Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1Oc1ccc(F)cc1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(4-fluorophenoxy)benzoic acid (step 2 of Example 67) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.16 (1H, d, J=2.6 Hz), 7.95 (2H, dd, J=6.6, 1.8 Hz), 7.88 (1H, d, J=7.4 Hz), 7.36–7.29 (3H, m), 7.23–6.96 (4H, m), 6.78 (1H, d, J=8.7 Hz), 5.32 (1H, dq, J=7.4, 6.9 Hz), 3.90 (3H, s), 1.51 (3H, d, J=6.9 Hz); MS (ESI) m/z 428 (M+H)+, 426 (M−H)−.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[CH2:7]([Sn:11](Cl)([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10]>O1CCCC1>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][Sn:11]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C#C[Si](C)(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
Under argon stream, 3.53 ml (25 mmol) of trimethylsilylacetylene was dissolved in 25 ml of tetrahydrofuran and cooled to -78° C. Into the solution was added dropwise 14.9 ml (24 mmol) of butyllithiumhexane solution, and the reaction was carried out with stirring for 30 minutes. Then, 6.5 ml (24 mmol) of tributyltin chloride was added dropwise, and the reaction was carried out with stirring for 22 hours, while elevating gradually the temperature of the reaction mixture to room temperature. After the reaction, the solvent was evaporated and the residue was distilled under reduced pressure (0.6 mm Hg, 100°-102° C.) to obtain 4.84 g of a transparent liquid (yield: 52.2%).
Reaction SMILES: [OH-].[Na+].[C:3](OC([O-])=O)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].O1CCCC1.[CH2:19]([NH:22][CH2:23][C@H:24]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N+:36]([O-:38])=[O:37])(=[O:29])=[O:28])[CH3:25])[CH:20]=[CH2:21]>O>[CH2:19]([N:22]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:23][C@H:24]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N+:36]([O-:38])=[O:37])(=[O:29])=[O:28])[CH3:25])[CH:20]=[CH2:21]
Reactant: C=CCNC[C@@H](C)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCN(C[C@@H](C)NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 85.6 %

Procedure:
A 2N aqueous NaOH solution (50 mL) and 6.1 g of tert-butyl dicarbonate were added to a tetrahydrofuran (100 mL) solution of 7 g of the compound obtained in Step 1, stirring at room temperature and reacted at room temperature for 6 hours. After the completion of reaction, 100 mL of water was added, followed by two extractions with 100 mL of ethyl acetate. The combined organic layer was washed with 100 mL of saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 8 g of the compound of interest as a yellow oil (86%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][C:37](=O)[CH3:38])[CH:32]=[CH:33][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH:37]([CH3:38])[CH2:36][CH2:35][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(=O)CCc1cccc(Cl)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4cccc(Cl)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-(3-chloro-phenyl)-butan-2-one.
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:16][C:17]1([F:24])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[F:16][C:17]1([F:24])[CH2:23][CH2:22][CH2:21][N:20]([C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:11][CH:10]=2)=[O:14])[CH2:19][CH2:18]1
Reactant: O=C(O)c1csc(-c2ccccc2)c1
Reactant: FC1(F)CCCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: O=C(c1csc(-c2ccccc2)c1)N1CCCC(F)(F)CC1
Yield: 42 %

