Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[CH3:13][C:14]1[CH:15]=[C:16]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:17]([N:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[NH2:20])=[O:18]>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:20][N:19]([C:17](=[O:18])[C:16]1[CH:15]=[C:14]([CH3:13])[CH:27]=[C:26]([CH3:28])[CH:25]=1)[C:21]([CH3:24])([CH3:23])[CH3:22])=[O:8]
Reactant: COc1cccc(C(=O)O)c1C
Reactant: Cc1cc(C)cc(C(=O)N(N)C(C)(C)C)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cccc(C(=O)NN(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
A solution of 3-methoxy-2-methylbenzoic acid (1.5 g, 0.01 tool) in thionyl chloride (10 mL) was refluxed for 45 minutes and then stripped under reduced pressure. The residue was dissolved in methylene chloride (50 mL) and added dropwise with cooling at 0° C. to a solution of N-(3,5-dimethylbenzoyl)-N-tertbutylhydrazine (4.4 g. 0.02 mol) in methylene chloride (50 mL). Following the addition, the solution was stirred overnight at room temperature and filtered. The filter-cake was washed extensively with water and ether, and then dried in vacuo to give 2.1 g (64.1% yield) of N-(3-methoxy-2-methylbenzoyl)-N'(3,5-dimethylbenzoyl)-N'-tert-butylhydrazine, melting at 204-204.5° C. 1H-NMR δppm 1.50 (s, 9H, tert-Bu), 1.63 (s, 3H, Ar-CH3), 2.25 (s, 6H, di-CH3) 3.75 (s, 6.26 (d, 1H, Ar), 6.93-7.20 (m, 5H, Ar).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[CH:13][C:12]=2[C:30]2[N:31]([CH3:36])[N:32]=[CH:33][C:34]=2[Cl:35])[CH2:4][CH2:3]1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>CC(N(C)C)=O>[Cl:35][C:34]1[CH:33]=[N:32][N:31]([CH3:36])[C:30]=1[C:12]1[CH:13]=[C:14]([NH:17][C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=2)[CH:15]=[CH:16][C:11]=1[O:10][CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([NH:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:7][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCCN1CCC(N)CC1
Solvent: CC(=O)N(C)C
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCCN1CCC(NS(C)(=O)=O)CC1
Yield: 35.6 %

Procedure:
N-[4-[2-(4-Amino-piperidin-1-yl)-ethoxy]-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide (0.038 g, 0.073 mmol) was dissolved in DMA (2.0 mL) in a vial with stir bar. Methanesulfonyl chloride (0.0085 g, 0.11 mmol) was added and the reaction was stirred at rt overnight. The reaction was concentrated, added to NaHCO3 (5 mL), and the solution was extracted with EtOAc (2×20 mL). The organic extracts were dried (Na2SO4), filtered, concd and purified by prep HPLC to afford the title compound (0.016 g, 0.026 mmol, 35%, TFA salt) as a white solid. LCMS m/z (%)=600 (M+H35Cl, 100), 602 (M+H37Cl, 36). 1H NMR (400 MHz, DMSO-d6) δ: 10.54 (s, 1H), 9.30 (s, 1H), 8.30 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 7.97 (m, 2H), 7.80 (m, 1H), 7.72 (d, J=2.6 Hz, 1H), 7.68 (s, 1H), 7.31 (m, 1H), 4.40 (m, 1H), 4.32 (m, 1H), 3.69 (s, 3H), 3.50-2.90 (m, 7H), 2.95 (s, 3H), 2.00-1.50 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][N:6]1C(OC)=O.C(O)(=O)C>Br>[F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][NH:6]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)cc1F
Agent: Br
Solvent: CC(=O)O
Product: O=c1cc([C@H]2CCN[C@@H](Cc3ccc(F)cc3F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.9 %

Procedure:
