Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:6][C:5]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=O)=[C:4]([N+:28]([O-])=O)[CH:3]=1.Cl.O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl.CO>[Br:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:6][C:5]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[NH:28][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(NC(=O)c3ccccn3)c([N+](=O)[O-])cc2Br)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2Br)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
145 ml of N-{4-bromo-5-(4-(methylsulfonyl)phenoxy]-2-nitrophenyl}-2-pyridinecarboxamide was suspended in 1 ml of dimethylformamide, 1 ml of methanol and 0.5 ml of concentrated hydrochloric acid, and 327 mg of tin(II) chloride dihydrate was added thereto and stirred at 70° C. for 30 minutes. The reaction liquid was neutralized with aqueous sodium bicarbonate solution, and diluted with chloroform. The insoluble matter was taken out through filtration, the filtrate was washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away to obtain 121 mg of the entitled compound as a pale yellow crystal.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9](Cl)[N:8]=2)=[CH:4][C:3]=1[CH:18]1[O:22][CH2:21][CH2:20][O:19]1.BrC1C=CC(OC2N=C(Cl)C=CC=2C#N)=CC=1C1OCCO1.C([O:52][CH2:53][CH2:54][NH:55][C:56]1N=C(OC2C=CC(Br)=C(C=O)C=2)C=CC=1C#N)C1C=CC=CC=1>C(#N)C>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([N:55]([CH2:54][CH2:53][OH:52])[CH3:56])[N:8]=2)=[CH:4][C:3]=1[CH:18]1[O:22][CH2:21][CH2:20][O:19]1
Reactant: N#Cc1ccc(Oc2ccc(Br)c(C=O)c2)nc1NCCOCc1ccccc1
Reactant: N#Cc1ccc(Oc2ccc(Br)c(C3OCCO3)c2)nc1Cl
Agent: N#Cc1ccc(Cl)nc1Oc1ccc(Br)c(C2OCCO2)c1
Solvent: CC#N
Product: CN(CCO)c1nc(Oc2ccc(Br)c(C3OCCO3)c2)ccc1C#N
Temperature: 80 °C
Yield: 36 %

Procedure:
To a solution of compound mixture, 6-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-2-chloro-nicotinonitrile and 2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-chloro-nicotinonitrile, (4+5, 1 g, 2.6 mmol) in acetonitrile (anhydrous, 30 mL) was added 2-methylamino-ethanol (6, 2.1 mL, 26 mmol). The reaction was heated at 80° C. for 2 hours. After the reaction, all volatile components were evaporated in vacuo. Purification was accomplished by silica gel chromatography, eluting with 10%-80% EtOAc/hexanes gradient, affording 400 mg (36% yield) of the title compound.
Reaction SMILES: OO.[NH2:3][C:4]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1)=[CH:5][C:6](=[S:12])[NH:7][CH2:8][CH:9]1[CH2:11][CH2:10]1>CO>[CH:9]1([CH2:8][NH:7][C:6]2[S:12][N:3]=[C:4]([C:13]3[CH:14]=[CH:15][C:16]([CH2:17][NH2:18])=[CH:19][CH:20]=3)[CH:5]=2)[CH2:11][CH2:10]1
Reactant: NCc1ccc(C(N)=CC(=S)NCC2CC2)cc1
Agent: OO
Solvent: CO
Product: NCc1ccc(-c2cc(NCC3CC3)sn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
Add 30% hydrogen peroxide solution (0.13 mL, 1.1 mmol) to a solution of 4-[1-amino-2-(cyclopropylmethyl-thiocarbamoyl)-vinyl]-benzylamine (150 mg, 0.57 mmol) in methanol (5 mL). Stir the solution for 16 h at room temperature. Quench the reaction with aqueous saturated sodium hydrogensulfite (1 mL). Extract the mixture with EtOAc (2×30 mL), collect the organic layer and concentrate in vacuo. Purify the residue by chromatography on silica gel (4 g) eluting with DCM/ammonia in methanol (97:3) to obtain the title compound as a yellow solid (68 mg, 46%). MS (ES+) m/z: 243.1 (M-NH3+H)+.
Reaction SMILES: C(O[C:6]1[C:7](=[O:16])[C:8](=[O:15])[C:9]=1[NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])CCC.[CH3:17][C:18]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:19]=1[CH2:20][NH2:21].C(N(CC)CC)C>O1CCCC1>[C:11]([NH:10][C:9]1[C:8](=[O:15])[C:7](=[O:16])[C:6]=1[NH:21][CH2:20][C:19]1[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:18]=1[CH3:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: Cc1ccc(C)c(CN)c1
Reactant: CCCCOc1c(NC(C)(C)C)c(=O)c1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C)c(CNc2c(NC(C)(C)C)c(=O)c2=O)c1
Yield: 48.7 %

