Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][CH2:8][P:9]([O:14][CH2:15][CH3:16])(=[O:13])[O:10][CH2:11][CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([O:7][CH2:8][P:9]([O:14][CH2:15][CH3:16])(=[O:13])[O:10][CH2:11][CH3:12])=[O:4]
Reactant: CC(Br)C(=O)Cl
Reactant: CCOP(=O)(CO)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(COC(=O)C(C)Br)OCC
Reaction time: 20 h
Yield: 32.3 %

Procedure:
A solution of 8.6 g (0.05 mol) of 2-bromo-propionyl chloride in 30 ml of methylene chloride was added dropwise to a mixture which had been cooled to 0°-10° C. and consisted of 8.4 g (0.05 mol) of diethyl hydroxymethanephosphonate, 6.1 g (0.06 mol) of triethylamine and 30 ml of methylene chloride. The reaction mixture was stirred for 20 hours at 10°-20° C., washed with aqueous sodium bicarbonate solution, dried, filtered, and evaporated down under reduced pressure. 4.9 g (32% of theory) of diethyl 2-bromopropionyloxymethanephosphonate were obtained as an oily residue.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@:11]([OH:31])([CH3:30])[CH2:12][N:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[O:15][C:14]2=[O:29])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+]>O1CCOCC1>[CH3:30][C@@:11]1([CH2:12][N:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[O:15][C:14]2=[O:29])[O:31][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: C[C@@](O)(Cn1cc([N+](=O)[O-])nc1Cl)Cn1nc(-c2ccc(OC(F)(F)F)cc2)oc1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@]1(Cn2nc(-c3ccc(OC(F)(F)F)cc3)oc2=O)Cn2cc([N+](=O)[O-])nc2O1
Yield: 39.8 %

Procedure:
To a solution of (R)-3-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-5-(4-trifluoromethoxyphenyl)-3H-[1,3,4]oxadiazol-2-one prepared in Example 539 (0.87 g, 1.88 mmol) in 1,4-dioxane (18 ml), sodium hydride (98 mg, 2.44 mmol) was added with cooling on ice-bath. The mixture was stirred under reflux for 5 hours, concentrated under reduced pressure, then water was added with cooling on ice-bath. The solution was extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate 9/1), and recrystallized from acetonitrile/isopropanol to afford (R)-3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-5-(4-trifluoromethoxyphenyl)-3H-[1,3,4]oxadiazol-2-one (0.32 g, yield 40%) as a white powder.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([CH2:26][OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[OH:27][CH2:26][CH:24]1[CH2:25][N:22]([C:3]2[C:2]([C:32]3[CH:31]=[N:30][C:29]([CH3:28])=[N:34][CH:33]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(CO)C2)c(Br)c1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC(CO)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 128 using 5-bromo-6-(3-(hydroxymethyl)azetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 135.1) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine. HPLC (Condition 4) tR=4.61 min, UPLC-MS (Condition 3) tR=0.95 min, m/z=460.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.55-2.63 (m, 1H) 2.67 (s, 3H) 3.39-3.52 (m, 4H) 3.73 (t, J=8.60 Hz, 2H) 4.69 (t, J=5.28 Hz, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.79-7.88 (m, 2H) 8.01 (d, J=2.35 Hz, 1H) 8.70-8.82 (m, 3H) 10.18 (s, 1H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])C=1C(O)=O.CN(C)C=O>ClCCl>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: COc1cccc(C(F)(F)F)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(C(F)(F)F)c1C(=O)Cl
Temperature: 25 °C

