Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:13][C:12]=1[C:22]1[CH:23]=[CH:24][C:25]2[O:30][CH2:29][CH2:28][CH2:27][C:26]=2[CH:31]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O>[C:1]([O:5][CH:6]([C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:13][C:12]=1[C:22]1[CH:23]=[CH:24][C:25]2[O:30][CH2:29][CH2:28][CH2:27][C:26]=2[CH:31]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1cc(-c2ccccc2)sc1-c1ccc2c(c1)CCCO2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(C(=O)O)c1cc(-c2ccccc2)sc1-c1ccc2c(c1)CCCO2
Yield: 84.6 %

Procedure:
A solution of methyl 2-(tert-butoxy)-2-[2-(3,4-dihydro-2H-1-benzopyran-6-yl)-5-phenylthiophen-3-yl]acetate (11j) (57 mg, 0.13 mmol) and potassium hydroxide (64 mg, 0.52 mmol) in a mixture of ethanol (2 mL) and water (6 mL) was refluxed for 4 hours. The mixture was concentrated in vacuo. Water (5 mL) was added and the aqueous layer was washed with diethyl ether (5 mL), then extracted with dichloromethane (5 mL). The organic layer was washed with 1N hydrochloric acid (5 mL), dried over sodium sulfate and evaporated to dryness to provide the desired acid (45 mg, 0.11 mmol, 81%) as a white solid.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[N:14]=[C:13]1[C:8]([CH:9]=[CH:10][CH:11]=[C:12]1[C:16]([OH:18])=[O:17])=[N:7]2.CC(O)=O.[NH:23]([CH3:25])[CH3:24]>O>[CH3:24][N:23]([CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[N:14]=[C:13]1[C:8]([CH:9]=[CH:10][CH:11]=[C:12]1[C:16]([OH:18])=[O:17])=[N:7]2
Reactant: O=C(O)c1cccc2nc3cccc(F)c3nc12
Reactant: CNC
Solvent: CC(=O)O
Solvent: O
Product: CN(C)c1cccc2nc3cccc(C(=O)O)c3nc12
Yield: 95 %

Procedure:
A solution of 9-fluorophenazine-1-carboxylic acid [Rewcastle et al., J. Synth Comm, 1987, 17, 1171] (200 mg, 0.8 mmol) in Me2NH (40% aqueous, 20 mL) was heated at 100° C. in a bomb for 3 h. The resulting intensely purple solution was diluted with water and then neutralized with AcOH. The aqueous solution was then extracted with CHCl3 (3×50 mL) until all color was extracted. The organic layer was further washed with water (1×150 mL), then dried over Na2SO4 and the solvent removed under reduced pressure. The resulting purple solid was dissolved in a minimal amount of CH2Cl2, and peteoleum ether was added until crystallization occurred, giving 9-(dimethylamino)phenazine-1-carboxylic acid as dark purple needles (210 g, 95%), mp 186-187.5° C. 1H NMR (CDCl3) δ 3.16 [s, 6 H, N(CH3)2 ], 7.26 (dd, J=6.8, 1.8 Hz, 1 H, H-6 or H-8), 7.81-7.88 (m, 2 H, H-7 and H-8 or H-6), 8.01 (dd, J=8.7, 7.0 Hz, 1 H, H-3), 8.48 (dd, J=8.7, 1.2 Hz, 1 H, H-4) and 8..91 (dd, J=7.0, 1.3 Hz, 1 H, H-2). Anal. (C15H13N3O2) C, H, N. Activation and coupling of this as above gave bis[((9-dimethylamino)phenazine-1-carboxamido)propyl]methylamine (54) as a red-purple oil (78%). 1H NMR (CDCl3) δ 1.91-2.00 (m, 4 H, 2×CH2CH2CH2), 2.29 (s, 3 H, NCH3), 2.57 (t, J=7.3 Hz, 4 H, CH2NCH3), 3.05 (s, 12 H, 2×N(CH3)2, 3.68 (q, J=6.5 Hz, 2 H, CH2NH), 7.07 (dd, J t 7.2, 1.3 Hz, 2 H, H-6 or H-8), 7.65 (dd, J=8.7, 7.3 Hz, 2 H, H-7), 7.70 (dd, J=8.7, 1.3 Hz, 2 H, H-8 or H-6), 7.90 (dd, J=8.6, 7.1 Hz, 2 H, H-3), 8.27 (dd, J=8.6, 1.4 Hz, 2 H, H-4), 8.87 (dd, J=7.1, 1.4 Hz, 2 H, H-2) and 10.99 (br t, J=5.1 Hz, 2 H, 2×CONH); HRMS (FAB+) m/z calcd for C37H42N9O2 644.3461 (MH+), found 644.3485.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[N+:19]([O-])=O)[CH2:7]1)=[O:5])[CH3:2].C(O)(=O)C>ClCCl.[Zn]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[NH2:19])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(Oc2ccc(Cl)cc2[N+](=O)[O-])C1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1CCC(Oc2ccc(Cl)cc2N)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
To a solution of 3-(4-chloro-2-nitro-phenoxy)-cyclopentanecarboxylic acid ethyl ester (280 mg) in dichloromethane (20 mL) was added zinc dust (2 g) followed by glacial acetic acid (1 mL) and the resulting mixture was stirred at room temperature for 20 minutes. The solid was filtered, washed with dichloromethane and discarded. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography (hexane/acetone, 80/20) to afford 200 mg of 3-(2-amino-4-chloro-phenoxy)-cyclopentanecarboxylic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:9][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.N1([C:23](N2C=CN=C2)=[O:24])C=CN=C1>O1CCCC1>[Br:1][C:2]1[N:3]=[C:4]2[N:9]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:11])[C:23](=[O:24])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(Nc1nc(Br)cnc1N)c1ccccc1
Solvent: C1CCOC1
Product: CC(c1ccccc1)n1c(=O)[nH]c2ncc(Br)nc21
Reaction time: 20 h
Yield: 85.1 %

