Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@@H:11]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])/[C:12](/O)=[CH:13]/[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:30].[C:31]([O-])(=O)[CH3:32].[NH4+].ClCC=O>>[C:17]([O:16][C:14]([C:13]1[CH:32]=[CH:31][NH:30][C:12]=1[C@H:11]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: N
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)/C=C(\O)[C@@H](CCOCc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=CCCl
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N[C@H](CCOCc1ccccc1)c1[nH]ccc1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
(R)-tert-Butyl 6-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-3-oxohexanoate (724a, 6.60 g, 16.20 mmol) was treated with NH3 (2 M in MeOH, 81 mL, 162 mmol) and ammonium acetate (9.36 g, 121 mmol) at RT. The resulting mixture was stirred for at 50° C. for 30 min, then treated with chloroacetaldehyde (50 wt % in water, 10.42 mL, 81 mmol) and stirred at 50° C. for 2 h. The reaction mixture was stirred at RT overnight (16 h). The reaction mixture was concentrated to remove most of MeOH and partitioned between sat'd NaHCO3 (100 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (2×50 mL), and the combined organic extracts were washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure (rotary evaporator) to afford the crude product as a brown oil. The crude residue was purified on an ISCO Combiflash RF (160 g Thomson SingleStep column, using a gradient of 0-10% EtOAc in DCM) affording (R)-tert-butyl 2-(3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)propyl)-1H-pyrrole-3-carboxylate (724b, 4.31 g, 10.01 mmol, 61.8% yield) as a light yellow viscous oil upon concentration of the product containing fractions. m/z (ESI, +ve) 453.2 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[Br:11]Br.O>C(O)(=O)C>[Br:11][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH3:1])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
To a solution of 4-hydroxyacetophenone (6.8 g, 0.05 mol, 1 eq) in 60% acetic acid (50 mL), was added a solution of bromine (2.6 mL, 0.05 mol, 1 eq) in 80% acetic acid (20 mL). After stirring at room temperature for 30 min, the reaction mixture was poured into 100 mL of cold water. The solid was filtered and the filtrate was further diluted with 500 mL of cold water. The white precipitate was collected by filtration, washed with water and dried under vacuum to afford 4.2 g (39%) of 1-(3-bromo-4-hydroxyphenyl)ethanone (15) as white solid. 1HNMR (CDCl3, 400 MHz): δ 8.15 (s, 1H), 7.86 (d, 1H), 7.18 (d, 1H), 5.96 (s, 1H), 2.56 (s, 3H). MS (ES-API): M+1=216.9. HPLC (Method B) tR=2.48 min.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[N:32]1[C:40]2[C:35](=[N:36][CH:37]=[CH:38][CH:39]=2)[N:34]([C:41]2[CH:42]=[C:43]3[C:47](=[CH:48][CH:49]=2)[CH:46]([C:50](O)=[O:51])[CH2:45][C:44]3=[O:53])[CH:33]=1.[C:54]([C:58]1[CH:59]=[C:60]([NH2:69])[N:61]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[N:62]=1)([CH3:57])([CH3:56])[CH3:55]>CN(C=O)C>[C:54]([C:58]1[CH:59]=[C:60]([NH:69][C:50]([CH:46]2[C:47]3[C:43](=[CH:42][C:41]([N:34]4[C:35]5=[N:36][CH:37]=[CH:38][CH:39]=[C:40]5[N:32]=[CH:33]4)=[CH:49][CH:48]=3)[C:44](=[O:53])[CH2:45]2)=[O:51])[N:61]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[N:62]=1)([CH3:57])([CH3:55])[CH3:56]
Reactant: O=C1CC(C(=O)O)c2ccc(-n3cnc4cccnc43)cc21
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)C2CC(=O)c3cc(-n4cnc5cccnc54)ccc32)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
HATU (46.7 mg, 0.12 mmol) and triethylamine (29.5 μL, 0.21 mmol) are added to a solution of (R/S)-5-imidazo[4,5-b]pyridine-3-yl-3-oxo-indan-1-carboxylic acid (30 mg, 0.1 mmol) in DMF (2.5 mL). The reaction is stirred at rt for 2 min then 5-tert-butyl-2-phenyl-2H-pyrazol-3-ylamine (21.5 mg, 0.1 mmol) is added. After stirring at rt for 8 h, DMF is removed in vacuo. The residue is purified by reversed phase MPLC using ACN/Water as eluant and 5-imidazo[4,5-b]pyridine-3-yl-3-oxo-indan-1-carboxylic acid (5-tert-butyl-2-phenyl-2H-pyrazol-3-yl)-amide is obtained as a white solid. Title compound: ES-MS: 491.00 [M+H]+, tR=1.6 min (System 2).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].S(OC)([O:11][CH3:12])(=O)=O.[CH3:15][O-].[Na+]>CO>[CH3:15][O:7][C:3]1([O:11][CH3:12])[CH2:4][CH2:5][CH2:6][N:2]1[CH3:1]