Procedure:
Tetrahydrofuran (10 mL), 3-butoxy-4-tert-butylamino-cyclobut-3-ene-1,2-dione (1.13 g, 5.0 mmol, Example 1), 2,5-dimethylbenzylamine (0.858 g, 5.0 mmol), and triethylamine (0.51 g, 5.0 mmol) were stirred together at room temperature for approximately 18 hours. Following removal of solvent, the residue was triturated with water, with diethyl ether, and dried to give 0.698 g of a cream-colored solid. Three recrystallizations of this material from methanol afforded 0.444 g of the title compound as a white solid: mp 246°-247° C. (softens 242° C.). MS (m/z) 287 ([M+H]+). HPLC indicates a major component (>99%).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=2)[N:5]=1)([CH3:3])[CH3:2].Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: ClCCN1CCOCC1
Reactant: Cc1cc(Nc2cc3cc(O)ccc3c(C(C)C)n2)n[nH]1
Product: Cc1cc(Nc2cc3cc(OCCN4CCOCC4)ccc3c(C(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 329 was used, starting from 1-Isopropyl-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol and N-(2-chloroethyl)-morpholine to give [1-Isopropyl-6-(2-morpholin-4-yl-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 396(MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[C:4]([F:24])[CH:3]=1.[OH:25][C:26]([CH3:45])([CH3:44])[CH2:27][N:28]1[C:32]([CH3:33])=[C:31]([C:34](O)=[O:35])[C:30](=[O:37])[N:29]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[F:24][C:4]1[CH:3]=[C:2]([NH:1][C:34]([C:31]2[C:30](=[O:37])[N:29]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:28]([CH2:27][C:26]([OH:25])([CH3:45])[CH3:44])[C:32]=2[CH3:33])=[O:35])[CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][N:14]=[C:13]2[C:8]=1[C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[C:11](=[O:17])[NH:12]2
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)c(F)c1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)c5ccccc5c34)c(F)c2)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Yield: 33.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 209 using Compound 182 (55 mg, 0.17 mmol) and 1-(2-hydroxy-2-methyl-propyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (60 mg, 0.21 mmol) to provide 210 (34 mg, 33% yield) as a white solid. LC-MS (M+H=594, obsd.=594).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7](C=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH3:29][O:30][CH:31](OC)[O:32][CH3:33]>CO>[CH3:29][O:30][CH:31]([O:32][CH3:33])[C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(OC)OC
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC(OC)c1ccc([N+](=O)[O-])cc1
Temperature: 50 °C

Procedure:
A flask equipped with a magnetic stir bar and vigreux column was charged with 4-nitrobenzaldehyde (5.0 g, 33.1 mmol), pyridinium p-toluenesulfonate (1.66 g, 6.62 mmol), trimethoxymethane (3.51 g, 33.1 mmol) and methanol (100 mL). The mixture was heated at 50° C. for 12 h and was concentrated in vacuo. The residue was redissolved in EtOAc and washed with aq. NaOH (1M), H2O and brine. The mixture was dried (Na2SO4), filtered and concentrated in vacuo to yield the title compound as a clear, light yellow oily product (6.36 g, 97%).
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[CH:9][C:8](O)=[C:7]([C:12]#[N:13])[C:6]1=[O:14])[CH2:2][CH2:3][CH3:4].O(Br)[Br:16].[P+3]>CN(C=O)C>[Br:16][C:8]1[CH:9]=[CH:10][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:14])[C:7]=1[C:12]#[N:13]
Reactant: BrOBr
Reactant: CCCCn1ccc(O)c(C#N)c1=O
Agent: [P+3]
Solvent: CN(C)C=O
Product: CCCCn1ccc(Br)c(C#N)c1=O
Temperature: 110 °C
Yield: 70.9 %

