Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:6]1.C(N(CC)CC)C.[CH2:27]([O:29][C:30](=[O:41])[C:31]1[CH:36]=[C:35]([CH2:37]Br)[CH:34]=[CH:33][C:32]=1[O:39][CH3:40])[CH3:28]>ClCCl>[CH2:27]([O:29][C:30](=[O:41])[C:31]1[CH:36]=[C:35]([CH2:37][N:17]2[CH2:18][CH2:19][CH:14]([C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH:6]=3)[CH2:15][CH2:16]2)[CH:34]=[CH:33][C:32]=1[O:39][CH3:40])[CH3:28]
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Reactant: COCCn1cc(C2CCNCC2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(CN2CCC(c3cn(CCOC)c4ccccc34)CC2)ccc1OC
Yield: 87.9 %

Procedure:
Over a solution of 6.5 g (0.025 mol) of 1-(2-methoxyethyl)-3-piperidin-4-yl-1H-indole in 90 ml of dichloromethane and 3.9 ml (0.026 mol) of triethylamine, a solution of 7.2 g (0.026 mol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester in 15 ml of dichloromethane was added. The crude mixture was stirred at room temperature for 24 hours. After standard work-up and purification by chromatography over silica gel, 9.9 g (70% of yield) of 2-methoxy-5-{4-[1-(2-methoxyethyl)-1H-indol-3-yl]piperidin-1-ylmethy}-benzoic acid ethyl ester were obtained.
Reaction SMILES: I[CH3:2].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH2:14])=[S:13])=[CH:7][CH:6]=1)#[N:4]>CC(C)=O>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]=[C:12]([S:13][CH3:2])[NH2:14])=[CH:9][CH:10]=1)#[N:4]
Reactant: N#Cc1ccc(NC(N)=S)cc1
Reactant: CI
Solvent: CC(C)=O
Product: CSC(N)=Nc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Iodomethane (1.76 ml) was added to 4-cyanophenyl-thiourea (5.0 g) in acetone (100 ml). The reaction mixture was stirred overnight at RT. The precipitate was filtered off, dried and dissolved in DCM. The organic solution was washed with NH3 (aq.) (excess), dried with potassium carbonate, filtered, and the solvent was evaporated, yielding 4.53 g (84%, white solid) of methyl N′-(4-cyanophenyl)-carbamimidothioate (intermediate 6).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:28])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:27])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[C:5](=[O:12])[CH2:6]C(OCC)=O.Br[CH2:30][C:31]([CH3:58])=[CH:32][CH2:33][CH2:34][C:35]([CH3:57])=[CH:36][CH2:37][CH2:38][C:39]([CH3:56])=[CH:40][CH2:41][CH2:42][C:43]([CH3:55])=[CH:44][CH2:45][CH2:46][C:47]([CH3:54])=[CH:48][CH2:49][O:50]C(=O)C>CCOCC>[CH3:54][C:47]([CH2:46][CH2:45][CH:44]=[C:43]([CH3:55])[CH2:42][CH2:41][CH:40]=[C:39]([CH3:56])[CH2:38][CH2:37][CH:36]=[C:35]([CH3:57])[CH2:34][CH2:33][CH:32]=[C:31]([CH3:58])[CH2:30][CH2:6][C:5](=[O:12])[CH:4]([CH3:3])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:28])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:27])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[CH:48][CH2:49][OH:50]
Reactant: CC(=O)OCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CBr
Reactant: CCOC(=O)CC(=O)C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)C(=O)CCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
To a suspension of sodium hydride (2.64 g) in ether (100 ml), a solution of ethyl 3,7,11,15-tetramethyl-6,10,14-hexadecatrien-2-one-1-carboxylate (18.1 g) in ether (18 ml) is dropwise added, and the resulting mixture is dropwise added, and the resulting mixture is stirred for 30 minutes. Then, a solution of 1-bromo-2,6,10,14,18-pentamethyl-20-acetoxy-2,6,10,14,18-eicosapentaene (26 g) in ether (26 ml) is dropwise added thereto. The reaction mixture is poured into ice water. The ether layer is washed with water, dried and evaporated. The residual material is treated as in Example 1 (4) to give 3,7,11,15,19,23,27,31, 35-nonamethyl-2,6,10,14,18,26,30,34-hexatriacontaoctaen-22-on-1-ol (29 g). IR: 3400, 1000 cm-1 (OH); 1705 cm-1 (C=O); 