Procedure:
To a solution of 5-bromo-N3-(1-phenylethyl)pyrazine-2,3-diamine (1.77 g, 6.04 mmol) in anhydrous tetrahydrofuran (30 mL) was added diimidazol-1-ylmethanone (1.47 g, 9.06 mmol) at room temperature. After stirring for 20 h, the reaction was concentrated under reduced pressure. Purification of the resultant residue by flash chromatography [silica gel; hexanes/ethyl acetate (2:1)] afforded 6-bromo-1-(1-phenylethyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one as a red brown solid (1.64 g, 85%). 1H NMR (300 MHz, DMSO): δ 12.31 (s, 1H), 8.04 (s, 1H), 7.40-7.27 (m, 5H), 5.61 (q, J=7.2 Hz, 1H), 1.90 (d, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1[C:35](OC)=[O:36].C(OCC)(OCC)OCC.COC1C=CC(N)=CC=1>C(O)(=O)C>[CH3:35][O:36][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)=[CH:2][CH:3]=1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: COc1ccc(N)cc1
Product: COc1ccc(-n2cnc3c(-c4ccccc4)csc3c2=O)cc1
Yield: 31 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (58 mg, 0.25 mmol), triethyl orthoformate (0.5 ml), p-anisidine (58 mg, 0.47 mmol), and acetic acid (0.06 ml) were used to give 26 mg (0.078 mmol, 31% yield) of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=1.[CH3:40]I.O>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([N:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH3:40])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=1
Reactant: CI
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)NCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)N(C)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon atmosphere, 60% sodium hydride (30 mg) was added at 0° C. to a solution of Compound 1 (253.8 mg) in tetrahydrofuran (5 mL), and the mixture was stirred for 30 minutes at room temperature. Under cooling with ice, methyl iodide (0.16 mL) was added thereto, and the resultant mixture was stirred for 88 hours at room temperature. Water was added to the reaction mixture, and the solvent was distilled off. The residue was subjected to extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant crude product was subjected to purification through silica gel column chromatography (ethyl acetate-hexane=1:4 to 1:2), to thereby yield 139.3 mg of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.[CH2:29]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[CH2:42]O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[CH2:42][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([C:10]2[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][C:7]=3[S:8][C:9]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:12])=[CH:18][CH:17]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OCC1CCCCN1Cc1ccccc1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCC3CCCCN3Cc3ccccc3)cc2)cc1
Yield: 36 %

Procedure:
The product from Step 2 (600 mg) was coupled with (1-benzyl-piperidin-2-yl)-methanol (379 mg) as is Example 10, Step 3 to yield the title compound (320 mg) after silica gel chromatography with 10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes as the gradient eluant.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH:13]=[N:12][C:11]([O:15][CH3:16])=[CH:10]2)=[O:4].[OH-].[K+]>C(O)C.O>[CH3:16][O:15][C:11]1[N:12]=[CH:13][C:14]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cccc2cc(OC)ncc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc2cccc(C(=O)O)c2cn1
Yield: 115.7 %

