Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CS(C)=O.O>[CH2:24]([S:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1CCc2cc(OCCCCS)ccc2N1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CCc2cc(OCCCCSCc3ccccc3)ccc2N1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 2.5 gm of 6-(4-mercapto-butoxy)-3,4-dihydro-carbostyril in 25 ml of dimethysulfoxide was mixed whilst stirring with 1.4 gm of potassium carbonate and subsequently with 1.3 ml of benzyl chloride. After stirring for 15 hours at room temperature, the reaction mixture was diluted with 200 ml of water, and the precipitated oily substance was separated and recrystallized from ethyl acetate.
Reaction SMILES: [H-].[Na+].[C:3]1([C@H:9]2[C@H:18]3[CH2:19][CH2:20][N:21]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[C@H:17]3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:32]I.O>CN(C=O)C>[CH3:32][N:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[C@@H:17]2[N:21]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:20][CH2:19][C@@H:18]2[C@@H:9]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CI
Reactant: O=C(OCc1ccccc1)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1c2ccccc2[C@H]2[C@H](CCN2C(=O)OCc2ccccc2)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.1 %

Procedure:
Sodium hydride (60% in oil, 120 mg, 3.0 mmol) was suspended in DMF (12 ml), benzyl (3aR*,4R*,9bR*)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (960 mg, 2.5 mmol) was added, and the mixture was stirred at room temperature for 10 min. Thereto was added methyl iodide (426 mg, 3.0 mmol), and the mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous Na2SO4), and the solvent was evaporated. The residue was subjected to column chromatography using silica gel (30 g) and eluted with hexane-ethyl acetate (5:1, v/v) to give the title compound (330 mg, 33%) as an amorphous form.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:27])[CH2:6][S:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:3])[CH3:2].[C:28](NC(=S)CCC1C=CC=CC=1)(=O)C>>[C:1]([N:4]([CH3:28])[C:5](=[O:27])[CH2:6][S:7][CH2:8][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)NC(=S)CCc1ccccc1
Product: CC(=O)N(C)C(=O)CSCc1ccccc1

Procedure:
Employing the procedure described above, but substituting for the N-acetyl-2-(triphenylmethylthio) acetamide an equivalent amount of N-acetyl-2-benzylthio acetamide, there is produced N-acetyl-N-methyl-2-(benzylthio) acetamide.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:2]#[C:1][C:3]2[N:4]=[CH:5][N:6]3[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:28]=1
Reactant: C#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Brc1cccnc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3cnc(C#Cc4cccnc4)c3n2)cc1

Procedure:
The title compound was prepared from 8-ethynyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (example C.18) (130 mg, 0.37 mmol) and commercially available 3-bromo-pyridine (58 mg, 0.37 mmol) according to general procedure II. Obtained as a dark red solid (54 mg, 34%). MS (ISP) 433.0 [(M+H)+]; mp 199° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:37]1[C:42]2[CH:43]=[CH:44][C:45](B(O)O)=[CH:46][C:41]=2[O:40][CH2:39][CH2:38]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:45]2[CH:44]=[CH:43][C:42]3[O:37][CH2:38][CH2:39][O:40][C:41]=3[CH:46]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: OB(O)c1ccc2c(c1)OCCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)n1c(C(=CC2CCCC2)c2ccc3c(c2)OCCO3)cc2cccnc21
Yield: 95.4 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.15 g, 0.28 mmol), 1,4-benzodioxane-6-boronic acid (0.13 g, 0.72 mmol) and dichlorobis(triphenylphosphine)palladium (II) (21 mg, 0.03 mmol) in dioxane (3 mL) was added an aqueous sodium carbonate solution (2 M, 0.36 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (130 mg, 96%) as a white solid: LC/MS m/e calcd for C28H26N2O4S [M+H]+ 487.59, observed 487.2.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[S:3])[NH2:2].Br[CH2:18][C:19](=O)[C:20]([F:23])([F:22])[F:21]>O1CCOCC1>[F:21][C:20]([F:23])([F:22])[C:19]1[N:2]=[C:1]([NH:4][C:5]2[CH:6]=[CH:7][C:8]([CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[S:3][CH:18]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: COC(=O)C(C)c1ccc(NC(N)=S)cc1
Solvent: C1COCCO1
Product: COC(=O)C(C)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
In a 250 ml round-bottomed flask equipped with condenser and magnetic stirrer, a solution of methyl 2-[4-(carbamothioylamino)phenyl]propanoate (10.7 g, 48.4 mmol) in 1,4-dioxane (200 ml) was treated at room temperature with 3-bromo-1,1,1-trifluoro-propan-2-one (5 ml, 48.4 mmol) and the reaction mixture was refluxed for 2 h. After cooling at room temperature, the solvent was distilled under vacuum, the residue dissolved in CH2Cl2 (200 ml), washed with a saturated solution of NaHCO3 (3×100 ml), dried over anhydrous Na2SO4 and evaporated under vacuum to give pure methyl 2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoate (12.8 g, 38.7 mmol) as yellow oil (80%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:14][C:15]([CH:17]=[CH2:18])=O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]=[CH:14][CH:15]=[C:17]2[CH3:18]
Reactant: Nc1ccc(Br)cc1
Reactant: C=CC(C)=O
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccnc2ccc(Br)cc12