(2R,4S)-Methyl 2-(2,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (399 mg, 1.13 mmol) was dissolved in hydrogen bromide (33% in acetic acid (8.2 mL, 46.87 mmol) and stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-(2,4-difluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (146 mg, 44%). 1H NMR (400 MHz, cd3od) δ 1.43 (q, 1H), 1.67 (dq, 1H), 1.99-2.12 (m, 2H), 2.79-2.97 (m, 4H), 3.14-3.24 (m, 1H), 3.27-3.35 (m, 1H), 5.52 (s, 1H), 6.91-7.02 (m, 2H), 7.27-7.36 (m, 1H). HRMS Calculated for [C15H16F2N2O2+H]+: 295.1258. Found: 295.1252
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[C:10](=O)[NH:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].N>C1COCC1.O>[CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][NH:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCC2CCC1N2Cc1ccccc1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CN2C3CCC2CNC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Example 1E (2.88 g, 13.3 mmol) in 40 mL THF was added via cannula to a mixture of LiAlH4 (1.52 g, 39.9 mmol) in 40 mL THF at 0° C. After the addition was complete, the reaction mixture was allowed to warm to ambient temperature and stir for 2 h. The mixture was warmed to reflux and stirred for 1 h. The reaction was cooled to 0° C. then 1.5 mL H2O, 1.5 mL 15% NaOH and 4.5 mL H2O were added sequentially to quench the reaction. The material was filtered, the residue was washed with EtOAc, and the filtrate was concentrated under reduced pressure and carried on directly to the next reaction. MS (DCl/NH3) m/z 203 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:26](Cl)(=[O:28])[CH3:27].O>C(Cl)Cl>[CH:1]([O:4][C:5]([C:7]1([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:26](=[O:28])[CH3:27])=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)C1(c2ccc(-c3ccccc3)cc2)CC1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2ccc(C3(C(=O)OC(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 108.6 %

Procedure:
To 1-(biphenyl-4-yl)cyclopropanecarboxylic acid isopropyl ester (10.2 g, 36 mmol) in CH2Cl2 (100 mL) was added aluminum chloride (10.2 g, 76.5 mmol) followed by acetyl chloride (5.97 g, 76.5 mmol). The solution was stirred at room temperature for 1.5 hours then slowly poured into water. The organic layer was separated and extracted 1 time with sodium potassium tartrate solution (20 g in 250 mL water). The organic layer was dried and evaporated to yield 12.6 g of the title compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH:7][C@H:8]([C:13]([O:15][CH2:16][C@H:17]1[O:21][C@@H:20]([N:22]2[CH:29]=[C:28]([F:30])[C:26](=[O:27])[NH:25][C:23]2=[O:24])[C@H:19]([OH:31])[C@@H:18]1[OH:32])=[O:14])[C@H:9]([CH2:11][CH3:12])[CH3:10])=[O:6])[CH3:4].[CH2:33]([O:40][C:41]([NH:43][C@H:44]([C:60](O)=[O:61])[CH2:45][CH2:46][CH2:47][CH2:48][NH:49][C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C)C=O>[CH2:33]([O:40][C:41]([NH:43][C@H:44]([C:60]([NH:2][C@H:3]([C:5]([NH:7][C@H:8]([C:13]([O:15][CH2:16][C@H:17]1[O:21][C@@H:20]([N:22]2[CH:29]=[C:28]([F:30])[C:26](=[O:27])[NH:25][C:23]2=[O:24])[C@H:19]([OH:31])[C@@H:18]1[OH:32])=[O:14])[C@H:9]([CH2:11][CH3:12])[CH3:10])=[O:6])[CH3:4])=[O:61])[CH2:45][CH2:46][CH2:47][CH2:48][NH:49][C:50]([O:52][CH2:53][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)=[O:51])=[O:42])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)N)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Agent: CCP(=O)(C#N)CC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