Procedure:
Oxalyl chloride (3 mL, 34.27 mmol) was added dropwise to a mixture of 2-methoxy-6-(trifluoromethyl)benzoic acid (1.5 g, 6.81 mmol) (prepared according to known method, see: EP0897904B1), N,N-dimethylformamide (0.3 mL), and dichloromethane (40 mL) with stirring at rt. The reaction mixture was stirred overnight. Evaporation of solvent and excess oxalyl chloride and drying under vacuum afforded 2-methoxy-6-(trifluoromethyl)benzoyl chloride as a solid, which was used without purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[H-].[Na+].[CH2:14](Br)[CH:15]=[CH2:16]>C1COCC1.CN(C=O)C>[CH2:16]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)[CH:15]=[CH2:14]
Reactant: O=C1CCc2cc(O)ccc21
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCOc1ccc2c(c1)CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a solution of 5-hydroxy-1-indanone (4.27 g, 0.0288 mol) in THF/DMF (5 mL/10 mL) at 0° C. was added NaH (60%, 1.21 g, 0.0303 mol) followed by allyl bromide (2.7 mL, 0.0317 mol). The reaction was warmed to room temperature and stirred overnight The reaction mixture was quenched with water and extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography eluted with EtOAc/hexane (1:1) to give 4.29 g (79%) of the desired product as brown oil. MS (DCI/NH3) m/z: 189.1 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.53-2.64 (m, 2H), 2.96-3.11 (m, 2H), 4.64-4.72 (m, 2H), 5.29 (dd, J=10.51, 1.36 Hz, 1H), 5.42 (dd, J=17.29, 1.70 Hz, 1H), 6.06 (m, 1H), 6.98 (dd, J=8.48, 2.37 Hz, 1H), 7.10 (d, J=2.03 Hz, 1H) 7.56 (d, J=8.48 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2([C:15]([F:18])([F:17])[F:16])[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[NH:19][C:20]1[NH:24][C:23]2[CH:25]=[C:26]([O:34][CH2:35][CH:36]([F:38])[F:37])[C:27]([C:29]([O:31]CC)=O)=[CH:28][C:22]=2[N:21]=1.[Br:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1.C[Al](C)C.C1(C)C=CC=CC=1>O1CCOCC1>[Br:39][C:40]1[CH:46]=[CH:45][C:43]([NH:44][C:29]([C:27]2[C:26]([O:34][CH2:35][CH:36]([F:37])[F:38])=[CH:25][C:23]3[NH:24][C:20]([NH:19][C:3]4[CH:4]=[C:5]([CH2:8][NH:9][C:10]([C:12]5([C:15]([F:18])([F:17])[F:16])[CH2:13][CH2:14]5)=[O:11])[CH:6]=[CH:7][C:2]=4[Cl:1])=[N:21][C:22]=3[CH:28]=2)=[O:31])=[CH:42][CH:41]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CCOC(=O)c1cc2nc(Nc3cc(CNC(=O)C4(C(F)(F)F)CC4)ccc3Cl)[nH]c2cc1OCC(F)F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Br)cc1)c1cc2nc(Nc3cc(CNC(=O)C4(C(F)(F)F)CC4)ccc3Cl)[nH]c2cc1OCC(F)F

Procedure:
The title compound was prepared in accordance with Example 59 (i) using ethyl 2-(2-chloro-5-{[(1-trifluoromethyl-cyclopropanecarbonyl)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1H-benzimidazole-5-carboxylate (0.200 g; 0.36 mmol), 4-bromoaniline (0.184 g; 1.07 mmol), Me3Al in toluene (0.900 mL; 2 M; 1.80 mmol) and 1,4-dioxane (10 mL). Yield: 0.115 g (47%). 400 MHz 1H-NMR (DMSO-d6, ppm) 11.3-11.1 (1H, br s) 10.17 (1H, s) 9.1-8.8 (1H, br s) 8.65-8.57 (1H, m) 8.53 (1H, t, J=5.8 Hz) 7.95-7.90 (1H, m) 7.80-7.73 (2H, m) 7.63-7.57 (2H, m) 7.49 (1H, d, J=8.4 Hz) 7.31-7.26 (1H, m) 6.94 (1H, dd, J=8.2, 1.6 Hz) 6.59 (1H, tt, J=54.3, 3.1 Hz) 4.57 (2H, td, J=14.9, 3.0 Hz) 4.38 (2H, d, J=5.8 Hz) 1.54-1.47 (2H, m) 1.38-1.31 (2H, m). MS m/z: 686, 688, 690 [M+H]+.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]1[S:9][S:10][C:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2CF)=[CH:12][CH:13]=1)(C)(C)C.[F-:26].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(O)(=O)C>[OH:6][CH2:7][C:8]1[S:9][S:10][C:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:26])=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC=C(COc2ccccc2CF)SS1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OCC1=CC=C(COc2ccccc2F)SS1
Reaction time: 5 h
Yield: 68 %