Procedure:
Stir a solution of 4-bromo-phenylamine (1 eq), in 1,4-dioxane and cool to approximately 12° C. Slowly-add sulfuric acid (2 eq) and heat at reflux. Add methylvinyl ketone (1.5 eq) dropwise into the refluxing solution. Heat the solution for 1 hour after addition is complete. Evaporate the reaction solution to dryness and dissolve in methylene chloride. Adjust the solution to pH 8 with 1 M sodium carbonate and extract three times with water. Chromatograph the residue on SiO2 (70/30 hexane/ethyl acetate) to obtain the desired subtitled intermediate. MS ES+ m/e =158.2 (M+1).
Reaction SMILES: [I:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.[C:18]1([C:24]2(Cl)[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:31][C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CO>N1C=CC=CC=1>[I:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][O:13][C:24]2([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:31][C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@@H:9]([OH:10])[CH2:8]1
Reactant: ClC1(c2ccccc2)c2ccccc2Oc2ccccc21
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Solvent: CO
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC3(c4ccccc4)c4ccccc4Oc4ccccc43)O2)cc1I
Reaction time: 0.5 h
Yield: 70 %

Procedure:
5-Iodo-2'-deoxyuridine (IDU) (3.54 g, 10 mmol) was coevaporated with dry pyridine (3×20 mL). The IDU was redissolved in dry pyridine (15mL) and 9-phenyl-9-chloroxanthen (3.82 g, 13 mmol) was added to the stirring solution in two equal portions over 0.5 h. After 1h, MeOH (5 mL) was added and the solution stirred for a further 0.5 h. The solvent was then removed under vacuum, and the residue recrystallized from a 1% Et2N/ethyl acetate solution giving 7 as colourless crystals (4.27 g, 70%), mp 200-2° C. 1H NMR (d6 -DMSO): δ2.20 (m, 2H, H2'), 2.99 (dd, 1H, H5', J-10.5, 4.2 Hz), 3.10 (dd, 1H, H5", J=10.5, 2.7 Hz), 3.85 (m, 1H, H4'), 4.15 (m, 1H, H3'), 5.29 (d, 1H, 3'OH, J=4.2 Hz), 6.08 (t, 1H, H1', J=7.0 Hz), 7.10-7.42 (m, 13H, Px CH), 8.08 (s, 1H, H6). 13C NMR (d6 -DMSO): δ40.4 (C2'), 63.8 (C5'), 69.9 (C5), 71.0 (C3'), 75.6 (Px C9), 85.2 (Cl'), 85.9 (C4'), 116.3, 116.4 (Px CH), 122.3, 122.4 (Px C8a and C9a), 123.8, 124.0, 125.8, 126.8, 128.2, 129.3, 129.69, 129.7, 129.73 (Px CH), 143.9 (C6), 148.4(Px Cl'), 150.0 (C2), 150.51, 150.58 (Px C4a and C10a), 160.6 (C4). FABMS m/z 633 (M+Na'). Anal. calcd for C28H23N2P6I: C, 55.1; H,3.81, N, 4.59. Found: C, 55.0; H, 3.81, N, 4.54.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C.Br[C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:22]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)O)c(Oc2ccc(Br)cc2)c1
Temperature: 110 °C