Procedure:
5-Phenyl-thiophene-3-carboxylic acid (0.20 g, 1.11 mmol) and 4,4-difluoro-azepane hydrochloride (0.19 g, 1.11 mmol) were stirred in acetonitrile (10 mL) with silica-supported diethylamine (1.32 mmol/g, 2.5 g) and HATU (0.40 g, 1.11 mmol) for 18 hours. The reaction mixture was filtered and the solvent was removed by evaporation then the crude material was purified by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid) over 20 minutes. The fractions containing the desired product were evaporated to give the title compound as a gum (0.15 g). LCMS m/z 322.19 [M+H]+ R.T.=11.14 min (Analytical Method 2).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][NH:12][CH3:13]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([CH3:13])[CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In a 500 mL round-bottomed flask, 6-chloronicotinoyl chloride (8 g, 45.5 mmol, Eq: 1.00) was dissolved in DCM (200 ml) under argon and cooled to 0° C. To this solution, dimethylamine (90.9 ml of 2M in THF, 182 mmol, Eq: 4) was added drop-wise over 15 min maintaining the temperature below 10° C. The ice bath was removed and the reaction was stirred for 3 h.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]1([F:54])[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:47][C:48]1([F:54])[CH2:53][CH2:52][N:51]([C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[O:11])=[CH:20][CH:19]=3)=[O:22])[CH2:50][CH2:49]1
Reactant: FC1(F)CCNCC1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4,4-difluoropiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: C([N:8]1[CH2:13][C@H:12]([OH:14])[CH2:11][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[C@H:9]1[C:19]([O:21]CC1C=CC=CC=1)=[O:20])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:14][C@H:12]1[CH2:13][NH:8][C@H:9]([C:19]([OH:21])=[O:20])[C@@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]1
Reactant: [H][H]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H]1C[C@@H](O)CN[C@@H]1C(=O)O

Procedure:
A mixture of 2-benzyl 3-methyl (2S,3S,5R)-1-benzyl-5-hydroxypiperidine-2,3-dicarboxylate (1.00 g, 0.00261 mol) in 10 mL of methanol was hydrogenated in the presence of 10% Pd/C, under a balloon pressure of hydrogen, for 3 h. After filtered off the catalyst, the filtration was concentrated to dry in vacuo and used directly in next step. MS (ESI): (M+H)+=204.0.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[NH:15][CH:16]=O>C1COCC1>[CH3:16][NH:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=1[Cl:7]
Reactant: O=CNc1cccc(F)c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1cccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 98.3 %

Procedure:
To a stirred suspension of 95% lithium aluminum hydride (2.19 g, 58 mmol) in anhydrous THF (10 mL) at 0° C., was added dropwise a solution of N-(2-chloro-3-fluoro phenyl)-formamide (2.3 g, 13.2 mmol) in anhydrous THF (20 mL). The reaction mixture was allowed to slowly warm to room temperature and was stirred for a further 40 mins. The mixture was cooled to 0° C. and was quenched via the sequential addition of water (4 mL), 15% aq. NaOH (2 mL), then water (4 mL). Organics were extracted into a mixture of 3:1 DCM: IPA (100 mL) and washed with water (50 mL). The organic layer was separated and dried over MgSO4. Filtration then concentration in vacuo gave N-methyl-2-chloro-3-fluoroaniline 29-1 (2.07 g, 99%) as a yellow oil. MS (M+H)+: 160.1, tR=2.21 min (method 1).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][CH:6]([CH3:38])[CH2:7][CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([C:27]([OH:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[C:12]2[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34]C)=[CH:33][C:11]=2[N:10]=1>ClCCl>[CH3:5][CH:6]([CH3:38])[CH2:7][CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([C:27]([OH:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[C:12]2[CH:30]=[C:31]([O:36][CH3:37])[C:32]([OH:34])=[CH:33][C:11]=2[N:10]=1
Reactant: COc1cc2nc(CCC(C)C)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2c(cc1O)nc(CCC(C)C)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
3 g of aluminium trichloride are added to a suspension of 600 mg (1.3 mmol) of 4'-[(2-(3-methylbutyl)-5,6-dimethoxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid in 50 ml of dry dichloromethane and the mixture is heated under reflux for 15 minutes. The solvent is then distilled off, the residue is filtered off under suction, washed using 30 ml of water and dried. 360 mg (62% of theoretical) of a mixture of the isomeric products is obtained after chromatographing over silica gel (eluting agent: dichloromethane/ethanol=9:1).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[N:12][CH:11]=[CH:10]2>ClCCl.C(OCC)C>[Cl:4][C:8]1[C:7]([OH:6])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]=[CH:13]2
Reactant: Oc1ccc2cnccc2c1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Oc1ccc2cnccc2c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.8 %