Reactant: COS(=O)(=O)OC
Reactant: CN1CCCC1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC1(OC)CCCN1C
Temperature: 90 °C

Procedure:
To a mixture containing 10 mL (10.28 g, 104 mmol) of N-methyl-2-pyrrolidinone and 10 mL (13.25 g, 105 mmol) of dimethyl sulfate was stirred and heated at 90° C. for 1.5 h, then allowed to cool to room temperature. A solution containing 25 mL of 25% methanolic sodium methoxide and 72 mL of methanol was added at −10° C. under Ar over a period of 1 h. The precipitated solid was filtered and the solvent was concentrated under diminished pressure. The residue was dissolved in 100 mL of ether and stirred for 1 h, then the precipitated solid was filtered. The solid was washed with two 10-mL portions of ether. After concentration under diminished pressure, the residue was distilled in vacuo to give 2,2-dimethoxy-1-methylpyrrolidine as a yellow liquid: yield 4.42 g (29%); 1H NMR (CDCl3) δ 1.62-1.74 (m, 2H), 1.83 (t, 2H, J=7.8 Hz), 2.28 (s, 3H), 2.78 (t, 2H, J=6.6 Hz), 3.15 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=2)[CH:6]=1.[CH3:29][S:30]([O-:32])=[O:31].[Na+].N1CCC[C@H]1C(O)=O.CS(C)=O>O.[Cu]I>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:11]=2)[CH:6]=1
Reactant: CS(=O)[O-]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc3ccc(Br)cc23)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc3ccc(S(C)(=O)=O)cc23)cc1
Temperature: 115 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
A mixture of [6-bromo-4-(4-ethanesulfonyl-phenoxy)-naphthalen-2-yl]-acetic acid methyl ester (32 mg, 0.07 mmol, methyl ester of example 15-1), sodium methanesulfinate (10 mg, 0.09 mmol), L-proline (4 mg, 0.028 mmol), copper(I) iodide (3 mg, 0.014 mmol) and dimethyl sulfoxide (0.3 mL) was stirred at 115° C. overnight under an argon atmosphere. The resulting mixture was diluted with water (5 mL), and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (30% ethyl acetate in petroleum ether) to give [4-(4-ethanesulfonyl-phenoxy)-6-methanesulfonyl-naphthalen-2-yl]-acetic acid methyl ester (11 mg) as a yellow solid.
Reaction SMILES: N#CN.C(O)(=O)C.C(O)(=O)C.C(N)=N.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=1[N+:25]([O-])=O>[Ni].CO>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[NH2:25]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: N#CN
Agent: N=CN
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc(Cl)c(N)c1
Reaction time: 1 h

Procedure:
1.5 g of cyanamide, 1.5 g of acetic acid, 2 g of Raney nickel (60%, aqueous), and 120 ml of methanol are introduced in an autoclave equipped with gas introduction stirrer. Under a hydrogen pressure of 4 bar and a temperature of 25° C., the cyanamide is hydrogenated quantitatively to the formamidine acetate. 40.8 g of 1-chloro-2,4-dinitrobenzene are then added to the autoclave, and the hydrogenation is carried out at a pressure of 10 bar and a temperature of 60° C. The hydrogenation time is 1 hour. 1-Chloro-2,4-diaminobenzene, 97.5% pure (analysed as 1-Chloro-2,4-acetamidobenzene by liquid chromatography), is obtained in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.[H-].[Na+].O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH2:16][C:15]3[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Clc1nccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1ccc(Cn2ncc3c(Cl)nccc32)cc1

Procedure:
To 4-chloro-1H-pyrazolo[4,3-c]pyridine (60 mg, 0.40 mmol) in 2 ml DMF was added 4-Fluorobenzylbromide (0.060 ml, 0.48 mmol) then add NaH (20 mg, 0.4 mmol) and stir at room temperature overnight. Work up by adding water and EtOAc and extract three times with EtOAc. Pool all organics and wash one time with brine then dry over sodium sulfate, filter and concentrate to dryness. The residue was purified by chromatography over silica gel (eluted with Hexanes/EtOAc 99:1 to 50:50) to provide 38 mg of major isomer A and 15 mg of minor isomer B.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:21]2[C:22]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=3[O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:9]=[C:10]([N:12](S(C)(=O)=O)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[CH2:35]([O:34][C:28]1[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:27]=1[C:22]1[C:21]([C:8]2[CH:9]=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2-c2cc(Cl)ccc2OCc2ccccc2)cc(N(S(C)(=O)=O)S(C)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Nc1cc(C(=O)O)cc(-c2ccccc2-c2cc(Cl)ccc2OCc2ccccc2)c1