Procedure:
4-Bromophenol (0.87 g, 5 mmol), Cs2CO3 (1.6 g, 5 mmol), CuOTf toluene complex (2:1) (0.0625 mmol, 5 mol % Cu, 33 mg), ethyl acetate (0.013 ml, 0.125 mmol) were added to a solution of 2-bromo-4-methylbenzoic acid (0.86 g, 5 mmol) in toluene (2 mL) in a sealed tube. The reaction mixture was purged with N2, and was heated to 110° C. until the aryl halide was consumed as determined by LC-MS (48 h). After cooling to rt, the mixture was filtered through a Celite plug. The Celite plug was washed with EtOAc. The mixture was acidified by 1N HCl, and extracted w/EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. This residue was purified via column chromatography on silica gel (gradient elution with 0-10% MeOH/DCM) to afford 2-(4-bromophenoxy)-4-methylbenzoic acid, MS m/z=309.1 [M+H]+. Calc'd for C14H11BrO3: 307.1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[N:21][CH:22]=2)=[CH:12][CH:11]=3)[CH:4]=[N:3]1.[N:24]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]2[CH:18]=[C:19]([NH:23][S:30]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)(=[O:32])=[O:31])[CH:20]=[N:21][CH:22]=2)=[CH:12][CH:11]=3)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3ccc(-c4cncc(N)c4)cc3n2)cn1
Reactant: O=S(=O)(Cl)N1CCOCC1
Solvent: c1ccncc1
Product: Cn1cc(-c2cnc3ccc(-c4cncc(NS(=O)(=O)N5CCOCC5)c4)cc3n2)cn1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
In an oven-dried flask under nitrogen, a solution of 5-[3-(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinyl]-3-pyridinamine (99 mg, 0.327 mmol) in pyridine (3 mL) at room temperature was treated with morpholine-4-sulfonyl chloride (96 mg, 0.491 mmol) by syringe. The reaction was stirred at room temperature for 16.5 hours. The reaction was very sluggish so the reaction was placed in an oil bath at 50° C. and stirred at that temperature for 23 hours. The reaction was progressing to the desired product as determined by LCMS but was not yet complete. The reaction mixture was stirred for an additional 4 days at 50° C. The reaction did not progress to completion. The reaction was cooled to room temperature and concentrated in vacuo. The residue was taken up into 200 mL ethyl acetate and 50 mL water. The organic layer was washed with saturated aqueous sodium bicarbonate solution (100 mL) followed by brine (100 mL), dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography eluting with 0-10% methanol in dichloromethane provided the desired product as a residue which was not pure. Addition of dichloromethane/ether resulted in precipitate formation. The precipitate was collected by filtration. Recrystallization of the precipitate from ethanol provided the title compound (26 mg, 18%) as a rust-coloured solid. MS(ES)+ m/e 452.0 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([CH2:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2)=[C:2]=[O:3].[CH3:27][NH:28][CH3:29]>O1CCCC1.O>[CH3:27][N:28]([CH3:29])[C:2](=[O:3])[NH:1][C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([CH2:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2
Reactant: CNC
Reactant: CCc1c(C)c2c(c(N=C=O)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Solvent: O
Solvent: C1CCOC1
Product: CCc1c(C)c2c(c(NC(=O)N(C)C)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2

