15.29 mmol) and 1-hydroxybenzotriazole (2.1 g, 15.29 mmol) in DMF (10 ml) and DCM (10 ml). The reaction mixture was stirred for 20 min at 0° C. A saturated solution of ammonia in methanol (17 ml) was added. The reaction mixture was stirred for 16 hours, while it was warming up to room temperature. It was diluted with ethyl acetate (100 ml) and washed with a 10% aqueous solution of sodium hydrogen sulphate (100 ml). The aqueous phase was extracted with ethyl acetate (2×80 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica, using DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 1.99 g of 4-trifluoromethylcyclohexanecarboxylic acid amide.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:8][CH:7]=2.[N:31]1([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32]1>C(#N)C>[CH3:20][S:17]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=1)[C:3]([CH2:2][N:39]1[CH2:40][CH2:41][CH:36]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:37][CH2:38]1)=[C:12]2[C:13]([O:15][CH3:16])=[O:14])(=[O:18])=[O:19]
Reactant: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Reactant: C1CCN(C2CCNCC2)C1
Solvent: CC#N
Product: COC(=O)c1c(CN2CCC(N3CCCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
An orange suspension of methyl 3-(bromomethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.068 g, 2.126 mmol) and 4-(1-pyrrolidinyl)piperidine (0.492 g, 3.19 mmol) in acetonitrile (14.17 ml) was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The residue was absorbed onto florisil and was purified via column chromatography (ISCO, 12 g silica, 5-10% methanol/dichloromethane) to give methyl 6-(methylsulfonyl)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.14 g, 88% yield). MS (m/z) 576.2 (M+H+).
Reaction SMILES: Br[C:2]1[C:6]2[O:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:9][C:10](=[O:11])[C:5]=2[S:4][CH:3]=1.O1CCOCC1.C(N(C(C)C)CC)(C)C.CC1(C)C(C)(C)[O:37][BH:36][O:35]1>ClCCl.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:15]1[CH2:16][CH2:17][N:12]([C:8]2[O:7][C:6]3[C:2]([B:36]([OH:37])[OH:35])=[CH:3][S:4][C:5]=3[C:10](=[O:11])[CH:9]=2)[CH2:13][CH2:14]1
Reactant: CC1(C)OBOC1(C)C
Reactant: O=c1cc(N2CCOCC2)oc2c(Br)csc12
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=c1cc(N2CCOCC2)oc2c(B(O)O)csc12
Temperature: 160 °C
Yield: 109.2 %

Procedure:
A 20 mL microwave vial was charged with a magnetic stirring bar, 3-bromo-5-morpholino-7H-thieno[3,2-b]pyran-7-one (103) (1.20 g, 3.80 mmol), 1,3-bis(diphenylphosphino)propane (156 mg, 0.38 mmol), 1,3-bis(diphenylphosphino)propane nickel(II) chloride (205 mg, 0.38 mmol), dioxane (8 mL), diisopropylethylamine (1.98 mL, 11.39 mmol), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.10 mL, 7.59 mmol). The reaction mixture magnetically stirred and heated via microwave irradiation for 15 minutes at 160° C. Upon cooling to room temperature, the reaction was transferred to a separatory funnel, diluted with dichloromethane (100 mL), and washed three times with saturated aqueous ammonium chloride solution (100 mL). The dichloromethane layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting brown foam was stirred in aqueous hydrochloric acid (1.0M, 100 mL) for 30 minutes, frozen, and lyophilized to give 5-morpholino-7-oxo-7H-thieno[3,2-b]pyran-3-ylboronic acid (69) (1.51 g, 4.15 mmol) as a brown solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([C:19]2[C:20]([CH3:31])=[N:21][O:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=2)[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43]([C:27]3[CH:28]=[CH:29][C:24]([C:23]4[O:22][N:21]=[C:20]([CH3:31])[C:19]=4[CH:13]([C:11]4[N:10]=[N:9][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:12]=4)[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:25][CH:26]=3)=[CH:42][CH:41]=2)[CH2:38][CH2:39]1)=[O:36])[CH3:33]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(NS(C)(=O)=O)c1cn(Cc2ccccc2)nn1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(NS(C)(=O)=O)c4cn(Cc5ccccc5)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using N-{(1-benzyl-1H-[1,2,3]triazol-4-yl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methyl}-methanesulfonamide and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.