Temperature: 50 °C

Procedure:
2-Benzyloxy-5-chloro-5″-dimethanesulfonylamino-[1,1′;2′,1″]terphenyl-3″-carboxylic acid ethyl ester was dissolved in ethanol (5 ml) and 1M sodium hydroxide (1 ml, 1 mmol) and left at room temperature for 5 hours then heated at 50° C. for 1 hour. The resulting solution was diluted with water, acidified with 1M hydrochloric acid and extracted with diethyl ether. The organic phase was dried (MgSO4), evaporated to dryness and triturated with diethyl ether/iso-hexane to yield the title compound as a white solid. (21 mg, 46%).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][NH:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7].[OH-].[K+].[CH3:28][CH2:29][OH:30]>>[CH2:29]([O:30][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:8]([C:6]([NH:5][CH2:4][C:3]([OH:2])=[O:25])=[O:7])[N:9]=1)[CH3:28]
Reactant: CCO
Reactant: COC(=O)CNC(=O)c1nc(Cl)c2ccccc2c1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: CCOc1nc(C(=O)NCC(=O)O)c(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of [(1-Chloro-4-phenyl-isoquinoline-3-carbonyl)-amino]-acetic acid methyl ester (177 mg, 0.5 mmol), KOH (325 mg, 5 mmol) and EtOH (10 ml) was stirred at ambient temperature for 90 min before the solvent was evaporated in vacuo. The residue was dissolved in water (10 ml). The solution was acidified by addition of concentrated aqueous HCl and extracted with EtOAc (2×15 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo to give the title compound as a slightly yellowish solid (169 mg); MS-(+)-ion: M+1=351.0.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:2]1=2.[CH3:11][C:12](=O)[CH2:13][CH2:14][C:15](=O)[CH3:16].C(O)(=O)C>C1C=CC=CC=1.C(OCC)C>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([N:10]3[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]3[CH3:11])[CH:8]=[CH:9][C:2]1=2
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1ccc2sccc2c1
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: Cc1ccc(C)n1-c1ccc2sccc2c1
Temperature: 25 °C
Yield: 95 %

Procedure:
A stirred solution of benzo[b]thiophen-5-amine (2.48 g, 17.0 mmol), hexane-2,5-dione (1.95 mL, 17.0 mmol) and glacial acetic acid (0.2 mL) in benzene (35 mL) was heated to reflux under a Dean-Stark head. After 14 h the reaction was cooled to r.t., diluted with diethyl ether (40 mL), and successively washed with aqueous 2 N hydrochloric acid (30 mL), brine (30 mL), a saturated aqueous solution of sodium hydrogen carbonate (30 mL) and finally brine (30 mL). The organic layer was separated, dried over magnesium sulfate, filtered and the solvent evaporated in vacuo to yield 1-(benzo[b]thiophen-5-yl)-2,5-dimethyl-1H-pyrrole (3.67 g, 97%) as a light orange crystalline solid. 1H NMR δ (CDCl3, 400 MHz) 2.04 (s, 6H), 5.93 (s, 2H), 7.19 (dd, J=8, 2 Hz, 1H), 7.37 (d, J=5 Hz, 1H), 7.55 (d, J=5 Hz, 1H), 7.66 (d, J=2 Hz, 1H), 7.94 (d, J=9 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH2:8][N:7]([C:14](=[O:16])[CH3:15])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1>>[C:14]([N:7]1[CH2:8][CH2:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:19]3[N:24]=[C:23]([NH:25][C:26]4[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=4[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=3)=[CH:17][C:6]1=2)(=[O:16])[CH3:15]