Procedure:
A solution of 0.65 g (1.8 mmol) of methyl (E)-6-(1,3-dihydro-4-isocyanato-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate in 10 ml of tetrahydrofuran is treated with 5 ml of a solution of 40% dimethylamine in water. After 1 hour the reaction is partitioned between water and ethyl acetate. The organic phase is washed with water three times, dried over magnesium sulfate, and concentrated under reduced pressure to give methyl (E)-6-[1,3-dihydro-4-(3,3-dimethylureido)-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl]-4-methyl-4-hexenoate.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[C:16]([CH3:21])=[N:17][CH:18]=[CH:19][CH:20]=1.[C:22](=O)([O:26]CC)[O:23][CH2:24][CH3:25]>C1COCC1>[CH3:13][O:14][C:15]1[C:16]([CH2:21][C:22]([O:23][CH2:24][CH3:25])=[O:26])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccnc1C
Reactant: CCOC(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)Cc1ncccc1OC
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
A stirred solution of diisopropylamine (0.385 mL, 2.70 mmol) in THF (2 mL) at 0° C. was treated slowly with 1.6 M n-butyllithium in hexanes (1.69 mL, 2.70 mmol). The mixture was stirred for 15 min, then was added over 5 min to a stirred solution of 3-methoxy-2-picoline (0.133 g, 1.08 mmol) and diethyl carbonate (0.262 mL, 2.16 mmol) in THF (5 mL) at −78° C. After stirring for 45 min more, the cooling bath was removed and stirring was continued overnight at room temperature. The mixture was treated with saturated aqueous NH4Cl and diluted with EtOAc. The organic phase was separated, washed sequentially with saturated aqueous NaHCO3 and brine, and dried and concentrated. The residue was purified by column chromatography on silica gel (12 g), eluting with 50% EtOAc-hexanes, to provide ethyl 2-(3-methoxypyridin-2-yl)acetate as an oil (0.17 g, 81% yield). Mass spectrum m/z 196 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH2:9]2)[CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH2:9]2)[N+:7]=1[O-:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC(c2cccc(Cl)n2)c2cc(C#N)ccc2O1
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(c2cccc(Cl)[n+]2[O-])c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 10 h
Yield: 20.6 %

Procedure:
152 mg of 4-(6-chloro-2-pyridyl)-3.4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile and 136 mg of m-chloroperbenzoic acid were heated at reflux in 15 ml of chloroform. After 10 hours and 20 hours 80 mg and 50 mg, respectively., of m-chloroperbenzoic acid were added. After 30 hours the mixture was allowed to cool to room temperature, washed in succession with sodium bisulphite solution and sodium bicarbonate solution, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate for the elution to give, after trituration with n-hexane, a solid which was recrystallized from acetonitrile. There were obtained 33 mg of 2-chloro-6-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 195°-196° C.
Reaction SMILES: [O:1]=[CH:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6]>C(O)C.[Pd]>[O:1]=[CH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6]
Reactant: CC(C)COC(=O)/C=C/C=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)COC(=O)CCC=O
Yield: 99.5 %

Procedure:
To a solution of isobutyl (E)-4-oxo-2-butenoate (97 g, 0.62 mol) in 96% ethanol (800 ml), 5% palladium on charcoal (9.7 g) was added and hydrogen was bubbled at 5°-10° C. and at atmospheric pressure for 20 hours. Removal of the catalyst and evaporation of the solvent gave 97.6 g (99%) of the title compound; Rf=0.41 (silica gel plates, eluent: cyclohexane-ethyl acetate 6:4). NMR (CDCl3): deltaH =12.5 (d, J=1 Hz, 1H, CHO); 3.85 (d, J=6 Hz, 2H, COOCH2); 2.80-2.40 (c.a., 4H, CH2CH2CO); 2.10-1.70 (c.a., 1H, CH2CHMe2); 0.90 (d, J=6 Hz, 6H, CH3). MS (E.I., 70 eV, 1.5 mA) m/z=103 (M-C3H3O)+, 85 (M-C3H5O2)+, 57 (M-C4H5O3)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.[F:15][C:16]1[CH:33]=[CH:32][C:19]([CH2:20][O:21][C:22]2[N:27]=[CH:26][C:25]([CH:28]([NH2:30])[CH3:29])=[CH:24][C:23]=2[CH3:31])=[CH:18][CH:17]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:30]([CH:28]([C:25]3[CH:26]=[N:27][C:22]([O:21][CH2:20][C:19]4[CH:18]=[CH:17][C:16]([F:15])=[CH:33][CH:32]=4)=[C:23]([CH3:31])[CH:24]=3)[CH3:29])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)cnc1OCc1ccc(F)cc1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCc1ccc(F)cc1
Yield: 92 %