Procedure:
To a solution of methyl-3-methoxyisoquinoline-8-carboxylate (Description 55; 280 mg, 1 mmol) in ethanol (10 ml) was added potassium hydroxide (145 mg, 3 mmol) in water (6 ml). This mixture was heated at reflux for 30 minutes, cooled and the ethanol removed by evaporation. The remaining aqueous mixture was acidified with 1M HCl (3 ml) to pH 5. The solid was collected by filtration and dried in a vacuum oven to give the title compound (235 mg, 90%).
Reaction SMILES: C([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:38])[CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:26][CH:25]=2)=[O:22])[CH2:5][CH2:4]1)=O.Cl.C(=O)([O-])O.[Na+].O>C(OCC)(=O)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[CH:10][C:9]3[NH:3][CH2:4][CH2:5][C:6]([C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:38])[CH:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)=[CH:26][CH:25]=4)=[O:22])=[CH:7][C:8]=3[CH:13]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To 1-formyl-7-(4-methylphenyl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (1177 mg) was added 1N hydrochloric acid (20 ml), and the mixture was stirred at 100° C. for 1 hour. The mixture was dilute with ethyl acetate(50 ml) and made weakly basic with saturated sodium hydrogen carbonate solution (45 ml). To the mixture were added ethyl acetate (250 ml) and water (100 ml), and separated. The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (75 g, ethyl acetate/ethanol=9:1) to give 7-(4-methylphenyl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 318) (804 mg, 72%) as amorphous.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1O.C(O[S:26]([O-])(=O)=O)CCCCCCCCCCC.[Na+].C(OC(=O)C)(=O)C>O>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[SH:26]
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Reactant: Nc1c(O)ccc2ccccc12
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Nc1c(S)ccc2ccccc12
Yield: 73 %

Procedure:
5 mmol of 1-aminonaphthalene-2-ol was added to 20 mL of water, and 20 mg of sodium dodecylsulfate was added while agitating to obtain a uniform mixture. 7.5 mmol of acetic anhydride was added for 5 minutes. An acetylated product was precipitated in in 5-10 minutes. The precipitation product was filtrated and rinsed with 1 ml of water twice followed by drying under vacuum. A non-precipitated reaction mixture was extracted with 25 ml of ethyl acetate twice. The separated organic layer was dried with anhydrous sodium sulfate, and a solvent was removed using a rotatary evaporator under a reduced pressure to obtain 1-aminonaphthalene-2-thiol at a yield of 73%.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][CH:6]1Br)(=[O:3])[CH3:2].[C:20]([C:28]1[C:32]2[CH:33]=[C:34]([OH:37])[CH:35]=[CH:36][C:31]=2[O:30][CH:29]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:37][C:34]1[CH:35]=[CH:36][C:31]2[O:30][CH:29]=[C:28]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:32]=2[CH:33]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Reactant: O=C(c1ccccc1)c1coc2ccc(O)cc12
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc2occ(C(=O)c3ccccc3)c2c1
Yield: 20 %

