Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([NH:18][C:17](=[O:19])[C:16]3[CH:20]=[C:21](/[CH:24]=[CH:25]/[C:26]([NH:28][O:29]C4CCCCO4)=[O:27])[CH:22]=[CH:23][C:15]=3[O:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([NH:18][C:17](=[O:19])[C:16]3[CH:20]=[C:21](/[CH:24]=[CH:25]/[C:26]([NH:28][OH:29])=[O:27])[CH:22]=[CH:23][C:15]=3[O:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3ccccc3)C1)O2)NOC1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3ccccc3)C1)O2)NO
Yield: 81.3 %

Procedure:
(±)-(E)-3-{1′-Benzyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (120 mg, 0.25 mmol) in DCM (7 ml) was treated with 4 M HCl in dioxane (1.0 ml) as described in Example 30, STEP C to give (±)-(E)-3-{1′-benzyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-hydroxy-acrylamide (80 mg, hydrochloride salt) as a white solid.
Reaction SMILES: [CH3:1][Li].[Br:3][C:4]1[CH:26]=[CH:25][C:7]2[O:8][CH2:9][CH2:10][C:11]([C:21]([O:23][CH3:24])=[O:22])=[C:12](OS(C(F)(F)F)(=O)=O)[C:6]=2[CH:5]=1>C(OCC)C.[Cu]I>[Br:3][C:4]1[CH:26]=[CH:25][C:7]2[O:8][CH2:9][CH2:10][C:11]([C:21]([O:23][CH3:24])=[O:22])=[C:12]([CH3:1])[C:6]=2[CH:5]=1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)c2cc(Br)ccc2OCC1
Reactant: [Li]C
Agent: [Cu]I
Solvent: CCOCC
Product: COC(=O)C1=C(C)c2cc(Br)ccc2OCC1
Reaction time: 0.33 h
Yield: 97 %

Procedure:
A solution of 0.4 M (Me)2CuLi was prepared via dropwise addition of methyl lithium in hexanes (1.6 M, 72 mmol, 45 mL) to a suspension of CuI (6.86 g, 36 mmol) in anhydrous diethyl ether (45 mL) in a ice-salt bath. After stirring for 20 min, a homogeneous solution resulted. The solution of dimethyl cuprate was slowly added to a solution of methyl 7-bromo-5-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydrobenzo[b]oxepine-4-carboxylate from step H4 (5.1 g, 11.8 mmol) in diethyl ether (40 mL) at −78° C. The mixture was stirred from −78° C. to −40° C. over 2 h. The reaction was quenched with 30 mL of water and the mixture was extracted with diethyl ether (2×200 mL). The combined organic layers were dried over sodium sulfate and concentrated to give methyl 7-bromo-5-methyl-2,3-dihydrobenzo[b]oxepine-4-carboxylate (3.41 g, 11.5 mmol, 97% yield). The crude mixture was used in the next step without purification. 1H NMR (500 MHz, chloroform-d) δ 7.45 (d, J=2.4 Hz, 1H), 7.40 (dd, J=8.5, 2.4 Hz, 1H), 6.95 (d, J=8.5 Hz, 1H), 4.53 (t, J=6.1 Hz, 2H), 3.84 (s, 3H), 2.54-2.49 (m, 2H), 2.45-2.42 (m, 3H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].C(Cl)(Cl)(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-].[C:18]1([CH:24]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:25]([OH:27])=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(Cl)(Cl)(Cl)Cl>[C:5]([C:24]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:25]([OH:27])=[O:26])(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCC(C(=O)O)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCC(C(C)=O)(C(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
A 500 ml reaction vessel was charged with 200 mls freshly distilled carbon tetrachloride and the CCl4 was cooled to 0°-5° C. Aluminum chloride (0.33 moles) was added, via Gooch tubing, to the CCl4 over a period of 20 minutes. Acetyl chloride (0.35 mol) was added to an addition funnel and charged to the CCl4 -AlCl3 mixture. Phenylstearic acid (0.125 moles) was then slowly added to the reaction mixture from an addition funnel while maintaining the temperature of the reaction mixture at 0°-5° C. The temperature was maintained at 0°-5° C. for one hour and at room temperature for an additional two hours. The evolution of HCl was observed.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C1COCC1>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][O:9][S:18]([CH3:17])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCCC1CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCCC1CCOS(C)(=O)=O