0.46 Gram of 5'-O-(N-alanylisoleucyl)-5-fluorouridine hydrochloride obtained in Example 4 was dissolved in dimethylformamide (30 ml), and 1.42 g (3.42 mmol) of Nα,Nε -di-benzyloxycarbonyllysine and 0.90 g (5.52 mmol) of diethylphosphoryl cyanide were then added. To this solution was added under ice-cooling a solution of 1.30 g (12.9 mmol) of triethylamine in dimethylformamide, and the mixture was stirred for 1 hour at room temperature, allowed to stand overnight at room temperature and concentrated under reduced pressure. The residue was subjected to separation/purification by way of silica gel column chromatography (5×20 cm; a linear gradient of chloroform containing 3%→6% methanol) whereby 1.20 g (45.9%) of 5'-O-[N-{N-(Nα,Nε -di benzyloxycarbonyllysyl)alanyl}isoleucyl]-5-fluorouridine was obtained as a colorless powdery solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:27])=[CH:21][CH:20]=1)#[N:2].[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37]>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]([OH:16])[CH2:17][N:38]([CH2:39][CH3:40])[CH2:36][CH3:37])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)=[O:27])=[CH:21][CH:20]=1)#[N:2]
Reactant: CCNCC
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1OC[C@H]1CO1
Solvent: C1CCOC1
Product: CCN(CC)C[C@@H](O)COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1C#N
Temperature: 60 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
After dissolving N-(4-(6-cyano-7-((2R)-oxiran-2-yl)methoxy-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea (200 mg, 0.425 mmol) in tetrahydrofuran (5.0 ml) under a nitrogen atmosphere, diethylamine (1.0 ml) was added and the mixture was stirred overnight at 60° C. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (eluent—ethyl acetate:methanol=9:1), the fraction containing the target substance was concentrated, methanol (5 ml) was added for crystallization, and the crystals were filtered out and blow-dried to obtain the title compound (126.4 mg, 0.233 mmol, 54.7%) as light yellow crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[C:12]3=[CH:11][C:10]=2[CH:9]=1)#[N:2].NC(C(O)=O)CS>FC(F)(F)C(O)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]3[CH2:17][CH2:18][CH:19]([CH2:20][C:21]([OH:23])=[O:22])[C:12]3=[CH:11][C:10]=2[CH:9]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3ccc(C4CCCCC4)c(C#N)c3)ccc12
Agent: NC(CS)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)ccc1C1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
To tert-butyl 2-(7-(3-cyano-4-cyclohexylbenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (51.4 mg, 0.106 mmol) was added a solution of DL-cysteine (19.87 mg, 0.159 mmol) in trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 15 min. The reaction mixture was poured into an ice water to form a solid. The solid was filtered and washed with water to provide the title compound as an off-white solid (41.8 mg). LCMS m/z=429.6 [M+H]+; 1H NMR (400 MHz, DMSO-d6) α ppm 1.19-1.31 (m, 1H), 1.32-1.55 (m, 4H), 1.69-1.75 (m, 1H), 1.75-1.85 (m, 4H), 2.14-2.25 (m, 1H), 2.56 (dd, J=12.00, 8.00 Hz, 1H), 2.67 (dd, J=12.00, 8.00 Hz, 1H), 2.71-2.78 (m, 1H), 2.79-2.90 (m, 1H), 3.57 (t, J=7.39 Hz, 1H), 3.87-3.99 (m, 1H), 4.02-4.16 (m, 1H), 5.08 (s, 2H), 6.00 (s, 1H), 6.76 (dd, J=8.72, 2.40 Hz, 1H), 7.05 (d, J=2.40 Hz, 1H), 7.18 (d, J=8.72 Hz, 1H), 7.51 (d, J=8.21 Hz, 1H), 7.72 (dd, J=8.21, 1.64 Hz, 1H), 7.81 (d, J=1.52 Hz, 1H), 12.26 (bs, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]>CC(C)=O>[CH3:2][C:3]1([CH3:5])[O:6][C@H:5]2[C@@H:7]3[O:8][C:9]([CH3:11])([CH3:7])[O:10][C@:9]3([CH2:11][OH:12])[O:4][C@H:3]2[CH2:2][O:1]1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Solvent: CC(C)=O