Reactant: CC(=O)N1CCCC(C)(C)c2ccc(N)cc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)N(C(C)=O)CCCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 1-(8-Amino-5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide to yield a yellow solid (43%). LCMS: m/z=511.47 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.89 (bs, 1H), 8.08 (s, 1H), 7.60 (d, 1H, J=1.8 Hz), 7.39 (m, 2H), 7.25 (m, 3H), 6.91 (d, 1H, J=8.3 Hz), 6.85 (bs, 1H), 4.62 (m, 1H), 2.97 (d, 3H, J=4.8 Hz), 2.41 (m, 1H), 2.15 (m, 1H), 1.72 (s, 3H), 1.65 (m, 2H), 1.47 (m, 1H), 1.34 (s, 3H), 1.13 (s, 3H).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH:7]([CH:9]1[C:13]2([CH2:15][CH2:14]2)[NH:12][C:11](=[O:16])[CH2:10]1)=C>CO.O.[Os](=O)(=O)(=O)=O>[O:16]=[C:11]1[CH2:10][CH:9]([CH:7]=[O:2])[C:13]2([CH2:15][CH2:14]2)[NH:12]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC1CC(=O)NC12CC2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=CC1CC(=O)NC12CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Osmium tetroxide (55 mg, 0.22 mmol) and sodium periodate (1.4 g, 6.6 mmol) were added in portions to a solution of 7-ethenyl-4-azaspiro[2.4]heptan-5-one (0.50 g, 3.3 mmol) in methanol (8 mL) and water (12 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered and the filtrate was dried under reduced pressure to afford 5-oxo-4-azaspiro[2.4]heptane-7-carbaldehyde. The material was used in the next step without purification. MS ESI calc'd. for C7H10NO2 [M+H]+ 140. found 140.
Reaction SMILES: [H-].[Na+].[C:3]([C:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[C:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:11]([CH3:29])[NH:10][C:9]=1[CH3:30])([O:5][CH2:6][CH3:7])=[O:4].CN(C)C=[O:34].[O:36]1[CH2:40][CH2:39]C[CH2:37]1>C(#N)C>[C:37]([N:10]1[C:9]([CH3:30])=[C:8]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[C:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:11]1[CH3:29])([O:36][CH2:40][CH3:39])=[O:34]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)C1=C(C)N(C(=O)OCC)C(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F

Procedure:
To 1.2 g. of sodium hydride (57% dispersion in mineral oil) suspended in tetrahydrofuran is added dropwise with stirring a solution of 10 g. of 3,5-dicarbethoxy-1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)pyridine in tetrahydrofuran. The mixture is heated on a steam bath for 15 minutes, then it is cooled and enough dimethylformamide is added to dissolve the solid which has separated. To the resulting solution is added dropwise 3.04 g. of ethyl chloroformate and the reaction mixture is stirred at 25° for 15 minutes then heated on a steam bath for 12 hours. The mixture is filtered and concentrated to give an oil which is dissolved in acetonitrile. The solution is extracted with petroleum ether then concentrated to give an oil which is stirred with petroleum ether. The solid formed is filtered and the filtrate is concentrated in vacuo to give an oil which is chromatographed on an alumina "dry column" with methylene chloride as eluant to give 1,3,5-tricarbethoxy-1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl)pyridine, m.p. 56°-58°C.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7](Cl)[C:6]([CH:10]([CH3:12])[CH3:11])=[C:5]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH:21]3[O:25][CH2:24][CH2:23][O:22]3)[CH:15]=2)[N:4]=1.[CH2:26]([OH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][C:3]1[N:8]=[C:7]([O:22][CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:14][CH:15]=2)[C:6]([CH:10]([CH3:12])[CH3:11])=[C:5]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH:21]3[O:25][CH2:24][CH2:23][O:22]3)[CH:15]=2)[N:4]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cc(Oc2nc(Cl)nc(Cl)c2C(C)C)cc(C2OCCO2)c1
Reactant: OCc1ccccc1
Agent: [Na]
Product: Cc1cc(Oc2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)cc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a stirred anhydrous benzyl alcohol (10 ml) under nitrogen atmosphere at room temperature, was added sodium metal (285 mg, 12.41 mmol). After 1 hr., 2,4-dichloro-6-(3-[1,3]dioxolan-2-yl-5-methyl-phenoxy)-5-isopropyl-pyrimidine (1.91 g, 5.17 mmol) in anhydrous benzyl alcohol (7 ml) was added. After stirring for overnight at room temperature, the mixture was evaporated in vacuo. The residue was dissolved in dichloromethane, filtered through a celite pad and the pad was washed with dichloromethane. The combined filtrate was then evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:10)) to afford 1.52 g (57%) of a colorless syrup. 1H NMR (200 MHz, CDCl3) δ 1.30 (6H, d, J=7.2 Hz), 2.39 (3H, s), 3.43 (1H, m), 4.02-4.13 (4H, m), 5.12 (2H, s), 5.42 (2H, s), 5.81 (1H, s), 6.92 (1H, s), 7.07 (1H, s), 7.16 (1H, s), 7.20-7.43 (10H, m).