Procedure:
The 1-methyl-2-pyrrolidineethanol (Aldrich, 0.16 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [Cl-:1].[NH2:2][N+:3]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[C:4]=1[CH2:21][CH3:22].[CH3:23][N:24]([CH3:33])[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1>C(O)(=O)C>[Cl-:1].[CH2:21]([C:4]1[N:5]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:6]=[CH:7][N+:3]=1[N:2]=[CH:29][C:28]1[CH:31]=[CH:32][C:25]([N:24]([CH3:33])[CH3:23])=[CH:26][CH:27]=1)[CH3:22]
Reactant: CCc1n(Cc2cc(OC)c(OC)c(OC)c2)cc[n+]1N
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCc1n(Cc2cc(OC)c(OC)c(OC)c2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 52 h

Procedure:
1.9 g (5.8 mmol) of 1-amino-2-ethyl-3-(3,4,5-trimethoxybenzyl)imidazolium chloride are dissolved in 38 ml of glacial acetic acid, whereupon the solution is treated with 0.86 g (5.8 mmol) of p-dimethylaminobenzaldehyde, stirred at room temperature for 52 hours and then evaporated. The product is recrystallized from ethanol/ether. There is obtained 2-ethyl-1-[[p-(dimethylamino)benzylidene]amino]-3-(3,4,5-trimethyoxybenzyl)imidazolium chloride of melting point 211°.
Reaction SMILES: [C:1]([NH:4][C:5]12[CH2:10][CH:9]1[CH2:8][NH:7][CH2:6]2)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl[C:19]1[N:28]=[C:27]2[C:22]([C:23](=[O:35])[C:24]([C:32]([OH:34])=[O:33])=[CH:25][N:26]2[CH:29]2[CH2:31][CH2:30]2)=[CH:21][C:20]=1[F:36]>C(#N)C>[C:1]([NH:4][C:5]12[CH2:10][CH:9]1[CH2:8][N:7]([C:19]1[N:28]=[C:27]3[C:22]([C:23](=[O:35])[C:24]([C:32]([OH:34])=[O:33])=[CH:25][N:26]3[CH:29]3[CH2:31][CH2:30]3)=[CH:21][C:20]=1[F:36])[CH2:6]2)(=[O:3])[CH3:2]
Reactant: CC(=O)NC12CNCC1C2
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)NC12CC1CN(c1nc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Yield: 51 %

Procedure:
A mixture of 1-acetylamino-3-azabicyclo[3.1.0]hexane (150 mg, 0.70 mmol) and triethylamine (0.48 ml, 3.5 mmol) in acetonitrile (7 ml) was treated with 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (192.1 mg, 0.68 mmol) and heated to 80° for 18 hours. Filtration of the reaction mixture provided the title product as a white solid, mp 275° with decomposition (135.8 mg, 0.35 mmol, 51% yield). 1H NMR (CDCl3): 8.55 (s, 1H), 8.49 (s, 1H), 7.96 (d, J=13 Hz, 1H), 4.22 (m, 1H), 3.98 (bs, 2H), 3.81 (m, 1H), 3.68 (m, 1H), 1.82 (bs, 4H), 1.12 (m, 5H), 0.78 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:16]=[C:15]([CH:17]=O)[CH:14]=[CH:13][CH:12]=3)[S:10][C:3]=12.[CH3:19][NH:20][CH3:21].[BH3-]C#N.[Na+].CC([O-])=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:16]=[C:15]([CH2:17][N:20]([CH3:21])[CH3:19])[CH:14]=[CH:13][CH:12]=3)[S:10][C:3]=12
Reactant: CNC
Reactant: O=Cc1cccc(-c2cc3nccc(Cl)c3s2)n1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)Cc1cccc(-c2cc3nccc(Cl)c3s2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of 6-(7-chlorothieno[3,2-b]pyridin-2-yl)pyridine-2-carbaldehyde 52a (0.127 g, 0.46 mmole) in THF (20 ml) was added 2.0 M dimethylamine in THF (1.5 ml, 2.3 mmole), NaCNBH3 (0.063 g, 0.92 mmole) and NaOAc (0.076 g, 0.92 mmole). The reaction mixture was stirred at room temperature overnight and concentrated. The residue was purified by flash column chromatography eluting with 2–10% CH3OH in CHCl3 to give a yellow solid (0.086 g, 61%). 1H NMR (300 MHz, CD3OD) δ 8.50 (1H, d, J=5.3 Hz), 8.11 (1H, s), 8.03 (1H, d, J=7.9 Hz), 7.90 (1H, t, J=7.9 Hz), 7.41 (2H, m), 4.16 (2H, s), 2.71 (6H, s).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1O)=[O:3].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][C:18]([C:19]2[O:20][C:5]3[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:4]=3[C:2](=[O:3])[CH:1]=2)=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COc1cccc(O)c1C(C)=O
Product: COc1cccc2oc(-c3ccc(C(F)(F)F)cc3)cc(=O)c12