Procedure:
By carrying out the process in a manner similar to example 7, starting from 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide and 3-benzoyl-5-hydroxybenzofuran, the desired product is obtained in the form of a white solid with a yield of 20%.
Reaction SMILES: [C:1]([C:3]1([NH:9][C:10](=[O:40])[C@@H:11]([NH:20][C@@H:21]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:22]([F:32])([F:31])[O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:12][S:13]([CH2:16][CH:17]2[CH2:19][CH2:18]2)(=[O:15])=[O:14])[CH2:8][CH2:7]S[CH2:5][CH2:4]1)#[N:2].OO[S:43]([O-:45])=[O:44].[K+]>CO.O>[C:1]([C:3]1([NH:9][C:10](=[O:40])[C@@H:11]([NH:20][C@@H:21]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:22]([F:32])([F:31])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:12][S:13]([CH2:16][CH:17]2[CH2:19][CH2:18]2)(=[O:15])=[O:14])[CH2:4][CH2:5][S:43](=[O:45])(=[O:44])[CH2:7][CH2:8]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@H](CS(=O)(=O)CC2CC2)N[C@@H](c2ccc(F)cc2)C(F)(F)Oc2ccc(F)cc2)CCSCC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#CC1(NC(=O)[C@H](CS(=O)(=O)CC2CC2)N[C@@H](c2ccc(F)cc2)C(F)(F)Oc2ccc(F)cc2)CCS(=O)(=O)CC1
Temperature: 45 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a solution of N-(4-cyanotetrahydrothiopyran-4-yl)-3-cyclopropylmethanesulfonyl-2(R)-[2,2-difluoro-2-(4-fluorophenoxy)-1(S)-(4-fluorophenyl)ethylamino]propionamide (0.063 g, 0.1 mmol) in MeOH (10 ml) at 45° C., a solution of OXONE (0.3 mmol) in water (1 ml) was added. After stirring for 3 h at 45° C., the solvent was evaporated under vacuum and the residue was partitioned between DCM (15 ml) and water (15 ml). The organic phase was separated and the aqueous solution was extracted with DCM. The combined organic layers were washed with brine and dried over sodium sulfate. After removal of the solvent under vacuum, the crude was purified by preparative TLC, using ethyl acetate/hexanes (1/1) as mobile phase to give the title compound as a white solid (55%). 1HNMR (DMSO-d6): δ 8.82 (1H, s), 7.47 (2H, dd), 7.17 (6H, m), 4.32 (1H, q), 3.96 (1H, m), 3.40 (1H, m), 3.37 (4H, m), 3.00 (2H, m), 2.37 (2H), 1.15 (2H, m), 0.59 (3H, m), 0.30 (3H, m). LC/MS, M+1: 632.5; M−1: 630.6.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][CH:22]([NH:35][C:36](=[O:38])[CH3:37])[CH2:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25].C(OC([N+](C(OCC)=O)=[N-])=O)C.C(O)(=[S:53])C.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(CC(NC(=O)C)CS(C1C=CC(OC)=CC=1)(=O)=O)(=S)C.C[O-].[Na+].Cl>O1CCCC1.CO>[SH:53][CH2:21][CH:22]([NH:35][C:36](=[O:38])[CH3:37])[CH2:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: CC(O)=S
Reactant: COc1ccc(S(=O)(=O)CC(CO)NC(C)=O)cc1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: COc1ccc(S(=O)(=O)CC(CC(C)=S)NC(C)=O)cc1
Agent: C[O-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)CC(CS)NC(C)=O)cc1
Reaction time: 2 h
Yield: 27.5 %

Procedure:
Part C: (471 mg, 1.8 mmol) of triphenylphosphine and (520 mg, 1.8 mmol) of N-[1-(hydroxymethyl)-2-[(4-methoxyphenyl)sulfonyl)ethyl)acetamide were dissolved in 15 mL of tetrahydrofuran and cooled to zero C. under nitrogen atmosphere. To this was added (313 mg, 1.8 mmol) of diethyldiazodicarboxylate, followed by (140 mg, 1.8 mmol) of thioacetic acid and the solution stirred for 2 hours. The resulting clear solution was concentrated by rotory evaporation and subjected to silica gel chromatography using 15% methanol in ethyl acetate as the eluant to provide a mixture of triphenylphosphine oxide and the desired N-[1-(thioacetylmethyl)-2-[(4-methoxyphenyl)sulfonyl)ethyl)acetamide in equal molar ratios. This mixture was dissolved in 10 ml of methanol and to this was added 1 mL of 25% sodium methoxide in methanol and this stirred for 30 minutes. The solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The resulting organics were concentrated and purified by reverse phase C18 chromatography to yield 150 mg of N-[1-(mercaptomethyl)-2-[(4-methoxyphenyl)sulfonyl)ethyl)acetamide, m/e=310 (M+Li).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][O:27][C:28]1[N:33]=[C:32](B(O)O)[CH:31]=[CH:30][CH:29]=1>CCCCCCC.CCOC(C)=O>[CH3:26][O:27][C:28]1[N:33]=[C:32]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COc1cccc(B(O)O)n1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1cccc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide and 6-methoxypyridin-2-ylboronic acid (CAS RN 372963-51-4) and using a gradient of n-heptane:EtOAc (100:0 to 60:40) for the chromatographic purification. The product was purified a second time by preparative HPLC (Phenomenex Gemini® column) eluting with a gradient of acetonitrile:water (50:50 to 95:5). Colorless oil (17%). MS (ESI): m/z=456.114 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:22]1(O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>CCCCCC>[C:22]1([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: Oc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)Oc1ccccc1
Yield: 42 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using phenol (10 mg, 0.1 mmol) as the coupling partner. Chromatography (1:1 ethyl acetate:hexane) through SiO2 yielded 26 mg (42%) of the titled compound. ESI-MS m/z 368 (MH+), 366 (M−H−).
Reaction SMILES: C1CNC(=O)C1.[Br:7][Br-]Br.[O:10]=[C:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13].N1CCCC1=O>O1CCCC1>[Br:7][CH:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11](=[O:10])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=O)Cc1ccccc1
Agent: O=C1CCCN1
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(Br)c1ccccc1
Temperature: 50 °C
Yield: 92.2 %

