Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][NH:17][CH2:18]2.C(N(CC)CC)C.[S:30](Cl)([Cl:33])(=[O:32])=[O:31]>C(Cl)Cl>[Br:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][N:17]([S:30]([Cl:33])(=[O:32])=[O:31])[CH2:18]2
Reactant: O=S(=O)(Cl)Cl
Reactant: FC(F)(F)c1ccc(-c2cccc3c2CCNC3)c(Br)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Cl)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Reaction time: 2 h
Yield: 76.1 %

Procedure:
A 15-mL round-bottom flask was charged with 5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate D, 287.2 mg, 0.731 mmol) and triethylamine (224 μl, 1.609 mmol) in DCM (3.8 mL) to give a brown solution. The flask was cooled in an ice-bath for 10 min, then sulfuryl chloride (125 μl, 1.536 mmol) was added dropwise. Stirring was continued for 2 hours at which time the mixture was quenched with water, then extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on a 40 g silica gel column with 0 to 40% EtOAc/Heptane to give 5-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonyl chloride (253.01 mg, 0.556 mmol) as a clear, very viscous oil that was immediately used in the next step. A vial was charged with 5-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonyl chloride (40.045 mg, 0.088 mmol), pyrimidin-4-amine (41.9 mg, 0.440 mmol), chloroform (587 μl), and pyridine (71.2 μl, 0.881 mmol) and was placed into a 50° C. bath. The mixture was heated overnight before being allowed to cool to rt. The mixture was concentrated under a vacuum, and the residue was chromatographed on a 12 g silica gel column with 0 to 6% MeOH/DCM to give 5-(2-bromo-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (29.77 mg, 0.058 mmol) as a yellow solid. [M+H]+=513.0. 1H NMR (400 MHz, DMSO-d6) δ ppm=9.55 (br. s., 1H), 9.07 (br. s., 1H), 8.57 (br. s., 1H), 8.13 (d, J=1.3 Hz, 1H), 7.99 (br. s., 1H), 7.83 (dd, J=1.1, 8.0 Hz, 1H), 7.55-7.44 (m, 1H), 7.35-7.21 (m, 2H), 7.02 (dd, J=2.0, 6.8 Hz, 1H), 4.71 (d, J=6.4 Hz, 1H), 4.32-4.17 (m, 2H), 3.24-3.07 (m, 2H), 2.45 (br. s., 2H).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[N+](=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N-]>C(OCC)C.CCCCC.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH:2]([CH:3]1[CH2:4][CH:7]1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH2:1]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=CC=C
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: CCCCC
Product: C=CC1CC1C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Butadiene (200 ml, Aldrich) condensed at -700 was transferred to a glass lined autoclave vessel and ethyl diazoacetate (20 g, 0.175 mol, Aldrich) and rhodium acetate dimer (0.3 g, Aldrich) added. The suspension was stirred in a sealed autoclave for 24 hours at ambient temperature. The contents were diluted with 2% diethyl ether in pentane and passed through a silica pad (50 g). The pad was washed with a little ethanol and further ether-pentane. The eluant containing ethanol was treated separately. The organic phases were concentrated at reduced pressure (<5°) and subjected to short path bulb to bulb disillation (90-105° at 12 mm) to give the product as a colourless liquid (14.6 g).
Reaction SMILES: Cl.[F:2][C:3]([F:31])([F:30])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:29])[C:17]([C:19]3[CH:28]=[CH:27][C:22]4[NH:23][C:24](=[O:26])[S:25][C:21]=4[CH:20]=3)=[O:18])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[BH4-].[Na+].Cl>CO>[OH:18][CH:17]([C:19]1[CH:28]=[CH:27][C:22]2[NH:23][C:24](=[O:26])[S:25][C:21]=2[CH:20]=1)[CH:16]([N:13]1[CH2:12][CH2:11][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:2])([F:30])[F:31])[CH:5]=2)[CH2:15][CH2:14]1)[CH3:29]
Reactant: CC(C(=O)c1ccc2[nH]c(=O)sc2c1)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C(O)c1ccc2[nH]c(=O)sc2c1)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.9 %