1668 cm-1 (C=C). NMR (carbon tetrachloride): δ 1.59 (s), 1.66 (s), 2.01 (m), 2.7 (m), 4.1 (m), 5.05 (m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[C:22]([CH:25]2[CH2:29][O:28]C(C)(C)[O:26]2)[CH:21]=[CH:20]3)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].Cl>C1COCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[C:22]([CH:25]([OH:26])[CH2:29][OH:28])[CH:21]=[CH:20]3)[CH2:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(C4COC(C)(C)O4)nc23)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(C(O)CO)nc23)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To tert-butyl(1-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)quinolin-8-yl)piperidin-4-yl)methylcarbamate (81 mg, 0.18 mmol) in THF (3 mL) was added HCl (20 mg, 0.55 mmol) (6M). The reaction was stirred for 3 hours at ambient temperature and then diluted with EtOAc (10 mL) and saturated NaHCO3 (5 mL). The phases were separated, and the organic layer was dried and concentrated to give crude product.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6](=[O:27])[C:7](=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]=[N+:14]=[N-:15])#[N:2].[NH2:28]/[C:29](/[CH3:35])=[CH:30]\[C:31]([O:33][CH3:34])=[O:32]>CCO>[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][C:8]1[NH:28][C:29]([CH3:35])=[C:30]([C:31]([O:33][CH3:34])=[O:32])[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[C:7]=1[C:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])=[O:27])=[N+:14]=[N-:15]
Reactant: COC(=O)/C=C(/C)N
Reactant: N#CCCOC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)CCCCN=[N+]=[N-]
Solvent: CCO
Product: COC(=O)C1=C(C)NC(CCCCN=[N+]=[N-])=C(C(=O)OCCC#N)C1c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 7-azido-2-[(4-nitrophenyl)methylene]-3-oxoheptanoicacid2-cyanoethyl ester (2.87 g, 7.73 mmol) and methyl 3-aminocrotonate (0.900 g, 7.73 mmol) in 50 ml of EtOH was refluxed for 48 hrs. After the EtOH was removed in vacuo, the residue was dissolved in 150 ml of CHCl3, washed with water (2×100 ml) and dried over Na2SO4. After filtration and evaporation of solvent, the product was purified by chromatography (SiO2, CHCl3 :MeOH=95:5). 2-(4-Azidobutyl)-3-(2-cyanoethoxy)carbonyl-1,4-dihydro-5-methoxycarbonyl-6-methyl-4-(4-nitrophenyl)pyridine was obtain as a yellow oil (2.43 g, 67% yield).
Reaction SMILES: Cl[C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22].[NH4+:23].[OH-]>O1CCOCC1>[NH2:23][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22]
Reactant: [NH4+]
Reactant: C[C@]12CCC(=O)C(Cl)=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@]12CCC(=O)C(N)=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 24 h
Yield: 31 %

Procedure:
A mixture of 4-chloroandrost-4-ene-3,17-dione (1.93 g, 6 mmole), dioxane (60 ml) and 30% NH4OH aqueous solution (120 ml) is stirred at room temperature during 24 hours. The organic solvent and excess of ammonia are evaporated in vacuo and the resulting aqueous residue is acidified to pH 1 by carefully adding conc. HCl. The aqueous solution is washed twice with ethyl acetate and brought to pH 11 by carefully adding conc. NaOH. The resulting precipitate is filtered off, washed with water and dried under vacuum at 40° C. There are obtained 559 mg (1.86 mmole, 31% yield) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([CH:19]([OH:29])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-])=O)[C:15]([O:17]C)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.O.[Fe]>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]2[CH:19]([OH:29])[C:20]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:26][C:15]2=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(C1CCN(Cc2ccccc2)CC1)C(O)c1ccccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2C(O)C1C1CCN(Cc2ccccc2)CC1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