Procedure:
0.61 mL (1.02 g, 7.6 mmol) of sulfuryl chloride were added to a solution of 1.0 g (6.9 mmol) of compound 7 in 30 mL of dichloromethane. Three drops diethyl ether were added and the reaction was stirred at room temperature for 5 h. The solvents were removed by distillation and the remainder was treated with aqueous NaHCO3 solution. The precipitate was filtered, washed with water and dried to give 1.1 g (89%) of compound 8 as a green-yellow solid.
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][N:15]=[C:14]([CH3:17])[CH:13]=1)=[O:11])[C:4]1[O:8][CH:7]=[CH:6][CH:5]=1)#[N:2].C(N(CC)CC)C.[SH2:25]>O1CCCC1>[C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][N:15]=[C:14]([CH3:17])[CH:13]=1)=[O:11])[C:4]1[O:8][CH:7]=[CH:6][CH:5]=1)(=[S:25])[NH2:2]
Reactant: S
Reactant: Cc1cc(C(=O)NC(C#N)c2ccco2)sn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NC(C(N)=S)c2ccco2)sn1
Temperature: 25 °C

Procedure:
1.0 g of N-(alpha-cyanofurfuryl)-3-methylisothiazole-5-carboxylic acid amide was dissolved in 30 ml of tetrahydrofuran, and 0.6 ml of triethylamine was added. With stirring at room temperature, hydrogen sulfide gas was introduced into the mixture. Five hours later, the reaction solvent was evaporated under reduced pressure. Water was added to the residue. The precipitated crystals were separated by filtration to give 1.1 g of the desired N-[(alpha-thiocarbamoyl)furfuryl]-3-methylisothiazole-5-carboxylic acid amide.
Reaction SMILES: [CH3:1][NH2:2].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2>CN(C=O)C.O=[Mn]=O>[N:2]1[C:5]2=[C:6]3[C:10](=[CH:11][CH:12]=[C:4]2[O:3][CH:1]=1)[NH:9][CH:8]=[CH:7]3
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: CN
Agent: O=[Mn]=O
Solvent: CN(C)C=O
Product: c1cc2c(ccc3ocnc32)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.5 mmol of methylamine and 4.13 mmol of MnO2 are added to a solution of 0.4 mmol of 5-hydroxy-1H-indole in 3 ml of DMF, and the mixture is stirred at room temperature for 18 hours. The suspension is filtered through Celite and subjected to conventional work-up, giving 6H-oxazolo[4,5-e]indole; ESI 159.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](F)[CH:7]=1.[NH2:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH:5]=[N:4][C:3]=1[C:9]#[N:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: N#Cc1ncc(F)cc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Br)c1
Temperature: 110 °C
Reaction time: 14 h

Procedure:
To a flask were added 3-bromo-5-fluoropyridine-2-carbonitrile (14.8 g, 73.5 mmol), tert-butyl [(1S,2R)-2-aminocyclohexyl]carbamate (15 g, 70 mmol) and DIPEA (49 mL, 280 mmol). The resulting mixture was heated at 110° C. After 14 hours, the reaction mixture was cooled to room temperature, diluted with dichloromethane, absorbed on silica gel, and purified via silica gel chromatography to afford tert-butyl {(1S,2R)-2-[(5-bromo-6-cyanopyridin-3-yl)amino]cyclohexyl}carbamate. 1H NMR (600 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.22 (s, 1H), 6.86 (d, J=7.8 Hz, 1H), 6.68 (d, J=7.8 Hz, 1H), 3.78 (s, 1H), 3.62 (s, 1H), 1.64-1.44 (m, 6H), 1.30 (s, 9), 1.14-1.08 (m, 2H).
Reaction SMILES: [Na].[NH3:2].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[C:12]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[C:13]([C:29]#[N:30])[C:14](=[C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:18]=1[Cl:19])[C:15]#[N:16]>C(O)CC>[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[C:12]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[C:13]2[C:14](=[C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:18]=1[Cl:19])[C:15](=[NH:16])[NH:30][C:29]2=[NH:2]
Reactant: N
Reactant: CCCCCCCCOc1c(Cl)c(Sc2ccccc2N)c(OCCCCCCCC)c(C#N)c1C#N
Agent: [Na]
Solvent: CCCO
Product: CCCCCCCCOc1c(Cl)c(Sc2ccccc2N)c(OCCCCCCCC)c2c1C(=N)NC2=N
Reaction time: 20 h
Yield: 44.4 %