Procedure:
The 6-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propanoyl)benzo[d]thiazol-2(3H)-one hydrochloride (1.89 g, 4 mmol) was dissolved in 50 ml of methanol solution, and sodium borohydride (0.15 g, 8.4 mmol) was added in proportions, mixed and stirred at room temperature for 3 hours. Working up according to general procedure B gave 0.61 g of (1RS, 2SR)-6-(1-hydroxy-2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)benzo[d]thiazol-2(3H)-one (IV-5) hydrochloride having a melting point of 217 to 219° C., with a yield of 32.2%; and 0.57 g of (1RS,2RS)-6-(1-hydroxy-2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)benzo[d]thiazol-2(3H)-one (IV-6) hydrochloride having a melting point of 235 to 237° C., with a yield of 30%.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[S-:10][C:11]#[N:12].[Na+].BrBr.[Br-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[Cl:1][C:2]1[C:8]([Cl:9])=[C:7]([S:10][C:11]#[N:12])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: N#C[S-]
Reactant: Nc1cccc(Cl)c1Cl
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: CO
Product: N#CSc1ccc(N)c(Cl)c1Cl
Reaction time: 1 h
Yield: 88 %

Procedure:
To a cold (0-5° C.) solution of 2,3-dichloroaniline (2 g) and sodium thiocyanate (3 g) in MeOH (30 ml), was added a solution of bromine (2 g) in MeOH (10 ml) saturated with sodium bromide. The solution was left to stir for 1 hour. The reaction mixture was poured into water (200 ml) and neutralised with sodium carbonate to pH 8. The solid was collected by filtration and dried to yield the title compound as a white solid (2.38 g) 88%. NMR: 6.35 (s, 2H), 6.81 (d, 1H), 7.55 (d, 1H); m/z (EI+): 218.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:39])[NH:25][C@H:26]([C:32]3[CH:33]=[N:34][CH:35]=[C:36]([OH:38])[CH:37]=3)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][F:65])(=O)=O)=CC=1.C1(C)C=CC=CC=1>CN(C=O)C>[F:65][CH2:64][CH2:63][O:62][CH2:61][CH2:60][O:59][CH2:58][CH2:57][O:38][C:36]1[CH:37]=[C:32]([C@@H:26]([NH:25][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]3)[CH2:19]2)=[O:39])[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:33]=[N:34][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCF)cc1
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCCOCCOCCF)c1
Temperature: 25 °C
Yield: 40.9 %

Procedure:
To tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(5-hydroxypyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (30 mg, 60 μmol) in DMF (7.6 mL) was added cesium carbonate (44.7 mg, 140 μmol) and 2-[2-(2-fluoroethoxy)ethoxy]ethyl 4-methylbenzenesulfonate (25 mg, 80 μmol) while stirring at room temperature. After 5 hours toluene was added and the mixture was concentrated in vacuum. The DMF free residue was purified by preparative thin layer chromatography on silica gel (ethyl acetate) to yield 16.7 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-1-(5-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}pyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: NC1N=C(N)C2C(=NC=C(CN(C3C=CC=CC=3)C3C=CC=CC=3)N=2)N=1.[CH:27]1[C:37]2[CH:36]=[CH:35][C:34]3[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=3[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1.[H-].[Na+].Br.[NH2:45][C:46]1[N:47]=[C:48]([NH2:58])[C:49]2[CH:55]=[C:54]([CH2:56]Br)[CH:53]=[N:52][C:50]=2[N:51]=1>>[NH2:45][C:46]1[N:47]=[C:48]([NH2:58])[C:49]2[CH:55]=[C:54]([CH2:56][C:38]3[C:34]4[CH:35]=[CH:36][C:37]5[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=5[NH:32][C:33]=4[CH:41]=[CH:40][CH:39]=3)[CH:53]=[N:52][C:50]=2[N:51]=1
Reactant: Nc1nc(N)c2cc(CBr)cnc2n1
Reactant: C1=Cc2ccccc2Nc2ccccc21
Agent: Br
Agent: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Agent: [H-]
Product: Nc1nc(N)c2cc(Cc3cccc4c3C=Cc3ccccc3N4)cnc2n1

Procedure:
9-[(2,4-Diaminopyrido[2,3-d]pyrimidin-6-yl)methyl]dibenz[b,f]azepine (Formula I: Ar=2,4-diaminopyrido[2,3-d]pyrimidin-6-yl; W=CH2; X=N; Z=CH═CH; m=n=0) is prepared similarly to N-[(2,4-diaminopteridin-6-yl)methyl]-N,N-diphenylamine as disclosed above by using dibenz[b,f]azepine (154 mg, 0.8 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-6-bromomethylpyrido[2,3-d]pyrimidine hydrobromide (100 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[Cl:32])=[O:9])[CH:5]=[CH:4][N:3]=1.[OH:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:32][C:12]1[CH:13]=[CH:14][C:15]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:21]=2)=[O:19])=[CH:16][C:11]=1[NH:10][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:39]2[CH2:40][CH2:41][N:36]([CH2:35][CH2:34][OH:33])[CH2:37][CH2:38]2)[CH:7]=1)=[O:9]
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(Cl)c2)c1)c1ccnc(N2CCOCC2)c1
Reactant: OCCN1CCNCC1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(N3CCN(CCO)CC3)c2)c1)c1ccnc(N2CCOCC2)c1
Yield: 62 %