Methyl 2-(1-benzylpiperidin-4-yl)-3-hydroxy-3-(2-nitrophenyl)propanoate (2.4 mmol, 950 mg) was dissolved in acetic acid (20 mL). Iron (17.7 mmol, 1.0 g) was added to the mixture. Reaction was heated at 85° C. and held with stirring for 1.5 hours. Mixture was cooled to room temperature then diluted with water (30 mL). Solids were decanted off. The aqueous solution was concentrated in vacuo. Residue was treated with ethyl acetate (50 mL). The mixture was made basic with aqueous sodium hydroxide. Celite was added to the resulting suspension to create a slurry. Mixture was filtered. Filtrate layers were separated. Aqueous layer was extracted 1× ethyl acetate. Combined organic layers were dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained without further purification as yellow oil in 69% yield. MS m/e (M+H)+=335.3.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH2:17]([N:20]1[C:28]2[C:23](=[CH:24][C:25](/[C:29](/[CH3:34])=[CH:30]/[C:31](O)=[O:32])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1)[CH2:18][CH3:19]>>[CH2:17]([N:20]1[C:28]2[C:23](=[CH:24][C:25](/[C:29](/[CH3:34])=[CH:30]/[C:31]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:32])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1)[CH2:18][CH3:19]
Reactant: CCCn1ccc2cc(/C(C)=C/C(=O)O)ccc21
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: CCCn1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
177 mg of compound 4 was obtained in a similar manner to those described in the Example 1 and 2 using 481 mg of ethyl 4-(2-aminophenoxy)butyrate and 262 mg of 3-(1-propylindol-5-yl)isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [C:1]([O:5][C:6]([O:8]N=C(C1C=CC=CC=1)C#N)=O)([CH3:4])([CH3:3])[CH3:2].[CH:19]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:21][CH2:20]1.Cl>C(OCC)(=O)C>[CH:19]1([N:22]2[CH2:27][CH2:26][N:25]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:8])[CH2:24][CH2:23]2)[CH2:21][CH2:20]1
Reactant: C1CN(C2CC2)CCN1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Solid 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile (3.2 g, 0.013 mole) was added in one portion to a solution of 1.5 g (0.012 mole) 1-cyclopropylpiperazine in 30 ml ethyl acetate. The solution was stirred at room temperature for 3 hours and then treated with 100 ml dilute aqueous HCl. The aqueous phase was separated, extracted with additional ethyl acetate (discarded), treated with excess 10% NaOH, and extracted with ether. The ether extracts were dried (MgSO4), filtered, and evaporated in vacuo to yield a semi-solid residue. Recrystallization from hexane at -70° C. gave 1.9 g white, crystalline solid, m.p. 65°-67° C. Calculated for C12H22N2O2 (226.32): C, 63.98; H, 9.80; N, 12.38; O, 14.14. Found: C, 63.82; H, 9.82; N, 12.60; O, 13.90.
Reaction SMILES: Br.[NH2:2][CH:3]1[CH2:7][CH2:6][O:5][C:4]1=[O:8].[C:9](=N)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.O>[C:10]1([C:9](=[N:2][CH:3]2[CH2:7][CH2:6][O:5][C:4]2=[O:8])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC1CCOC1=O
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: Br
Solvent: ClCCl
Solvent: O
Product: O=C1OCCC1N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3-aminodihydrofuran-2(3H)-one hydrobromide (5 g, 27.5 mmol) in DCM (50 mL) was added benzophenone imine (5 g, 27.5 mmol) and the reaction mixture was stirred at RT for 3 days. The reaction mixture was diluted with water and DCM, the organic layer was extracted, washed with aquous sodium bicarbonate, brine, dried over sodium sulfate and concentrated in vacuo to give 3-[(diphenylmethylene)amino]dihydrofuran-2(3H)-one as a thick colorless gel which crystallized to a white solid.