Procedure:
To a solution of intermediate 7 (39 g, 203 mmol) in DMF (600 ml) was added phosphorus(III) oxybromide (116 g, 406 mmol) and the mixture was heated at 110° C. for 1.5 hours. After cooling in an ice bath the solution was partitioned between water and EtOAc. After three extractions with EtOAc the combined organic fractions were washed with brine, dried over Na2SO4 and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 10 (36.7 g, 72%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17](=[O:20])[CH2:16]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.CN(C=O)C>C1COCC1>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17](=[O:20])[CH:16]2[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][CH2:37][N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: O=C1Cc2cccc(OCc3ccccc3)c2N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2c(C3C(=O)Nc4c(OCc5ccccc5)cccc43)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
Sodium hydride (36 mg, 1.5 mmol) was added in portions to a solution of 7-benzyloxyoxindole (360 mg, 1.5 mmol) in THF (8 ml), the mixture was stirred for 30 minutes at ambient temperature and a solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (204 mg, 0.6 mmol), (prepared as described for the starting material in Example 5), in THF (4 ml) and DMF (1.5 ml) was added. The mixture was stirred for 30 minutes at ambient temperature followed by 1.5 hours at 65° C. The THF was removed by evaporation, the mixture was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH8 with 2M hydrochloric acid. The precipitated product was collected by filtration, washed with water, ethyl acetate, and ether, and dried under vacuum to give 4-(7-benzyloxyoxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (190 mg, 58%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[S:13]([NH:16][C:17]1[N:22]=[C:21](Cl)[C:20]([S:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:19][N:18]=1)(=[O:15])=[O:14].CCOCC>C1COCC1>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[S:13]([NH:16][C:17]1[N:22]=[C:21]([NH:4][CH2:1][CH2:2][CH3:3])[C:20]([S:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([N:34]3[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]3)(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:19][N:18]=1)(=[O:14])=[O:15]
Reactant: O=S(=O)(Nc1ncc(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)c(Cl)n1)c1ccc(Cl)cc1Cl
Reactant: CCCN
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCNc1nc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
n-Propylamine (25 mg, 0.42 mmol) was added to a solution of 11 (50 mg, 0.08 mmol) in THF (5 mL) and the mixture was stirred at 50° C. for 2 hours. The solution was cooled to room temperature, filtered and the precipitate was washed with THF. The filtrate was concentrated under reduced pressure to afford a yellow oil. Trituration with ether gave a solid which was purified by flash column chromatography (2% MeOH in DCM) to afford 12 as a white solid (28 mg). 1H NMR (DMSO): δ 0.54 (t, 3H), 1.22 (q, 2H), 1.33-1.34 (m, 2H), 1.51 (quin, 4H), 2.80-2.84 (m, 6H), 7.32 (d, 2H), 7.56 (d, 1H), 7.58 (d, 2H), 7.70 (s, 1H), 7.97 (br s, 1H), 8.07 (d, 1H), 8.15, (s, 1H) ppm. Mass Spectrum m/e=618.0 (M+1)
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]#[C:13][Si](C)(C)C)[C:9]([OH:18])=[CH:8][N:7]=1)(=[O:3])[CH3:2].FC(F)(F)C([O-])=O>N1C=CC=CC=1.[Cu]I>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]2[CH:12]=[CH:13][O:18][C:9]2=[CH:8][N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(C#C[Si](C)(C)C)c(O)cn1
Agent: [Cu]I
Agent: O=C([O-])C(F)(F)F
Solvent: c1ccncc1
Product: CC(=O)OCc1cc2ccoc2cn1