Product: CC1(C)OC[C@@H]2O[C@@]3(CO)OC(C)(C)O[C@H]3[C@@H]2O1
Reaction time: 4 h
Yield: 167.5 %

Procedure:
To 250 ml of acetone were added 10.0 g of L-sorbose and 125 mg of anhydrous cupric chloride, and the mixture was stirred for 4 hours under reflux in a warm-water bath at 57° to 58° C. The refluxing solvent was continuously dried with 14 g of molecular sieves 3A which was placed between the reaction vessel and the cooling tube. After cooling, a small amount of aqueous sodium hydrogencarbonate is added to the reaction mixture, and the acetone was distilled off under reduced pressure. The residue was dissolved in about 150 ml of benzene and the benzene solution was washed with aqueous sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. When the benzene was distilled off under reduced pressure, there was obtained 12.1 g (84%) of 2,3:4,6-di-O-isopropylidene-L-sorbofuranose (purity of not less than 98%) as a residue. Its infra-red absorption spectrum and nuclear magnetic resonance spectrum were in accordance with those of the crystals as obtained in Example 5.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[OH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]2[C@H:19]3[C@H:29]([CH2:30][CH2:31][C@:14]12[CH3:15])[C@:27]1([CH3:28])[C:22]([C:23]([CH3:34])([CH3:33])[C:24](=[O:32])[CH2:25][CH2:26]1)=[CH:21][CH2:20]3.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:9]1[C@H:21]2[CH2:20][C@@H:19]3[C@@H:29]([C@@:27]4([CH3:28])[CH2:26][CH2:25][C:24](=[O:32])[C:23]([CH3:34])([CH3:33])[C@:22]124)[CH2:30][CH2:31][C@@:14]1([CH3:15])[C@H:16]3[CH2:17][CH2:18][C@@H:13]1[OH:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3C[C@@H]3O[C@]312
Reaction time: 8 h
Yield: 21.9 %

Procedure:
mCPBA (1.17 g) was added to a stirred solution of 17β-hydroxy-4,4-dimethylandrost-5-en-3-one (1.00 g) in DCM (30 ml). After 8 h at RT, a 10% Na2SO3 aqueous solution was added. The mixture was neutralized by addition of 5% aqueous NaHCO3 solution and was extracted with DCM (3×100 ml). The combined organic extracts were washed with H2O, dried over Na2SO4, and evaporated to dryness. The mixture was purified by flash chromatography (SiO2, n-hexane/EtOAc 70/30) to give 5α,6α-epoxy-4,4-dimethyl-17β-hydroxyandrostan-3-one (230 mg, 23%).
Reaction SMILES: [CH3:1][C:2]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15](C3C=CC(CO)=CC=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].OCC1C=CC(B(O)O)=CC=1.CC1(C)C(C)(C)OB([C:52]2[CH:57]=[CH:56][N:55]=[C:54]([N:58]3[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]3)[CH:53]=2)O1>>[CH3:1][C:2]1[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:52]3[CH:57]=[CH:56][N:55]=[C:54]([N:58]4[CH2:59][CH2:60][NH:61][CH2:62][CH2:63]4)[CH:53]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4ccc(CO)cc4)cccc32)c1C
Reactant: CC1(C)OB(c2ccnc(N3CCNCC3)c2)OC1(C)C
Agent: OCc1ccc(B(O)O)cc1