Procedure:
To a solution of sodium metal (0.9 g) in n-propyl alcohol (265 mL) was fed gaseous ammonia at a flow rate of 120 mL/min. at room temperature for 1 hour. Then, 35.8 g of 4-(2-aminophenylthio)-5-chloro-3,6-di-n-octyloxyphthalonitrile was added and the mixture was stirred at 50~60° C. for 20 hours. After cooling, the reaction mixture was worked up in the same manner as in Example 1 to provide 16.4 g (yield 44.4%) of 5-(2-aminophenylthio)-6-chloro-1,3-diimino-4,7-di-n-octyloxyisoindoline of the following chemical formula. ##STR10##
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4].[H][H]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([NH2:14])=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1cc2cccc([N+](=O)[O-])c2s1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2cccc(N)c2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.3 %

Procedure:
7-Nitro-benzo[b]thiophene-2-carboxylic acid methyl ester (1 g, 4.22 mmol) was suspended in EtOAc (40 mL) and a suspension of 10% Pd/C (400 mg) in 20 mL EtOAc was added. Hydrogen gas was introduced into the flask from an H2-filled balloon attached to a needle inserted through a septum. The black suspension was stirred 12 h at room temperature. After stirring 12 h, the black suspension was filtered through diatomaceous earth and the filter cake was washed several times with EtOAc. The combined filtrates were dried (MgSO4), filtered and the solvent was removed to afford 7-amino-benzo[b]thiophene-2-carboxylic acid methyl ester as a yellow solid (860 mg, 100%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:48])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43]Br)[C:24]=1[CH2:45][CH2:46][CH3:47])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:17][C:18](=[O:48])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:24]=1[CH2:45][CH2:46][CH3:47])[CH3:16]
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOCCOCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCOCCOCCOCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Reaction time: 25 h
Yield: 71.2 %

Procedure:
A mixture of 0.9500 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.677 g of 4-[4-acetyl-3-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester and 1.0 g of anhydrous potassium carbonate in 40 ml of anhydrous acetone was stirred at reflux for 17 hours. An additional 1.0 g of potassium carbonate was added and reflux was continued for 25 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was chromatographed on 200 g of silica gel. Elution with 30% ethyl acetate-toluene gave 2.3 g (71% yield) of 4-[4-acetyl-3-[2-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH2:15][OH:16])[C:5]([CH2:7][CH2:8][C:9](O)=[O:10])=O.O.[NH2:18][NH2:19]>>[OH:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:7][CH2:8][C:9](=[O:10])[NH:18][N:19]=2)[CH:12]=[CH:13][C:14]=1[CH2:15][OH:16]
Reactant: O=C(O)CCC(=O)c1ccc(CO)c(O)c1
Reactant: NN
Solvent: O
Product: O=C1CCC(c2ccc(CO)c(O)c2)=NN1

Procedure:
3-(3-Hydroxy-4-hydroxymethylbenzoyl)propionic acid was cyclised with hydrazine hydrate in a similar manner to that described in Example 3(i) to give 6-(3-hydroxy-4-hydroxymethylphenyl)-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])[CH:11]=[CH:12][C:13]=1[O:14]C.C(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-]>>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[O:18])[CH:11]=[CH:12][C:13]=1[OH:14]
Reactant: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Br)cnn1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O