Procedure:
To a stirred solution of the 3-[(tert-butyldimethyl-silyloxy)methyl]-6-[(2fluoromethylphenyloxy)methyl]-1,2-dithiin obtained above (250 mg, 0.65 mmol) in 5 mL THF was added a mixture of 3.0 mL of 1M tetrabutylammonium fluoride in THF and 2.0 mL of acetic acid. The reation mixture was stirred for 5 h until TLC analysis showed the reaction to be complete, then concentrated in vacuo. The residue was partitioned between 20 mL of water and 20 mL ethyl acetate. The organic phase was washed with 3% solution of aqueous sodium bicarbonate (50 mL), water, dried over sodium sulfate, and then concentrated to a small volume. The residue was purified by silica gel chromatography (ethyl acetate-hexane, 1:3) to yield 120 mg (68%) of the title compound; 1H NMR (CDCl3):δ7.12-6.9 (m, 4 H), 6.47 (d, J=6.0, 1 H), 6.39 (d, J=6.0, 1 H), 4.74 (s, 2 H), 4.28 (s, 2 H); MS (EI) 270.1 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[N+:15]([CH3:18])([O-:17])=[O:16].CN(C)C(=N)N(C)C>C(OCC)C.Cl>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[CH2:18][N+:15]([O-:17])=[O:16]
Reactant: COC(=O)C=Cc1ccc(OC)cc1
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCOCC
Product: COC(=O)CC(C[N+](=O)[O-])c1ccc(OC)cc1
Reaction time: 72 h

Procedure:
A mixture of 288 g of 4-methoxycinnamic acid methyl ester, 500 g of nitromethane and 23 g of tetramethylguanidine is allowed to stir for 72 hours. The solution is diluted with diethyl ether and aqueous hydrochloric acid solution (1 N, 1 liter) is added. The organic layer is separated, dried over anhydrous magnesium sulfate, and evaporated to give 4-nitro-3-(4-methoxyphenyl)butanoic acid methyl ester.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:9].[Na+]>Cl>[CH2:4]([CH2:5][CH2:6][NH2:7])[CH2:3][CH2:2][C:1]([OH:8])=[O:9]
Reactant: O=C1CCCCCN1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: NCCCCCC(=O)O

Procedure:
5 g of ε-caprolactam was dissolved in 10% HCl (20 g) and heated to reflux until the starting material was reacted completely. The pH of the mixture was adjusted to 7.6 by adding 10% NaOH(aq). The mixture was concentrated at 55° C. and then recrystallized in methanol to obtain aminocaproic acid containing inorganic salts.
Reaction SMILES: [CH3:1][C:2]([N:9]1[C:14](=[O:15])[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([CH3:22])[O:11][CH2:10]1)([CH2:7][CH3:8])[C:3]([O:5]C)=[O:4].[OH-].[Na+]>C(O)C>[CH3:1][C:2]([N:9]1[C:14](=[O:15])[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([CH3:22])[O:11][CH2:10]1)([CH2:7][CH3:8])[C:3]([OH:5])=[O:4]
Reactant: CCC(C)(C(=O)OC)N1COC(C)=C(c2ccccc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(C)(C(=O)O)N1COC(C)=C(c2ccccc2)C1=O
Reaction time: 24 h
Yield: 74.7 %