Procedure:
3 is prepared from 2-hydroxy-6-methoxyacetophenone and 4-trifluoromethylbenzoyl chloride by the procedure of Example 1. The material is purified by flash chromatography (gradient elution using 25% ethyl acetate in hexane, 40% ethyl acetate in hexane, 60% ethyl acetate in hexane; material is loaded on column in methylene chloride), yielding 3 with a melting point of 190°-191° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[CH3:30][NH:31][CH2:32][CH2:33][OH:34].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([N:31]([CH2:32][CH2:33][OH:34])[CH3:30])=[O:18])=[N:14][CH:15]=1
Reactant: CNCCO
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)N(C)CCO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.3 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (337 mg, 0.80 mmol) obtained in Example 12 in methylene chloride (8 ml), 2-(methylamino)ethanol (0.077 ml, 0.96 mmol), 1-hydroxybenzotriazole (130 mg, 0.96 mmol), 4-methylmorpholine (0.194 ml, 1.76 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (184 mg, 0.96 mmol) were added at room temperature. After stirring for 24 hours at room temperature, the reaction mixture was washed with 1 N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with ethyl acetate was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and diethyl ether, and was collected by filtration, to obtain the title compound (328 mg, 0.69 mmol, 85%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:22])[N:12]([CH2:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12.[H-].[Na+].[CH3:25]I>CN(C)C=O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:22])[N:12]([CH2:15][C:16]3[N:17]=[CH:18][N:19]([CH3:25])[C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12
Reactant: CI
Reactant: Cc1[nH]cnc1CN1CCc2c(C)c3ccccc3n2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c2n(c3ccccc13)C(=O)N(Cc1ncn(C)c1C)CC2
Reaction time: 0.5 h