Procedure:
Using an analogous procedure to that described in Example 21, 2-chloro-N-[2-chloro-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-4-carboxamide was reacted with N-(2-hydroxyethyl)piperazine to give the title compound in 62% yield; NMR Spectrum: (DMSOd6) 2.45 (m, 8H), 3.53 (m, 8H), 3.71 (m, 4H), 4.4 (t, 1H), 7.07 (t, 2H) 7,25 (d, 2H), 7.54 (d, 1H), 7.71 (d, 1H), 8.02 (s, 1H), 8.26 (t, 2H), 10.19 (s, 1H), 10.47 (s, 1H); Mass Spectrum: M+H+ 566.
Reaction SMILES: N.[NH2:2][C:3]1([C:8]([NH2:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH3:15].CC(CC(C)=O)C>O>[CH2:12]([CH:11]1[NH:10][C:8](=[O:9])[C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[NH:2]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCC=O
Reactant: NC(=O)C1(N)CCCC1
Agent: N
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CCCCC1NC(=O)C2(CCCC2)N1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
Ammonia solution (20%; 20 g, 0.30 mol.) is added to a solution of 126 g of 1-aminocyclopentanecarboxamide (>98%, 0.98 mol.) in 150 g of water. 86 g of valeraldehyde (0.99 mol.) are then added at 15° C., during which the temperature rises to 32° C. The reaction mixture is heated to 70° C. and stirred for 7 hours at that temperature. 350 ml of MIBK are added to the emulsion, and the mixture is cooled, with stirring, and the organic phase is separated off. The extract is extensively concentrated by evaporation (200 g), and 200 g of n-hexane are added, and the crystals are filtered off. After drying there remain 125 g of 2-butyl-1,3-diaza-spiro [4.4]nonan4-one (HPLC: 98.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])=[O:10])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].C(OO)(=[O:23])C>C(O)(=O)C>[N+:18]([C:3]1[CH:4]=[C:5]([CH2:8][S:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])(=[O:23])=[O:10])[CH:6]=[CH:7][C:2]=1[CH3:1])([O-:20])=[O:19]
Reactant: CC(=O)OO
Reactant: Cc1ccc(CS(=O)c2cccc[n+]2[O-])cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: Cc1ccc(CS(=O)(=O)c2cccc[n+]2[O-])cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a mixture of 12.1 g (0.042 mole) 2-[[(4-methyl-3-nitrophenyl)methyl]sulfinyl]-pyridine-1-oxide in 35 ml of acetic acid was added, dropwise at room temperature over one-half hour, a solution of 9.2 g (1. 16 mole) of 40% peracetic acid in acetic acid. The reaction mixture was heated to 70° C. for two hours, and then allowed to cool and stir at room temperature overnight. An additional period of heating at 70° C. for five hours was instituted after which time work-up of a small portion of the mixture indicated some starting material to still be present. Heating and stirring at 70° C. for two more hours, and then standing at room temperature over the weekend completed the reaction. Excess peracetic acid was then destroyed with sodium bisulfite followed by the addition of 100 ml of water and neutralization with potassium carbonate. The aqueous mixture was chilled in an ice bath to precipitate yellow/white crystals. These were filtered off, washed with water and dried. Recrystallization from ethanol gave 2.9 g of white fluffy needles, having a melting point of 154-156° C. Infrared and NMR spectra were in agreement with the proposed structure.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:28])=[C:5]([CH:10](O)[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]2[CH2:25][OH:26])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C(C=P(CCCC)(CCCC)CCCC)#N>C1C=CC=CC=1>[C:1]([C:3]1[C:4]([CH3:28])=[C:5]([CH:10]2[O:26][CH2:25][C@@H:13]3[CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][N:12]3[CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc(F)c1C#N
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: c1ccccc1
Product: Cc1c(C2CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)ccc(F)c1C#N
Temperature: 100 °C