Procedure:
To a solution of methyl 2-methyl-2-(6-methyl-5-phenyl-2, 3-dihydro-4-oxo-4 H-1,3-oxazin-3-yl)-butyrate (1.91 g) in 20 ml of ethanol was added at room temperature 30 ml of aq. NaOH (0.3N). After stirring for 24 h, ethanol was evaporated, and the mixture was acidified by hydrochloric acid. The precipitate was filtered off and dried to get the captioned compound (1.36 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9](=[O:21])[C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[N:15]=2)([CH3:12])[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[Cl:20][C:16]1[N:15]=[C:14]([O:13][C:10]([CH3:12])([CH3:11])[C:9]([NH:8][C:3]2[C:2]([NH:1][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:7][CH:6]=[CH:5][N:4]=2)=[O:21])[CH:19]=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(Oc1cccc(Cl)n1)C(=O)Nc1ncccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(Oc1cccc(Cl)n1)C(=O)Nc1ncccc1NS(C)(=O)=O
Reaction time: 1 h
Yield: 4.2 %

Procedure:
To a solution of N-(3-Amino-pyridin-2-yl)-2-(6-chloro-pyridin-2-yloxy)-2-methyl-propionamide (0.15 g, 4.9 mmol) and pyridine (0.042 g, 5.3 mmol) in DCM (5 ml) at 0° C. was added Methane sulfonyl chloride (0.06 g, 0.04 ml, 5.3 mmol) drop wise over a period of 5 min. The reaction mixture was stirred for 1 h. The reaction mixture was quenched with water (2 ml) extracted in DCM (20 ml), washed with brine (5 ml), dried over Na2SO4 and concentrated under reduced pressure to obtain crude product. The crude material thus obtained was purified by flash column affording 2-(6-Chloro-pyridin-2-yloxy)-N-(3-methanesulfonylamino-pyridin-2-yl)-2-methyl-propionamide (0.08 g, 5%). 1H NMR (400 MHz, CDCl3): δ 1.790 (s, 6H), 2.87 (s, 3H), 6.67 (t, 1H, J=8 Hz), 6.78 (d, 11-1, J=8 Hz), 6.91 (d, 1H, J=8 Hz), 7.18 (d, 1H, J=8 Hz), 7.57 (t, 1H, J=8 Hz), 8.69 (d, 1H, J=8 Hz), 9.11 (brs, 1H). MS (EI) m/z: 385 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-])=O)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:24]([N:31]1[C:35](=[O:36])[C:34](=[C:37]2[N:41]([CH3:42])[C:40]3[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=3[S:38]2)[S:33][CH2+:32]1SC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]1[C:35](=[O:36])[C:34](=[C:37]2[N:41]([CH3:42])[C:40]3[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=3[S:38]2)[S:33][C:32]1=[N:10][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:4]=1[NH:3][CH2:1][CH3:2])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1ccncc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccncc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4-ethylamino-3-nitropyridine was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 8.04–8.09 (2H, m), 7.53 (1H, d), 7.44–7.48 (2H, m), 7.27–7.38 (4H, m), 7.19 (1H, m), 7.07 (1H, d), 6.42 (1H, d), 5.19 (2H, s), 4.12 (1H, br t), 3.79 (3H, s), 3.02 (2H, m), 1.05 (3H, t); MS(ESI): 474 (MH+).
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([C:22](=[O:32])[C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH2:14][CH2:13][C:12]=1[CH:33]=O>CN(C)C=O>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([C:22]([N:15]2[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:11]3[S:3][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:33][C:12]=3[CH2:13][CH2:14]2)=[O:32])=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: O=CC1=C(Cl)c2ccccc2N(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(s1)-c1ccccc1N(C(=O)c1ccc([N+](=O)[O-])cc1)CC2
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