Procedure:
To a solution of 3,4-dihydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]pyrimido[1,6-a]indol-1(2H)-one (343 mg) in N,N-dimethylformamide (20 ml) was added sodium hydride (60% in mineral oil, 51.3 mg) at 5° C. and the mixture was stirred at the same temperature for 30 minutes. Methyl iodide (182 mg) in N,N-dimethylformamide (10 ml) was added dropwise to the solution at 50° C. during 2 hours. After 30 minutes of stirring at the same temperature, the reaction mixture was evaporated in vacuo. The residue was diluted with a mixture of tetrahydrofuran and ethyl acetate (1:3, 20 ml), washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (3% -methanol-chloroform) to give 3,4-dihydro-5-methyl-2-[(1,5-dimethylimidazol-4-yl)methyl]pyrimido[1,6-a]indol-1(2H)-one as crystal. The crystal was dissolved with 2N-hydrochloric acid (2 ml) and evaporated in vacuo. The crystalline residue was washed with acetone to give 3,4-dihydro-5-methyl-2-[(1,5-dimethylimidazol-4-yl)methyl]pyrimido[1,6-a]indol-1-(2H)one hydrochloride (0.2 g).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].OS([O-])(=O)=O.[Na+]>CO.O>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCCCCCCCCCCCc1ccc(C(=O)OC(C)(C)C)s1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(CCCCCCCCCCCCC(=O)O)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(12-Methoxycarbonyl-dodecyl)-thiophene-2-carboxylic acid tert-butyl ester (75 mg, 0.13 mmol) was dissolved in methanol (2 mL). A 20% solution of NaOH in water (0.36 mL) was added and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added and the mixture was acidified by the addition of 2 mL of a 10% solution of NaHSO4 in water. The precipitate was isolated by centrifuge and dried in vacuo, to yield 5-(12-carboxydodecyl)-thiophene-2-carboxylic acid tert-butyl ester, which was contaminated with some starting material was used in the subsequent step without any further purification.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCCN1CCNCC1
Reactant: BrCc1ccccc1
Product: OCCN1CCN(Cc2ccccc2)CC1

Procedure:
The title compound was synthesized by using 2-(1-piperazinyl)ethanol and benzyl bromide according to the same process as in Preparation Example 4.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[Br:14][C:15]1[C:20](F)=[C:19]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:17][C:16]=1[F:25]>C1COCC1.O>[Br:14][C:15]1[C:16]([F:25])=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[C:20]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1F
Reactant: Nc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(Br)c1Nc1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
Potassium tert-butoxide (2.82 g, 25.2 mmol) was added to a solution of 2-aminopyridine (1.25 g, 13.2 mmol) in THF (40 mL) at 0° C. and the reaction mixture stirred at 0° C. for 30 min. 2-Bromo-1,3-difluoro-4-nitrobenzene (3 g, 12.6 mmol) was added as a solution in THF (10 mL) and the reaction mixture stirred at 0° C. for 2 h. The reaction mixture was diluted with water and the product extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a yellow solid (2.38 g, 60%). 1H NMR 400 MHz δ (CDCl3): 8.16 (1H, ddd, J=5.1, 2.0, 1.0 Hz), 8.08 (1H, dd, J=9.3, 5.6 Hz), 7.82 (1H, br s), 7.62 (1H, ddd, J=8.1, 7.3, 1.8 Hz), 6.99 (1H, dd, J=9.2, 7.1 Hz), 6.91 (1H, ddd, J=7.3, 5.0, 1 Hz), 6.82 (1H, dt, J=8.3, 1.0 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[N:3]=2)=[CH:23][CH:22]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=C(O)CNC(=O)c1nc(Cl)c2ccccc2c1O
Product: O=C(O)CNC(=O)c1nc(Sc2ccc(Cl)cc2)c2ccccc2c1O

Procedure:
The title compound was prepared from [(1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid (U.S. Pat. No. 6,093,730) and 4-chlorobenzenethiol under conditions analogous to Example D-110; MS (+) m/z 389.06 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH2:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12]
Reactant: NCCc1ccccc1Br
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCc1ccccc1Br

Procedure:
In close analogy to the procedure described above, 2-(2-Bromo-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:17][CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:5]2[N:6]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29]>O1CCOCC1.C(N(C(C)C)CC)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[CH2:18][O:17][C:4]1[C:5]2[N:6]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=[C:2]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(Br)cn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(C#C[Si](C)(C)C)cn12
Temperature: 50 °C
Reaction time: 16 h