Procedure:
tert-Butyl (3S)-4-[2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl]-3-(hydroxymethyl)piperazine-1-carboxylate (18.5 g, 47.0 mmol) and cyanomethylenetri-n-butylphosphorane (20.4 g, 85.0 mmol) were dissolved in 180 mL of benzene. The reaction mixture was degassed and heated to 100° C. for 16 h. LC-MS analysis indicated product peak (M+1=376). The reaction was cooled and evaporated to dryness. The residue was purified by chromatography through a 330 g Redi-sep column, eluting with a 20% acetone/80% hexane mixture to yield a cis-trans mixture of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8].S(=O)(=O)(O)O.[CH:22]([OH:25])(C)C>CC(C)=O.C(OCC)C.CO.S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([C:14]([O:25][CH3:22])=[O:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCOCC
Solvent: CC(C)=O
Product: COC(=O)[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 25 °C

Procedure:
A solution of (5R)-(−)-3-[3-fluoro-4-iodophenyl]-5-hydroxymethyl-2-oxazolidinone (Step 1, 7.61 g, 22.58 mmol) in acetone (150 mL) at −10° C. is treated with a mixture of CrO3 (6.21 g, 62.1 mmol) in sulfuric acid (6M, 16.9 mL, 101 mmol) dropwise over 15 minutes. The resulting mixture is allowed to slowly warm to ambient temperature with vigorous stirring (slight exotherm to 35° C.) and is stirred for an additional 16 h. The mixture is then treated with isopropanol (35 mL), diluted with saline (150 mL) and diethyl ether (150 mL), stirred until all solids are dissolved, and the layers are separated. The aqueous phase is extracted with diethyl ether (100 mL), and the combined organic phase is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude carboxylic acid intermediate which is taken up in methanol (225 mL) and treated with concentrated sulfuric acid (8 drops). The resulting homogeneous mixture is stirred at ambient temperature for 20 h and is then concentrated under reduced pressure to give the crude methyl ester product which is chromatographed on two Flash 40M 90 g silica gel (32-63 μm) cartridges, eluting with a gradient of ethyl acetate/heptane (20/80-40/60). Pooling and concentration of those fractions with an Rf=0.36 by TLC (ethyl acetate/hexane, 50/50) gives the title compound, mp 106-109° C.; MS (ESI+) for C11H9FINO4 m/z 366 (M+H)+; [α]25D=−30 (c 0.93, DMSO).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1C=CC=CC=1>[C:14]1([N:13]=[C:1]=[C:3]2[S:7][C:6]([C:8]3[S:9][CH:10]=[CH:11][CH:12]=3)=[CH:5][CH2:4]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(-c2cccs2)s1
Reactant: Nc1ccccc1
Solvent: c1ccccc1
Product: C(=Nc1ccccc1)=C1CC=C(c2cccs2)S1
Temperature: 85 °C

Procedure:
5.0 g of 5-formyl-2,2'-bithiophene was dissolved in 45 ml of benzene. 2.4 ml of aniline was added and refluxed for 24 hours at 85° C. 6.9 g of crude product was obtained after removal of solvent under reduced pressure and the purer product could be obtained by recrystallization with ethanol.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([N+:20]([O-])=O)=[N:9][CH:10]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]=2)[CH2:5]CCC1.O.[C:24](O)(=[O:26])C>[Zn]>[CH3:24][O:26][CH2:5][CH2:1][O:6][C:7]1[C:8]([NH2:20])=[N:9][CH:10]=[C:11]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:12]=1
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1ncc(Oc2ccccc2)cc1OC1CCCC1
Agent: [Zn]
Solvent: O
Product: COCCOc1cc(Oc2ccccc2)cnc1N
Temperature: 100 °C
Yield: 72 %