Procedure:
{5-Hydroxy-4-[(trimethylsilyl)ethynyl]-2-pyridinyl}methyl acetate, trifluoroacetate) (10 g, 22 mmol) was dissolved in pyridine (200 ml) and treated with copper(I) iodide (5.2 g, 27 mmol) then heated under reflux for 18 h. The mixture was allowed to cool, evaporated to dryness and the residue partitioned between ethyl acetate and water. This mixture was filtered through kieselguhr to remove copper residues. The organic layer was separated from the filtrate, dried and chromatographed on silica gel, eluting with a gradient of 10-60% ethyl acetate in 40-60° C. petroleum ether. This gave furo[2,3-c]pyridin-5-ylmethyl acetate (1.15 g, 27%) and a less polar product [2-(trimethylsilyl)furo[2,3-c]pyridin-5-yl]methyl acetate (1.3 g, 23%) as oils.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:10][C:11](=[O:26])[C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2F)=[CH:16][CH:15]=[N:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1>[CH2:3]([N:10]1[C:19]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=2[C:17]2[C:12](=[CH:13][N:14]=[CH:15][CH:16]=2)[C:11]1=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(NCc1ccccc1)c1cnccc1-c1ccc(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c2cnccc2c2ccc(Cl)cc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a suspension of sodium hydride (96 mg, 3.99 mmol) in THF (13 mL) at 0° C. was added a solution of N-benzyl-4-(4-chloro-2-fluorophenyl)nicotinamide (680 mg, 1.995 mmol) in THF (10 mL) dropwise over a period of 10 min. The reaction mixture was stirred at 0° C. for 1 h and then warmed to room temperature and stirred for another 1 h. The reaction mixture was then treated with ice and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (1×5 mL), dried (Na2SO4) and concentrated under reduced pressure to afford crude 6-benzyl-8-chlorobenzo[c][2,7]naphthyridin-5(6H)-one (640 mg, 2.00 mmol, 100%). LC/MS (ESI) m/e 321.0 [(M+H)+, calcd for C19H14ClN2O 321.0]; LC/MS retention time (method A): tR=1.95 min.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:15][NH:14][C:13]([S:16][CH3:17])=[N:12][N:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].BrBr>C(O)(=O)C>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[N:12][C:13]([S:16][CH3:17])=[N:14][N:15]=2)=[CH:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(C2=NN=C(SC)NN2)cc1
Agent: BrBr
Solvent: CC(=O)O
Product: CCCc1ccc(-c2nnc(SC)nn2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
0.0163 Mol (4.05 g) of 6-(4-n-propylphenyl)-3-methylthio-1.2-dihydro-1,2,4,5-tetrazine is dissolved in 80 ml crystalline acetic acid at 40° C. and 18 ml of a 1-molar Br2 -crystalline acetic acid solution is added dropwise. The solution is stirred for one hour and subsequently poured over ice water. The red dyestuff is vacuum dried, washed with water and dried. Recrystallization from ethanol provides 3.4 g of red crystals. M.pt.: 78°-79° C. The compounds characterized in Table 7 are made in an analogous fashion manner.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@:10]([C:15]#[C:16][CH2:17]O)([OH:14])[C@@H:9]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([SnH:29]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@:10]2([O:14][CH2:17][C:16]([Sn:29]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:15]2)[C@@H:9]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](O)(C#CCO)[C@@H]1c1ccccc1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Pd]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1=C[C@@]2(CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)OC1
Yield: 66.7 %

Procedure:
Crude (2S,3R)-1-tert-butoxycarbonyl-3-(3-hydroxypropyn-1-yl)-2-phenylpiperidin-3-ol (Description 18; 45 g) was dissolved in toluene (750 ml) and degassed with nitrogen. Tetrakis(triphenylphosphine) palladium (0) (2.30 g, 2.0 mmol) in toluene (600 ml) was added and the mixture was degassed. Tributyltin hydride (35.78 ml, 38.71 g, 133 mmol) was added dropwise over 15 minutes, with stirring and cooling (internal temperature below 25° C.). The mixture was stirred at room temperature for 1 hour, then the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (600 ml) and triphenylphosphine (34.88 g, 133 mmol) was added. A solution of diethyl azodicarboxylate (20.94 ml, 23.16 g, 133 mmol) in tetrahydrofuran (150 ml) was added dropwise with stirring and cooling and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, acetonitrile (600 ml) was added and the mixture was extracted with hexane (8×150 ml). The hexane fractions were combined and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/ethyl acetate (100:0 increasing to 99:1) to give the title compound as a yellow oil (53.64 g, 67% from (2s,3S)-1-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidine). 1H NMR (CDCl3) δ 7.38-7.40 (2H, m), 7.15-7.25 (3H, m), 5.96 (1H, t, J 2.3 Hz), 4.93 (1H, s), 4.63 (1H, dd, J 2.23, 12.9 Hz), 4.22 (1H, dd, J 2.23, 12.9 Hz), 4.09-4.14 (1H, m), 3.09-3.17 (1H, m), 1.95-1.99 (1H, m), 1.83-1.86 (1H, m), 1.72-1.76 (2H, m), 1.40-1.51 (6H, m), 1.38 (9H, s), 1.25-1.32 (6H, m), and 0.86-0.99 (15H, m).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9]C)=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C([O-])(=O)C.[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[S:3]1[C:2]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][C:7](=[O:9])[C:6]=2[CH:5]=[CH:4]1
Reactant: Nc1ccccc1B(O)O
Reactant: COC(=O)c1ccsc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2c2sccc12
Temperature: 120 °C
Yield: 12 %