Procedure:
1 g of ethyl 6-bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 21A; 2.35 mmol; 1 equivalent) was initially charged in 52 ml of dioxane/diisopropylethylamine 1:1, and 165 mg of dichlorobis(triphenylphosphine)palladium(II) (0.24 mmol, 0.1 equivalents) and 45 mg of copper(I) iodide (0.24 mmol, 0.1 equivalents) were added. At RT, 1.3 ml of trimethylsilylacetylene (9.4 mmol, 4 equivalents) were slowly added dropwise. The resulting reaction mixture was stirred at 50° C. for 16 h. The mixture was then concentrated, water was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed twice with 10% strength aqueous sodium thiosulphate solution and then with saturated sodium chloride solution and dried over magnesium sulphate, and the filtrate was concentrated. The residue was dissolved in methanol and purified by preparative HPLC (column: Nucleodur C18 Gravity 50×200 mm, 10 μm, gradient: A=water+0.1% concentrated aqueous ammonia solution, B=acetonitrile, 0 min=30% B, 5 min=30% B, 23 min=100% B, 28 min=100% B, 28.2 min=30% B, 34 min=30% B, flow rate 110 ml/min, wavelength 220 nm). This gave 726 mg of a solid (89% pure, 62% of theory).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[C:6]1([P:12](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O.O1CCOCC1>[C:6]1([P:12]([O:3][NH2:2])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NO
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: NOP(=O)(c1ccccc1)c1ccccc1
Yield: 58.3 %

Procedure:
To a stirred solution of hydroxylamine hydrochloride (9.5 g, 137 mmol) in H2O (21 mL) was added aqueous sodium hydroxide (4.6 g, 116 mmol) in H2O (16 mL), followed by dioxane (66 mL). The resulting solution was cooled in an ice/salt bath, and diphenylphosphinyl chloride (11.8 g, 50 mmol) in dioxane (50 mL) was added in one portion with vigorous stirring. Stirring was continued for 5 minutes as copious precipitation ensued. Water (200 mL) was added, and the slurry filtered, and was purified by stirring the slurry with aqueous sodium hydroxide (1 g, 25 mmol) in water (100 mL) at 0° C. for 30 min, followed by filtration and drying in vacuo to afford 6.8 g (59%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.38-7.57 (m, 6H) 7.64-7.79 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=3[F:50])[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:51]=[O:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:53]=[O:54].[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=3[F:50])[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:53][OH:54])[CH:51]=[O:52])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cc2cc([C@]3(OC)O[C@H](C=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(Cc2cc([C@]3(OC)O[C@@](C=O)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 70 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 2k (1.24 g, 1.71 mmol) was dissolved in 15 mL 1,4-dioxane, followed by 37%-40% aqueous solution of formaldehyde (2.8 mL, 34.2 mmol) and 1.5 mL of sodium hydroxide solution (205 mg, 5.13 mmol). The reaction mixture was stirred overnight at 70° C. Thereafter, the reaction mixture was concentrated under reduced pressure and partitioned after 30 mL ethyl acetate and 15 mL saturated sodium chloride solution were added. The aqueous phase was extracted with ethyl acetate (15 mL×2) and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 2m (1.29 g, yellow grease), which was used directly in the next step without purification.
Reaction SMILES: Br[C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[N+:7]([O-:9])=[O:8].[Cu](C#N)[C:15]#[N:16].O>CN(C=O)C>[N+:7]([C:6]1[S:5][C:4]2[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=2[C:2]=1[C:15]#[N:16])([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1sc2ccccc2c1Br
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c([N+](=O)[O-])sc2ccccc12
Temperature: 25 °C
Yield: 90.3 %

Procedure:
Combine 3-bromo-2-nitro-benzo[b]thiophene (33.0 g, 127.4 mmol), copper cyanide (17.1 g, 191.1 mmol) in DMF (150 mL), heat to 120° C. for three hours. The reaction cool to RT, pour on ice, then filter. The filter cake wash with dichloromethane. The organic layer separate and dry over MgSO4, evaporation to give a DMF solution. Add water (400 mL) and the yellow solid precipitate out. After filtration, obtain a brownish solid (23.5 g, 90%). Mass spectrum (m/e): 205 (M+1); 1HNMR (300 MHz, DMSO-d6) δ: 7.78(m, 2H), 8.04(d, 1H), 8.29(d, 1H). 3CNMR(75 MHz, DMSO-d6) δ ppm: 105.9, 112.1, 125.0, 125.2, 128.8, 131.2, 135.9, 137.8, 158.0.