To a slurry of 0.240 g (6.01 mmol) of sodium hydride (60% in oil) in 20 ml of N,N-dimethylformamide, chilled in an ice bath, is added 0.656 ml (6.01 mmol) of ethyl 2-mercaptoacetate. The mixture is stirred for 10 minutes and a slurry of 2.14 g (6.01 mmol) of 2,3-dihydro-5-chloro-1-(4-nitrobenzoyl)-1H-1-benzazepine-4-carboxaldehyde in 6 ml of N,N-dimethylformamide is added dropwise. The mixture is stirred at room temperature overnight and then concentrated under high vacuum. The residue is partitioned between chloroform and water and the organic layer separated. The aqueous layer is extracted (twice) with chloroform and the organic layer and extracts combined and dried (Na2SO4). The solvent is removed and the residue chromatographed on silica gel with dichloromethane as eluent (2 liter) and then with 4% ethyl acetate in dichloromethane as eluent. Fractions containing product are combined and the solvent removed under vacuum to give 2.1 g of ethyl 4,5-dihydro-6-(4-nitrobenzoyl)-6H-thieno[3,2-d][1]benzazepine-2-carboxylate as a yellow foam.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]2)[CH2:9]1)=O)(C)(C)C.[ClH:21]>C(OCC)(=O)C>[ClH:21].[CH2:9]1[C:10]2([CH2:13][CH2:14][N:15]([C:18](=[O:20])[CH3:19])[CH2:16][CH2:17]2)[CH2:11][CH2:12][NH:8]1
Reactant: CC(=O)N1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC2(CCNC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 8-acetyl-2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.34 g) in ethyl acetate (10 ml), a 1 M ethyl acetate solution of HCl (20 ml). After stirring for 2 h at room temperature, the reaction mixture is evaporated down to give 1-(2,8-diaza-spiro[4.5]dec-8-yl)-ethanone hydrochloride as a solid.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)(=[O:4])[CH:2]=[CH2:3].[CH2:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[CH2:13]([N:20]1[CH2:25][CH2:24][N:23]([CH2:3][CH2:2][C:1]([NH:5][C:6]2[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=2)=[O:4])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=CC(=O)Nc1ccc(F)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CO
Product: O=C(CCN1CCN(Cc2ccccc2)CC1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
N-Acryloyl-4-fluoroaniline (12.2 g) and 1-benzyl piperazine (19.7 g) were dissolved in methanol (150 ml), and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated, and the residue was purified by Cromatorex NH silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (25 g, 100%) as a colorless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH3:22][C:23]#N>>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:8][CH2:7][CH2:10][CH2:11][C:22]3[CH:23]=[CH:6][CH:5]=[CH:4][CH:9]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: CC#N
Reactant: COc1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C2CCN(CCCCc3ccccc3)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-methoxyphenyl)piperidine hydrochloride (1.00 g, 4.39 mmol), 4-phenyl-p-tosylbutane (1.40 g, 4.61 mmol) and K2CO3 (1.24 g, 9.00 mmol) in CH3CN (25 mL) as a beige solid (979 mg, 69%): mp 48-50° C.; 1H NMR (CDCl3) 1.52-1.86 (m, 8H), 2.01 (td, J=11 and 3.6 Hz, 2H), 2.34-2.50 (m, 3H), 2.65 (t, J=7.2 Hz, 2H), 2.98-3.08 ((m, 2H), 3.79 (J, 3H), 6.85 (d, J=8.7 Hz, 2H), 7.12-7.32 (m, 7H).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)[C:21]#[C:22][CH3:23].O>N1C=CC=CC=1>[CH2:18]([O:17][C:15]([CH:11]1[CH2:10][N:9]([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:8])[CH2:14][CH2:13][N:12]1[S:31]([C:28]1[CH:27]=[CH:26][C:25]([O:24][CH2:20][C:21]#[C:22][CH3:23])=[CH:30][CH:29]=1)(=[O:33])=[O:32])=[O:16])[CH3:19]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C1CN(C(=O)N2CCOCC2)CCN1
Solvent: c1ccncc1
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)N3CCOCC3)CC2C(=O)OCC)cc1
Reaction time: 8 h
Yield: 80.7 %