Procedure:
3-Cyclopentyloxy-2-nitro-5-phenoxy-pyridine (0.46 mmol) is dissolved in acetic acid (1.5 ml). After addition of water (1.5 ml), zinc powder (6.2 eq.) is added and the reaction suspension is heated to 100° C. for 3 h. The reaction suspension is cooled to room temperature and filtrated. The filtrate is pored into 3.5% NaOH (30 ml) and extracted with dichloromethane. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 3-(2-Methoxyethoxy)-5-phenoxy-pyridine-2-ylamine is obtained as brown oil in a yield of 72%; HPLC (method C): 1.43 min; LC-MS (method A): 1.231 min, 271.15 (M+H+).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=2[O:8][CH:7]=1.C(OCC)C>CS(C)=O>[F:15][C:12]1[CH:13]=[CH:14][C:9]2[O:8][CH:7]=[C:6]([CH2:5][C:1]#[N:2])[C:10]=2[CH:11]=1
Reactant: [C-]#N
Reactant: Fc1ccc2occ(CCl)c2c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#CCc1coc2ccc(F)cc12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
Lithium aluminium hydride (15 g) was suspended in tetrahydrofuran (400 mL) under a nitrogen atmosphere followed by dropwise addition of a solution of methyl 5-fluorobenzofuran-3-carboxylate (58 g) in tetrahydrofuran (300 mL). The temperature increased to 55° C. during the addition. After stirring for 2 h the reaction was quenched succesively with water (30 mL), 15% aq. sodium hydroxide (15 mL), and water (75 mL). Further tetrahydrofuran (500 mL) was added and the mixture stirred for 1 h. The mixture was filtered and the precipitate extracted with a mixture of methylene chloride (1 L) and ethanol (0.5 L). The combined organic phases were concentrated in vacuo giving an oil which was applied to silica gel flash chromatography (eluent: methylene chloride/25% aq. NH3 99:1). The resulting yellow oil, 5-fluorobenzofuran-3-ylmethanol (14.4 g) crystallised on standing. A solution of 5-fluorobenzofuran-3-ylmethanol (14 g) in methylene chloride (250 mL) was treated succesively with 5 drops of dimethylformamide and thionyl chloride (28 mL). After stirring for 16 h at room temperature the reaction was concentrated in vacuo giving 3-chloromethyl-5-fluorobenzofuran as an oil (19.4 g). A suspension of sodium cyanide (10 g) in dimethylsulfoxide (150 mL) was heated to 80° C. followed by quick addition of a solution of 3-chloromethyl-5-fluorobenzofuran (10 g) in dimethylsulfoxide (50 mL). The mixture was kept at 80° C. for ½ h and then poured onto ice. Standard work-up with diethyl ether gave a dark crystalline material, 5-fluorobenzofuran-3-ylacetonitrile (8.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:15][C:16](=[O:26])[CH:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[Cl:18])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[N+:27]([C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]>>[Cl:18][CH:17]([C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:16]([NH:15][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:36]([C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([N+:27]([O-:29])=[O:28])[CH:31]=2)(=[O:37])=[O:38])[CH:3]=1)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:26]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CCOC(=O)CC(NC(=O)C(Cl)c1ccc(Cl)cc1)c1cccc(N)c1
Product: CCOC(=O)CC(NC(=O)C(Cl)c1ccc(Cl)cc1)c1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1

Procedure:
Corresponding to Example 3c, 900 mg of (5b) were reacted with 3-nitrophenylsulphonyl chloride. A solid was obtained (yield: 1.18 g).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7](=[O:8])[CH:3]([CH2:4]2)[CH2:2]1.O.O1CC[CH2:12][CH2:11]1>>[C:11]([C:7]1([OH:8])[CH2:6][CH:5]2[CH2:4][CH:3]1[CH2:2][CH2:1]2)#[CH:12]
Reactant: O=C1CC2CCC1C2
Reactant: C1CCOC1
Solvent: O
Product: C#CC1(O)CC2CCC1C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
500 mg of norcamphor was dissolved in 6 ml of tetrahydrofuran and the solution was added dropwise in a suspension of 543 mg of lithium acetylide-ethylenediamine complex in tetrahydrofuran at room temperature, and the resulting reaction mixture was stirred for 18 hours. After water was added to the resulting reaction mixture, it was evaporated while maintaining the temperature of the water bath at 25° C. The residue was extracted with ethyl acetate twice. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated, to give 523 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH2:16]1[O:25][C:24]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=2[O:17]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:21][C:20]2[CH:22]=[CH:23][C:24]3[O:25][CH2:16][O:17][C:18]=3[CH:19]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: Nc1ccc2c(c1)OCO2
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Nc2ccc3c(c2)OCO3)c1C(=O)OC
Yield: 67 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), 3,4-methylenedioxyaniline (0.43 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and then filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated, and the residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 0.69 g of the product at 85:15 hexanes-ethyl acetate, in 67% yield: 1H NMR (CDCl3) δ 3.87 (s, 3H), 3.88 (s, 3H), 5.97 (s, 2H), 6.63 (dd, J=8.2 Hz, J=2.1 Hz, 1H), 6.70 (d, J=2.1 Hz, 1H), 6.78 (d, J=8.2 Hz, 1H), 6.98 (dd, J=7.3 Hz, J=1.1 Hz, 1H), 7.13 (dd, J=7.3 Hz, J=1.1 Hz, 1H), 7.25 (t, J=7.9 Hz, 1H), 8.06 (br, 1H).