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4ccnc(N5CCNCC5)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to 4-(2,3-dimethylphenoxy)-1-(5-(4-(hydroxymethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one except that 4-(hydroxymethyl)phenylboronic acid was replaced by 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine. LCMS, [M+H]+=485.3. 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J=5.1 Hz, 1H), 7.22-7.28 (m, 2H), 7.07-7.13 (m, 1H), 7.03 (t, J=7.9 Hz, 1H), 6.76 (d, J=7.5 Hz, 1H), 6.67 (d, J=8.1 Hz, 1H), 6.53 (s, 1H), 6.50 (d, J=5.9 Hz, 1H), 3.98 (t, J=5.7 Hz, 2H), 3.80 (t, J=6.9 Hz, 2H), 3.47-3.59 (m, 4H), 2.95-3.04 (m, 4H), 2.77 (t, J=7.3 Hz, 2H), 2.53 (t, J=6.5 Hz, 2H), 2.16-2.27 (m, 5H), 2.00 (br. s, 3H), 1.85 (quin, J=6.7 Hz, 2H).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][N:16]([CH2:25][CH3:26])[CH2:17][CH2:18][CH2:19]OS(C)(=O)=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31]>C(#N)C>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[CH2:15][N:16]([CH2:25][CH3:26])[CH2:17][CH2:18][CH2:19][NH:27][CH2:28][CH2:29][CH2:30][OH:31])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: CCN(CCCOS(C)(=O)=O)Cc1c2ccccc2cc2ccccc12
Reactant: NCCCO
Solvent: CC#N
Product: CCN(CCCNCCCO)Cc1c2ccccc2cc2ccccc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
The mesylate 17 (384 mg, 1.04 mmol) and 3-amino-propanol (392 mg, 5.25 mmol) were dissolved in acetonitrile (20 mL). The mixture was then stirred at 75° C. under a N2 atmosphere overnight. After the confirmation of the disappearance of the mesylate by TLC, the solution was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (20 mL) and washed three times with aqueous sodium carbonate. The organic layer was separated, dried with anhydrous Na2SO4, filtered and concentrated under vacuum. Flash column chromatography of the residue gave 18 as a light yellow oil. Yield 65%; Rf=0.35 (1:6:83 NH4OH:MeOH:CH2Cl2); 1H NMR (CDCl3) δ 8.32 (d, 2H), 8.23 (s, 1H), 7.83 (d, 2H), 7.37 (m, 2H), 7.30 (m, 2H), 4.28 (s, 2H), 3.48 (t, 2H), 2.56 (q, 2H), 2.30 (t, 2H), 2.12 (t, 2H), 2.06 (t, 2H), 1.36 (q, 2H), 1.21 (q, 2H), 1.09 (t, 3H); 13C NMR (CDCl3) δ 131.3, 131.2, 130.5, 129.3, 129.0, 127.3, 125.5, 125.3, 124.8, 124.8, 63.8, 50.8, 50.5, 49.5, 48.3, 47.7, 30.5, 26.6, 11.7. HRMS (FAB) m/z calcd. for C23H30N2O (M+H)+ 351.2431; found 351.2430.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH:10]([F:12])[F:11])[NH2:5].CCN(C(C)C)C(C)C.Br[C:23]1[N:28]=[CH:27][C:26]([Br:29])=[CH:25][N:24]=1>C(O)CCC>[Br:29][C:26]1[CH:25]=[N:24][C:23]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][CH:10]([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[N:28][CH:27]=1
Reactant: Nc1ccc(OC(F)F)c(Cl)c1
Reactant: Brc1cnc(Br)nc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)Oc1ccc(Nc2ncc(Br)cn2)cc1Cl
Temperature: 120 °C
Reaction time: 12 h
Yield: 54.3 %

Procedure:
To a solution of 3-chloro-4-(difluoromethoxy)aniline (0.814 g, 4.20 mmol) in butan-1-ol (10 mL), were added DIPEA (2.203 mL, 12.61 mmol) and 2,5-dibromopyrimidine (1 g, 4.20 mmol). The reaction mixture was stirred at 120° C. for 12 h and concentrated. The crude product was purified by flash chromatography on silica gel using 3% ethyl acetate in petroleum ether to give 5-bromo-N-(3-chloro-4-(difluoromethoxy)phenyl)pyrimidin-2-amine (0.8 g, 64%). LCMS (ES-ES), m/z 349.98.