Reaction SMILES: C(OO)(=[O:3])C.[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1>>[N+:6]1([O-:3])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc2ncccc2c1
Reactant: CC(=O)OO
Product: [O-][n+]1cccc2ccccc21

Procedure:
Peracetic acid (7.5 mL, 39 mmole, 40%) and quinoline (5 g, 39 mmole) were stirred for 2 hours. Much of the acetic acid was removed from the reaction mixture in vacuo. The resulting residue was dissolved in methylene chloride (50 mL) and washed twice with saturated sodium bicarbonate solution. After drying over MgSO4 the solvent was evaporated and the residue was triturated with ether. The resulting tan solid was collected by filtration. This material was carried on without further characterization.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[C:5]2[CH:9]=[CH:10][S:11][C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:6]1[C:5]2[CH:9]=[CH:10][S:11][C:4]=2[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc2sccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc2sccc2c(Cl)n1

Procedure:
A solution of 6.2 g of 6-methylthieno[3,2-c]pyridin-4(5H)-one in 30 ml of phosphoryl chloride was heated under reflux for 1 hour. After being cooled, the excess phosphoryl chloride was removed under reduced pressure, and the residue was poured into ice water, made basic with aqueous 2N sodium hydroxide and extracted with chloroform. The extract was washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure to give 7.0 g of 4-chloro-6-methylthieno[3,2-c]pyridine as a brown oily material.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:3]=1.[Br:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1>>[CH2:19]([O:18][C:4]1[CH:3]=[C:2]([NH:1][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([Br:26])=[CH:28][CH:29]=2)[CH:17]=[CH:16][C:5]=1[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: O=Cc1ccc(Br)cc1
Product: O=C(OCc1ccccc1)c1ccc(NCc2ccc(Br)cc2)cc1OCc1ccccc1
Yield: 78 %

Procedure:
Primary aniline 1 was coupled to 4-bromobenzaldehyde on a 0.7 mmol scale via General Procedure A to furnish 2 (274 mg, 78%): δH (400 MHz, CDCl3) 4.12 (s, 2H, CH2, NHCH2Ph), 4.50 (br s, 1H, NH), 4.92 (s, 2H, CH2, CH2Ph), 5.18 (s, 2H, CH2, CH2Ph), 5.98 (d, J=1.8 Hz, 1H, CH (Ph)), 6.04 (dd, J=8.6 and 1.8 Hz, 1H, CH (Ph)), 7.02 (d, J=8.2 Hz, 2H, 2 CH (Ph)), 7.11-7.34 (m, 12H, 12 CH (Ph)), 7.70 (d, J=8.6 Hz, 1H, CH (Ph)); δC (100 MHz, CDCl3) 46.5, 65.4, 69.9, 97.0, 104.5, 108.2, 120.7, 126.4, 127.2, 127.4, 127.6, 128.0, 128.1, 128.4, 131.4, 133.9, 136.3, 137.0, 152.3, 160.4, 165.3; LRMS (ES+) calcd for [C28H24BrNO3+H] 502.10. found 502.06.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=O)=[N:9][NH:8][C:7]2=[O:22].[CH2:23]([O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:24].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([N:29]3[CH2:30][CH2:31][CH:26]([O:25][CH2:23][CH3:24])[CH2:27][CH2:28]3)=[O:18])[CH:14]=1)=[N:9][NH:8][C:7]2=[O:22]
Reactant: CCOC1CCNCC1
Reactant: O=C(O)c1cccc(Cc2n[nH]c(=O)c3cccc(Cl)c23)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4cccc(Cl)c34)c2)CC1
Yield: 41 %

Procedure:
3-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (118) (200 mg, 0.64 mmol) and 4-ethoxypiperidine were added to DMF (5 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.170 mL, 0.95 mmol) and then HBTU (362 mg, 0.95 mmol). The solvent was removed and the crude product dissolved in acetonitrile and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (111 mg, 41.0% yield); 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, t), 1.17-1.46 (2H, m), 1.58-1.92 (2H, m), 2.97-3.42 (4H, m), 3.42-3.55 (3H, m), 4.68 (2H, s), 7.13 (1H, s), 7.21 (2H, t), 7.35 (1H, t), 7.81 (1H, t), 7.94-7.99 (1H, m), 8.32-8.36 (1H, m), 12.91 (1H, s); m/z (LC-MS, ESI+), RT=1.96 (M+H 426.7)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].Br[CH2:28][CH:29]([OH:33])[CH2:30][CH2:31]Br>>[OH:33][CH:29]1[CH2:30][CH2:31][N:1]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[NH:8][C:9](=[O:26])[C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=2[O:24][CH3:25])[CH2:28]1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: OC(CBr)CCBr
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1CCCCC1N1CCC(O)C1

Procedure:
The title compounds, both light yellow solids, MS: m/e=455.3 [(M+H)+], were prepared in accordance with the general method of example 10 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and 1,4-dibromo-2-butanol. The 2 diastereomers could be separated by column chromatography however the relative configuration was not assigned.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][N:19]3[CH:26]=2)=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.B(Br)(Br)Br.CO>ClCCl>[OH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:17]=[C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][N:19]3[CH:26]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc2nc(-c3ccc(OC(=O)c4ccccc4)cc3)cn2c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc(-c2cn3cc(O)ccc3n2)cc1