Procedure:
In a microwave vessel, methyl 2-bromo-3-thiophene carboxylate (1.0 eq, 64 mg, 0.29 mmol), 2-amino phenyl boronic acid (1.2 eq, 48 mg, 0.35 mmol), sodium acetate (3.0 eq, 71 mg, 0.86 mmol) and PdCl2(dppf) (0.1 eq, 15 mg, 0.028 mmol) were mixed together in anhydrous DMF (0.2 ml). The mixture was heated in a microwave oven at 120° C. for 5 nm. The material was purified by preparative HPLC. Acetonitrile was evaporated, and the compound was extracted with CH2Cl2 (3×). The combined extracts were washed with water, dried over Na2SO4, and the solvents removed in vacuo. Recrystallization in EtOH provided thieno[3,2-c]quinolin-4(5H)-one as a tan crystalline solid (7 mg, 12% yield). LCMS (ES): 95% pure, m/z 202 [M+1]+; 1H NMR (CDCl3/CD3OD, 9:1, 400 MHz) δ 7.28 (m, 1H), 7.33 (m, 1H), 7.43-7.50 (m, 2H), 7.74 (d, J=4.4, 1H), 7.82 (d, J=7.6, 1H) ppm
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH:20]=1)[CH:18]=O>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH2:18][C:9]2[S:8][C:7]3[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[CH:10]=2)[CH:20]=1
Reactant: COc1ccc2ccsc2c1
Reactant: O=Cc1cc(Br)ccc1Cl
Product: COc1ccc2cc(Cc3cc(Br)ccc3Cl)sc2c1

Procedure:
6-Methoxybenzo[b]thiophene (see WO 97/25033) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH:4]=[C:3]([CH2:2][N:23]3[CH2:22][CH2:21][N:20]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[F:13])[CH2:25][CH2:24]3)[C:7]=2[CH:8]=1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Clc1ccc2scc(CBr)c2c1
Product: Fc1ccccc1N1CCN(Cc2csc3ccc(Cl)cc23)CC1

Procedure:
3-(Bromomethyl)-5-chloro-1-benzothiophene and 1-(2-fluorophenyl)piperazine were processed as described in Example 2 to provide the title compound. 1H NMR (d6-DMSO, 300 MHz) δ 2.65 (m, 2H), 3.02 (m, 6H), 3.78 (s, 2H), 6.92-7.10 (m, 4H), 7.40 (dd, 1H, J=8.7, 1.5), 7.67 (s, 1H), 7.78 (d, 1H, J=8.7 Hz), 8.06 (d, 1H, J=1.5 Hz). MS (DCI/NH3) m/z 361.0 (M+H)+. Anal. Calcd for C19H18N2SClF: C, 63.24;H, 5.03; N, 7.76. Found: C, 63.17;H, 4.90; N, 7.67.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][C:6]1([CH:14]2[NH:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:11]=[CH:10][CH:9]=[C:8]([O:12]C)[CH2:7]1>C(Cl)(Cl)Cl>[CH3:5][C:6]1([CH:14]2[NH:20][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH2:7]1
Reactant: COC1=CC=CC(C)(C2CCCCC(=O)N2)C1
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Product: CC1(C2CCCCC(=O)N2)C=CC=C(O)C1
Reaction time: 1 h

Procedure:
BBr3 (1M in CH2Cl2) (1 mL, 1 mmol) was added dropwise to a solution of 7-(1-methyl-3-methoxyphenyl)-azepan-2-one, as described in Step D above, (0.06 g, 0.26 mmol) in CHCl3 (1 mL) at 0° C. with stirring. The ice bath was removed and stirring was continued for 1 h. The reaction mixture was partitioned between EtOAc (100 mL)—H2O (100 mL), the organic layer separated, washed with H2O, dried (MgSO4), filtered and concentrated to give the title compound after SiO2 chromatography (CHCl3:MeOH, 10:1).
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][NH:19][S:20]([CH2:23][CH2:24][CH2:25][F:26])(=[O:22])=[O:21])[CH:16]=2)[CH2:11][CH2:10][CH:9]1[NH:27]C(=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[NH2:27][CH:9]1[CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]2[CH:16]=[C:15]([CH2:18][NH:19][S:20]([CH2:23][CH2:24][CH2:25][F:26])(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CNS(=O)(=O)CCCF)cc2C1Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCc2ccc(CNS(=O)(=O)CCCF)cc2C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-butyl [1-benzyl-7-({[(3-fluoropropyl)sulfonyl]amino}methyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (9.3 mg, 0.019 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (excess) was added. The reaction mixture was stirred at room temperature for 4 h. The solvent was evaporated in vacuo and the crude product was purified by flash chromatography (silica gel, dichloromethane, methanol). Yield: 4 mg (0.0079 mmol, 42%).