Reaction SMILES: C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Al+3:13].[C:14]([OH:18])(=[O:17])[CH:15]=[CH2:16]>>[C:14]([O-:18])(=[O:17])[CH:15]=[CH2:16].[C:14]([O-:18])(=[O:17])[CH:15]=[CH2:16].[C:14]([O-:18])(=[O:17])[CH:15]=[CH2:16].[Al+3:13]
Reactant: C=CC(=O)O
Agent: CC(C)[O-]
Agent: [Al+3]
Product: C=CC(=O)[O-]
Temperature: 32 °C

Procedure:
Into the flask described hereinabove there were placed 204.2 grams of aluminium tri-isopropanolate to which 216 grams of acrylic acid were added during 8 minutes at room temperature (25° C.). The procedure was as set forth hereinabove. Owing to the reaction heat, the temperature increased to 32° C. The resultant product was a white, solid substance. The rotary evaporator heating then was switched on and gradually heated to 70° C. At the same time the vacuum was gradually adjusted to 24 mbar. The isopropanol was thereby expelled yielding a white powder.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[CH:12]=[CH:11][C:10]=2[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:7])=[CH:4][N:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CCOC(C)=O>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:2]2[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]3[CH:14]=[C:13]([C:15]4[S:16][CH:17]=[CH:18][CH:19]=4)[CH:12]=[CH:11][C:10]=3[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:7])=[CH:4][N:3]=2)[CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(Cl)nc1
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(C(=O)Nc3cc(-c4cccs4)ccc3NC(=O)OC(C)(C)C)cn2)CC1
Temperature: 90 °C
Yield: 37.6 %

Procedure:
A mixture of chloride 46 (0.15 g, 0.35 mmol) and N-methylpiperazine (0.5 mL, 4.5 mmol) was heated to 90° C. in a sealed tube for 18 h. The reaction mixture was then diluted with AcOEt, washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (eluent: 2:1 AcOEt:hexane) to afford title compound 48 (65 mg, 38% yield).
Reaction SMILES: [CH:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2)([CH3:3])[CH3:2].[Br:14]Br.S([O-])([O-])=O.[Na+].[Na+]>>[Br:14][C:6]12[CH2:12][CH:10]3[CH2:9][CH:8]([CH2:13][C:4]([CH:1]([CH3:3])[CH3:2])([CH2:11]3)[CH2:5]1)[CH2:7]2
Reactant: BrBr
Reactant: CC(C)C12CC3CC(CC(C3)C1)C2
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: CC(C)C12CC3CC(CC(Br)(C3)C1)C2
Yield: 83 %

Procedure:
Mix 0.034 mol of isopropyl adamantane (IV) with a ten times excess of bromine (0.33 mol). Heat slowly and stir under reflux for 4 h. Subsequently, allow to cool and pour onto ice water. Decompose the excess bromine with sodium sulfite until the aqueous solution has discolored. Then extract with ether, wash the combined organic phases with sodium bicarbonate solution, dry with magnesium sulfate, filter and evaporate to dryness under vacuum. Recrystallize the residue from methanol. (Yield: 83%).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:32])[C:19]2[CH:24]=[N:23][CH:22]=[C:21]3[S:25][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:27][C:20]=23)=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.CS(C)=O.ClCCl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:19]2[C:20]3[C:21]([S:25][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH:27]=3)=[CH:22][N:23]([CH3:1])[CH:24]=2)=[O:32])=[CH:14][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1cc2c(C(O)c3ccc(Cl)cc3)cncc2s1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1C=C2C(=CN(C)C=C2C(=O)c2ccc(Cl)cc2)S1
Temperature: 78 °C
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
To a stirred solution of oxalyl chloride (0.023 mL, 0.26 mmol) in anhydrous dichloromethane (1 mL) at −78° C. was added DMSO (0.045 mL, 0.63 mmol). After 15 minutes, a solution of Example 237G (0.07 g, 0.21 mmol) in anhydrous 1:4 DMSO/dichloromethane (5 mL) was added dropwise. The reaction was stirred 1 hour at 78° C. then treated with triethylamine (0.15 mL, 1.05 mmol). After 5 minutes, reaction was allowed to warm to room temperature over 1 hour. The reaction was quenched with water (2 mL) and partitioned between EtOAc (50 mL) and sat. aq. NaHCO3 (50 mL). The organic layer was washed with 50% sat. aq. NaHCO3 (2×50 mL), brine (1×50 mL), dried (Na2SO4), filtered, and concentrated. The product was dried in a desiccator to yield the title compound as a white solid (0.07 g, 100%).