Temperature: -15 °C
Reaction time: 17 h
Yield: 89.5 %

Procedure:
4.90 g (corresponding to 14.83 mmol) of 2-(4′-benzoyloxyphenyl)-6-methoxyimidazo[1,2-a]pyridine that was sufficiently dried to remove moisture was dissolved in 245 mL of chloroform and cooled down to −15° C. To this solution, a solution of 12.62 mL (corresponding to 133.48 mmol) of boron tribromide in 134 mL of dichloromethane was added dropwise. After the temperature of the resulting solution was raised to room temperature, the solution was stirred for 17 hours. After the completion of the reaction, the reaction solution was cooled with ice and supplemented with 668 mL of methanol, and further stirred at room temperature for 3 hours. The reaction mixture was then concentrated under reduced pressure. The resulting crude product was supplemented with 290 mL of chloroform and 29 mL of methanol to obtain slurry, and then precipitates were filtered and recovered. The precipitates recovered were washed with chloroform and then dried under reduced pressure, to obtain 3.00 g (corresponding to 13.28 mmol) of 2-(4′-hydroxyphenyl)-6-hydroxyimidazo[1,2-a]pyridine (FIG. 3, Step 6).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([N:10]=[CH:11][C:12]([O:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([NH:25][C:26]([C:28]4[CH:29]=[CH:30][C:31]5[S:36][CH2:35][C:34](=[O:37])[NH:33][C:32]=5[CH:38]=4)=[O:27])[CH2:21][CH2:20]3)=[N:13]2)=[CH:8][CH:7]=1.C(N(CC)CC)C>CN(C)C=O>[O:37]=[C:34]1[NH:33][C:32]2[CH:38]=[C:28]([C:26]([NH:25][CH:22]3[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][O:16][C:12]4[CH:11]=[N:10][C:9]5[C:14]([N:13]=4)=[CH:15][C:6]([O:5][C:1](=[O:3])[CH3:2])=[CH:7][CH:8]=5)[CH2:20][CH2:21]3)=[O:27])[CH:29]=[CH:30][C:31]=2[S:36][CH2:35]1
Reactant: CC(=O)Cl
Reactant: O=C1CSc2ccc(C(=O)NC3CCN(CCOc4cnc5ccc(O)cc5n4)CC3)cc2N1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2ncc(OCCN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
Acetyl chloride (11.4 μL, 0.16 mmol, 1.1 eq) is added at room temperature to a stirred solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-hydroxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-amide (70 mg, 0.15 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed by triethylamine (40.7 μL, 0.29 mmol, 2.0 eq). After 1 hour stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×5 mL) and water (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford acetic acid 3-(2-{4-[(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)-amino]-piperidin-1-yl}-ethoxy)-quinoxalin-6-yl ester as a white powder (35 mg, 41% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-(3-bromophenyl)ethanol (7 g) in N,N-dimethylformamide (100 ml) were added tert-butyldimethylsilyl chloride (5.77 g) and imidazole (2.84 g) at 25° C. The mixture was stirred at 25° C. for 12 h. The reaction mixture was poured into water (500 ml) and extracted with ethyl acetate (100 ml×2). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography with mixed solvent of n-hexane and ethyl acetate to give [2-(3-bromophenyl)ethoxy](tert-butyl)dimethylsilane as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][C:10](=[O:23])[C:11]3[CH:17]=[C:16]([CH:18]([CH3:22])[C:19](N)=[O:20])[CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([OH:26])C.[OH-].[K+]>O>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][C:10](=[O:23])[C:11]3[CH:17]=[C:16]([CH:18]([CH3:22])[C:19]([OH:26])=[O:20])[CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1CC(=O)c1cc(C(C)C(N)=O)ccc1S2
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cccc2c1CC(=O)c1cc(C(C)C(=O)O)ccc1S2
Temperature: 85 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a mixture of 180 mg of 2-(10,11-dihydro-9-methoxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide and 5 ml of ethanol was added 700 mg of potassium hydroxide in 5 ml of water, and the resulting mixture was stirred at 75° C. for 1 hour and further at 85° C. for 2 hours. The solvent or ethanol was removed by distillation to obtain a mixture, to which was added water, and the resulting mixture washed with chloroform. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a red oily substance, which was chromatographed over 3 g of silica gel and eluted with chloroform, thereby obtaining 48 mg (yield: 27%) of 2-(10,11-dihydro-9-methoxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as a yellow oily substance.