Reaction SMILES: [CH2:1](I)[CH3:2].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9](=[CH2:13])[C:10]([OH:12])=[O:11].C(N(C(C)C)CC)(C)C>C(#N)C>[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9](=[CH2:13])[C:10]([O:12][CH2:1][CH3:2])=[O:11]
Reactant: CCI
Reactant: C=C(C(=O)O)c1ccco1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C(=O)OCC)c1ccco1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Ethyl iodide (64 mL, 0.796 mol) was added to furylacrylic acid (100 g, 0.724 mol), diisopropylethyl amine (140 mL, 0.796 mmol), in acetonitrile (1100 mL), and the mixture was heated to 60° C. After 18 h, the dark solution was cooled to room temperature and concentrated in vacuo. The resulting brown sludge was diluted with Et2O (500 mL), washed with 1 N aqueous HCl (2×250 mL), washed with 0.2 N aqueous NaOH (2×250 mL), washed with saturated aqueous NaH.CO3 (1×250 ML), dried (MgSO4), filtered, and concentrated to a black oil (114 g, 95%). 1H NMR (DMSO-d6, 300 MHz) δ 7.84 (d, J=1.7 Hz, 1H), 7.46 (d, J=15.6 Hz, 1H), 6.97 (d, J=3.4 Hz, 1H), 6.33 (dd, J=3.4 Hz, J=1.7 Hz, 1H), 6.22 (d, J=15.9 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H); MS (APCI) m/z 167 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]3[O:19][CH2:20][C:21]4[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=4[CH:23](O)[C:17]=3[CH:16]=1)=[N:7]2.[SH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35]>>[C:34]([CH2:33][CH2:32][S:31][CH:23]1[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[CH2:20][O:19][C:18]2[CH:29]=[CH:30][C:15]([O:14][CH2:13][C:6]3[CH:5]=[CH:4][C:3]4[C:8](=[CH:9][CH:10]=[C:11]([F:12])[C:2]=4[Cl:1])[N:7]=3)=[CH:16][C:17]1=2)([OH:36])=[O:35]
Reactant: O=C(O)CCS
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4c(Cl)c(F)ccc4n3)cc21
Product: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4c(Cl)c(F)ccc4n3)cc21

Procedure:
2-(5-Chloro-6-fluoroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[N:13]=[CH:14]2)=[CH:9][CH:8]=1)(=O)=O.[OH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[OH:23][C:24]1[CH:29]=[CH:28][C:27]([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[N:13]=[CH:14]3)=[CH:9][CH:8]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: COC(=O)c1cc2ccc(OS(=O)(=O)C(F)(F)F)cc2cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cc2ccc(-c3ccc(O)cc3)cc2cn1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 45.9 %

Procedure:
A suspension of 38 g (113 mmol) of methyl 7-{[(trifluoromethyl)sulfonyl]oxy}-3-isoquinolinecarboxylate, 23.4 g (170 mmol) of (4-hydroxyphenyl)boronic acid, 6.54 g (5.67 mmol) of tetrakistriphenylphosphine palladium(0) and 200 mL of 2.0 M Na2CO3 (aq) in 700 mL of 1,2-dimethoxyethane was stirred at 50° C. for 90 min. The suspension was filtered through a pad of Celite® and the filter cake was washed with EtOAc. The combined organics were washed with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine before being dried with Na2SO4, filtered and concentrated. Ethyl acetate was added and the mixture was stirred and heated. The mixture was filtered and the concentrated filtrate was purified by silica gel chromatography (eluting with 0-20% acetone in CH2Cl2). Fractions containing the product were combined and concentrated and combined with the solid which had been collected by filtration to give 14.50 g (46%) of methyl 7-(4-hydroxyphenyl)-3-isoquinolinecarboxylate. 1H NMR (400 MHz, DMSO-d6): δ 9.75 (s, 1H), 9.38 (s, 1H), 8.42 (s, 1H), 8.23 (s, 1H), 8.21 (d, J=8 Hz, 1H), 8.15 (d, J=8 Hz, 1H), 7.72 (d, J=9 Hz, 2H), 6.91 (d, J=9 Hz, 2H), 3.91 (s, 3H). ESI-LCMS m/z 280 (M+H)+.