Procedure:
The ethyl 4-(4-morpholinylcarbonyl)-2-piperazinecarboxylate (0.41 g, 1.55 mmol) was dissolved in pyridine (1.44 mL). To this solution was added a solution of 4-but-2-ynyloxy-benzenesulfonyl chloride (0.38 g, 1.55 mmol) in pyridine (1 mL). The reaction was stirred overnight and then poured into water. The mixture was extracted three times with chloroform. The organics were combined, washed with 10% HCl, twice with water, then brine and dried over Na2SO4. The solution was filtered and concentrated in vacuo to provide 0.6 g (81%) of 1-(4but-2-ynyloxy-benzenesulfonyl)-4-(morpholine4-carbonyl)- piperazine-2-carboxylic acid ethyl ester as a gold oil. Electrospray Mass Spec 480.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13](=O)[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:14])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: CC(=O)c1ccc(OC(F)(F)F)c(Cl)c1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OC(F)(F)F)c(Cl)c1
Yield: 81 %

Procedure:
The title compound is prepared in 81% yield (1.41 g, colorless oil) from 1-(3-chloro-4-(trifluoromethoxy)phenyl)ethanone (1.20 g, 5.03 mmol) and (R)-2-methylpropane-2-sulfinamide (914 mg, 7.54 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:32]C)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([NH:15][C:16]([C:18]2([C:21]3[CH:31]=[CH:30][C:24]4[O:25][C:26]([F:29])([F:28])[O:27][C:23]=4[CH:22]=3)[CH2:20][CH2:19]2)=[O:17])[N:9]=1.I[Si](C)(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3](=[O:32])[NH:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[C:10]([NH:15][C:16]([C:18]2([C:21]3[CH:31]=[CH:30][C:24]4[O:25][C:26]([F:28])([F:29])[O:27][C:23]=4[CH:22]=3)[CH2:20][CH2:19]2)=[O:17])[CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: COc1nccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)c1Cl
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cc[nH]c(=O)c1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To N-(3′-chloro-2′-methoxy-3-methyl-2,4′-bipyridin-6-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (71 mg, 0.15 mmol) in chloroform (2 mL) was added iodotrimethylsilane (90 mg, 0.45 mmol). The reaction mixture was stirred at room temperature for six hours. The reaction mixture was evaporated to dryness and purified by reverse phase preparative liquid chromatography to yield the product as a trifluoroacetic acid salt. The salt was dissolved in dichloromethane (5 mL) and washed with a saturated sodium bicarbonate solution (2×5 mL). The organics were dried over sodium sulfate and evaporated to yield the product (23 mg, 33%). ESI-MS m/z calc. 459.08. found 460.3 (M+1)+. Retention time 1.11 minutes. 1H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 9.11 (s, 1H), 7.97 (d, J=8.5 Hz, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.55 (m, 1H), 7.44 (d, J=6.6 Hz, 1H), 7.40-7.38 (m, 1H), 7.35-7.32 (m, 1H), 6.11 (d, J=6.6 Hz, 1H), 2.06 (s, 3H), 1.51-1.50 (m, 2H), 1.17-1.15 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].BrC[CH2:17][CH2:18][O:19][CH2:20]CCBr>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:17][CH2:18][O:19][CH3:20])[CH:7]=1
Reactant: BrCCCOCCCBr
Reactant: O=c1ccc(Br)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCn1cc(Br)ccc1=O
Temperature: 60 °C
Yield: 75.6 %

Procedure:
To a solution of 5-bromo-2(1H)-pyridone (0.10 g, 0.57 mmol) in acetone (5.0 ml) was added K2CO3 (0.18 g, 2.60 mmol followed by addition of 2-bromo-ethyl-methylether (0.24 g, 1.70 mmol). The resulting reaction mixture was heated to 60° C. for 16 h. After the completion of reaction (TLC monitoring), acetone was distilled off, added water and extracted with DCM (3×10 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (60-120 M, 1% MeOH-DCM) to obtain the desired product (0.10 g, 75%). MS: 232.01 (M+H)+.