Procedure:
The title compound is prepared in 92% yield (683 mg, colorless amorphous) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.80 mmol, Step-1 of Intermediate-1) and 1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethanamine (240 mg, 0.86 mmol, Amine-71, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[N:10][C:9]=2[C:18]2[C:19]([F:36])=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1.[CH3:37][Zn]C>>[F:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=1[S:25]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:9]2[N:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:37])[N:7]=2)[C:19]=1[F:36])(=[O:27])=[O:26]
Reactant: C[Zn]C
Reactant: CC(C)(CO)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Product: Cc1nccc(-c2sc(C(C)(C)CO)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(2-hydroxy-1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (200 mg, 0.360 mmol) and dimethylzinc (0.360 mL, 0.721 mmol) at 80° C. for 3 hours, the title compound was obtained as a solid (8 mg, 4% yield). MS (ESI): 534.9 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]=2[CH2:29][NH2:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]3[C:15]=2[CH2:29][NH:30][C:39](=[O:41])[N:21]3[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc(NCc3ccccc3)c2CN)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc3c2CNC(=O)N3Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The crude 4-(2-aminomethyl-3-benzylamino-6-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester of step 3 was dissolved in 10 mL dichloromethane and cooled to 0° C. Triethylamine (293 μL, 3 eq., 2.1 mmol) and 69 mg (1 eq., 0.233 mmol) triphosgene were added. The reaction mixture was stirred for 10 minutes. The mixture partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated. Column chromatography, eluting with acetone/dichlorometane provided 141 mg of 4-(1-benzyl-6-fluoro-2-oxo-1,2,3,4-tetrahydro-quinazolin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Br.Br.C([O:5][C:6]([C@@H:8]([NH:18][C@@H:19]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([OH:30])=[O:29])[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[S:21][CH2:20]1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:7])C.C(O)(=O)C>[OH-].[Na+]>[C:6]([C@@H:8]([NH:18][C@@H:19]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([OH:30])=[O:29])[C:23]2[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=2[S:21][CH2:20]1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([OH:7])=[O:5]
Reactant: CCOC(=O)[C@H](CCCC1CCNCC1)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCCC2CCNCC2)C(=O)O)CSc2ccccc21
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
In 12 ml of 1N aqueous sodium hydroxide solution is dissolved 0.5 g of 3(R)-[1(S)-ethoxycarbonyl-4-(4-piperidyl)butyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid.dihydrobromide, and the solution is allowed to stand at room temprature fof 30 minutes. The solution is neutralized with 2 ml of acetic acid, and purified by MCI-gel (CHP 20P, 150 to 300μ, Mitsubishi Chemical Industries, Japan) column chormatography (water:methanol=2:1). The eluent is concentrated under reduced pressure, and the residue is lyophilized to give 0.3 g of 3(R)-[1(S)-carboxy-4-(4-piperidyl)butyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]([C:5]2[N:4]([CH2:3][CH:2]([CH3:17])[CH3:1])[C:16]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=[CH:8][C:7]=3[N:6]=2)[OH:24])=[CH:21][CH:20]=1
Reactant: CC(C)Cn1cnc2cnc3ccccc3c21
Reactant: O=Cc1ccc(Cl)cc1
Product: CC(C)Cn1c(C(O)c2ccc(Cl)cc2)nc2cnc3ccccc3c21

Procedure:
Using the method of Example 45, 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (2.5 g) was reacted with 4-chlorobenzaldehyde to provide 3.1 g of a yellow solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.