Procedure:
To Compound 1 (see Example 1.16) in CH2Cl2 (1.170 g, 2.68 mmol) was added anhydrous AlCl3 (1.432 g, 10.74 mmol, 4.0 equiv.) slowly at 0° C., it was stirred under reflux overnight and then quenched with saturated NaHCO3. The mixture was extracted with EtOAc, the combined organic phase was washed with water and brine, dried over MgSO4, filtered and evaporated. It was first purified with SiO2 column chromatography (Eluent: EtOAc/Hexane=1/3 to 1/1) and the major fractions containing Compound 58 were then purified by HPLC. The pure fractions were neutralized with saturated NaHCO3, extracted with EtOAc and dried with anhydrous MgSO4. MgSO4 was filtered and the solvent was removed under vacuum to provide Compound 58 as a white solid. LCMS m/z (%)=421 (M+H79Br35Cl, 69), 423 (M+H81Br35Cl, 100), 425 (M+H81Br37Cl, 21). 1H NMR (400 MHz, acetone-d6) δ: 8.47 (s, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 7.44 (d, J=8.9 Hz, 2H), 7.38-7.43 (m, 1H), 7.35 (s, 1H), 7.26 (d, J=2.6 Hz, 1H), 7.15 (d, J=8.9 Hz, 2H), 6.87 (d, J=8.8 Hz, 1H), 3.62 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C@@H:12]([C:13]#[CH:14])[CH2:11][CH2:10][C@H:6]1[C:7]([NH2:9])=O)=[O:4].N1C=CN=C1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:5]1[C@@H:12]([C:13]#[CH:14])[CH2:11][CH2:10][C@H:6]1[C:7]#[N:9])=[O:4]
Reactant: C#C[C@H]1CC[C@@H](C(N)=O)N1C(=O)CCl
Agent: c1c[nH]cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reaction time: 1 h

Procedure:
To a stirred solution of (5R)-1-(chloroacetyl)-5-ethynyl-L-prolinamide (0.16 g, 0.745 mmol) and imidazole (0.05 g, 0.745 mmol) in dry pyridine (4 mL ) at −35° C. under nitrogen was added POCl3 (0.15 mL, 1.49 mmol) dropwise. The reaction mixture was stirred between −35° C. to −15° C. for 1 hour and evaporated. The residue was diluted with dichloromethane and washed with H2O (2×), dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash chromatography (10% ethyl acetate/hexane) provided the titled compound. MS (CI) m/z 197 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10]Br)=[CH:4][CH:3]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1
Reactant: c1cn[nH]c1
Reactant: BrCCOc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Brc1ccc(OCCn2cccn2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 104.9 %

Procedure:
The mixture of 1-bromo-4-(2-bromoethoxy)benzene (1.00 g, 3.57 mmol), pyrazole (0.360 g, 5.36 mmol) and cesium carbonate (1.75 g, 5.36 mmol) in acetonitrile (10 mL) was heated at 80° C. and stirred for 2 hours. The reaction mixture was filtered. The filtrate was concentrated in vacuo to give a white solid, which was purified by silica gel chromatography to give the title compound (1.0 g, 100%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.56 (d, 1H) 7.54 (d, 1H) 7.35 (d, 2H), 6.74 (d, 2H), 6.26 (m, 1H), 4.53 (t, 2H), 4.30 (t, 2H).
Reaction SMILES: [CH:1]1([C:7]#[N:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([OH:11])[CH3:10].[ClH:12]>O1CCOCC1>[ClH:12].[CH2:9]([O:11][C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[NH:8])[CH3:10]
Reactant: N#CC1CCCCC1
Reactant: CCO
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=N)C1CCCCC1
Yield: 80 %

Procedure:
Combine cyclohexanecarbonitrile (1.0 g, 9.20 mmol), ethanol (0.4 g, 9.20 mmol) and 4N hydrogen chloride in dioxane (8 mL) and stir the reaction mixture for 17 h at ambient temperature. Evaporate the solvent and triturate the residue with diethyl ether to obtain the desired intermediate as a white solid (1.4 g, 80%).