Procedure:
39.3 g (0.08 mole) of pyrrolidone hydrotribromide (PHT) are introduced portionwise at approximately 10° C. into a solution of 13.9 g (0.072 mole) of ethyl 2-oxo-3-phenylpropanoate (described by E. L. Eliel et al. J. Org. Chem. 37, 505, 1972) in 250 ml of tetrahydrofuran (THF) and 6.1 g (0.072 mole) of 2-pyrrolidone. The temperature of the mixture is allowed to return to 20° C. and the mixture is then heated to 50° C. for 1 h. The mixture is cooled and then poured onto ice. The mixture is extracted with ether and the organic phase washed with water, dried with MgSO4, filtered and evaporated. 18 g of oil are obtained, which is used in the crude state for the next stage of the reaction.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([C:12]1[N:16]2[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][C:23]3[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:30][CH3:31])[C:15]2=[N:14][C:13]=1[CH3:32])(OCC)=[O:8].O.[OH-].[Na+]>O1CCCC1>[CH2:30]([C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:23]=1[CH2:22][O:21][C:20]1[C:15]2[N:16]([C:12]([CH2:7][OH:8])=[C:13]([CH3:32])[N:14]=2)[CH:17]=[CH:18][CH:19]=1)[CH3:31]
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(C)cccc3CC)cccn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cccc(C)c1COc1cccn2c(CO)c(C)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
To a mixture of LiAlH4 (0.08 g, 2.1 mmol) in tetrahydrofuran (25 ml) was added 3-carboethoxy-8-(2-ethyl-6-methylbenzyloxy)-2-methylimidazo[1,2-a]pyridine (1.0 g, 2.8 mmol) in tetrahydrofuran (25 ml). After stirring the mixture at room temperature for 2 h., 0.2 ml of water was added dropwise, followed by 0.2 ml of 15% sodium hydroxide and then 0.6 ml of water. The solids were removed by filtration and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride:methanol (9:1) as eluent. Crystallization from diethyl ether gave 0.52 g (60%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:5]([NH2:13])=[C:4]([N+:14]([O-])=O)[CH:3]=1.Cl[Sn]Cl.O.[CH:21](O)=O>>[Cl:1][C:2]1[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:5]2[N:13]=[CH:21][NH:14][C:4]=2[CH:3]=1
Reactant: O=CO
Reactant: Nc1cc(N2CCCC2)c(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: Clc1cc2[nH]cnc2cc1N1CCCC1
Temperature: 130 °C
Yield: 70 %

Procedure:
Formic acid (2.9 mL) was added to a mixture of 4-chloro-2-nitro-5-pyrrolidin-1-yl-phenylamine (0.240 g, 1.00 mmol) and SnCl2.H2O (0.680 g, 3.00 mmol), and the mixture was heated to 130° C. in a microwave reactor for 5 min. Six reactions were performed on the same scale. The combined crude mixture was filtered and washed with EtOAc (100 mL). The organic layer was treated with water (25 mL) and neutralized with aqueous 6M NaOH. The aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (50 mL), dried, filtered, and concentrated under reduced pressure. The residue was triturated with EtOAc and the solid was collected to yield the titled compound (1.08 g, 70%) as the formate salt. MS (ESI/CI): mass calcd. for C11H12ClN3, 221.1; m/z found, 222.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.84-12.16 (br s, 1H), 8.13 (s, 1H), 8.11 (s, 1H), 7.59 (s, 1H), 7.20 (s, 1H), 3.20 (t, J=6.3 Hz, 4H), 2.06-1.66 (m, 4H).