Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=1)[S:11]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12].[OH-].[Na+]>CO>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:10]([S:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:31])=[O:2])=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCc1ccc(CN(CCCCCCC(=O)OC)S(=O)(=O)c2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1ccc(CN(CCCCCCC(=O)O)S(=O)(=O)c2cccnc2)cc1

Procedure:
A solution of 7-((4-butyl-benzyl)-(pyridine-3-sulfonyl)-amino)-heptanoic acid methyl ester prepared of Example 1, Step B (0.040 g, 0.158 mmol), in 2 mL MeOH and 0.5 mL 2N NaOH was stirred at room temperature overnight. The mixture was quenched with 2N HCl and was diluted with CH2Cl2 The organic layer was washed with 1N HCl and water, dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (2% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2) to afford the title compound (42 mg). 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.77 (d, 1H), 8.08 (d, 1H), 7.48 (dd, 1H), 7.09 (m, 4H), 4.32 (s, 2H), 3.12 (s, 2H), 2.55 (t, 2H), 2.25 (t, 2H), 1.12-1.58 (m, 12H), 0.88 (t, 3H); MS 431 (M−1).
Reaction SMILES: [C:1]1([CH2:7][C:8](OC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH2:22][C:23]1[C:28]([CH:29]=O)=[CH:27][N:26]=[C:25]([S:31][CH2:32][CH3:33])[N:24]=1.P(Cl)(Cl)([Cl:36])=O>C1COCC1.CC#N>[Cl:36][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:29][C:28]2[CH:27]=[N:26][C:25]([S:31][CH2:32][CH3:33])=[N:24][C:23]=2[N:22]=1
Reactant: COC(=O)Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCSc1ncc(C=O)c(N)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CCSc1ncc2cc(-c3ccccc3)c(Cl)nc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl phenylacetate (15.5 mL, 110 mmol) in THF (300 mL) at −78° C. was added LHMDS (1 M, 120 mL, 2.3 mmol) and stirred for 1 hr. 4-amino-2-(ethylthio)pyrimidine-5-carbaldehyde (6-2) (9.6 g, 52 mmol) was added. The mixture was warmed to room temperature and stirred for 12 hr. The reaction was quenched with saturated NH4Cl solution and extracted with CH2Cl2. The combined organic layer was dried, filtered and concentrated. The resulting solid was triturated with Et2O and the white purified solid was filtered. A portion of the solid (2.5 g, 8.8 mmol) was dissolved in CH3CN and phosphorus oxychloride (8.0 mL, 88 mmol) was added. The mixture was heated to reflux for 12 hr. After 12 hr, the solvent and POCl3 were distilled off using a dean stark apparatus until 15 mL remained in the flask. Upon cooling, a white solid formed and was filtered. The solid washed with Et2O and dried under vacuum to afford the salt of (6-3). The mother liquor was basified by slowly adding Et3N dropwise until pH=7, diluted with water, and extracted with CH2Cl2. The combined organic layer was dried, filtered and concentrated. The residue was purified by trituration with Et2O and filtered to yield pure (6-3) as a free base. LRMS m/z (M+H) Calcd: 302.0, found: 302.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][C:7](O)=[O:8].B>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[O:5][CH2:6][CH2:7][OH:8]
Reactant: O=C(O)COc1ccc(Cl)c(Cl)c1
Agent: B
Solvent: C1CCOC1
Product: OCCOc1ccc(Cl)c(Cl)c1
Yield: 91 %

Procedure:
The title compound was prepared by reduction of 2-(3,4-dichlorophenoxy)acetic acid (Aldrich, 96% pure) with borane in tetrahydrofuran (Aldrich, 1M solution) using the procedure of N. M. Yoon, et al. in J. Org. Chem 38(#16) p. 2786 (1973). The yield was 91% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH2:44]([N:48]([CH2:52][CH2:53][CH2:54][CH3:55])[CH2:49][CH2:50][NH2:51])[CH2:45][CH2:46][CH3:47]>C(Cl)(Cl)Cl.O>[CH2:44]([N:48]([CH2:52][CH2:53][CH2:54][CH3:55])[CH2:49][CH2:50][NH:51][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][C:18]=1[O:23][CH3:24])=[O:42])[CH2:45][CH2:46][CH3:47]
Reactant: CCCCN(CCN)CCCC
Reactant: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCN(CCCC)CCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methoxyaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (139 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-dibutyl-1,2-ethanediamine (81 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (79 mg, yield 49%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:19][O:20][CH2:21]Cl.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:18])([CH3:17])[CH2:15][O:16][CH2:19][O:20][CH3:21])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CO)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: COCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COCOCC(C)(C)c1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
2-(4′-Bromobiphenyl-4-yl)-2-methylpropan-1-ol (5.0 g, 16 mmol) was dissolved in toluene (40 mL), and chloromethyl methyl ether (2.5 mL, 33 mmol) and N,N-diisopropylethylamine (3.6 mL, 21 mmol) were added, followed by stirring at room temperature for 17 hours. After the reaction solution was diluted with ethyl acetate, the organic layer was washed with water. After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.45 (hexane/ethyl acetate=10/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (5.8 g, 16 mmol) as a white solid (yield 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:32]2[CH:33]=[N:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=2)[CH:3]=1)=[O:15]
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C(F)(F)F)nc3)cc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (110 mg, 0.264 mmol) and [6-(trifluoromethyl)-3-pyridinyl]boronic acid (75 mg, 0.395 mmol). The product was collected as a solid (75 mg, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 9.30 (d, J=2.02 Hz, 1H) 8.66 (t, J=4.93 Hz, 1H) 8.58 (dd, J=8.08, 2.02 Hz, 1H) 8.45 (s, 1H) 8.38 (s, 1H) 8.07 (d, J=8.34 Hz, 1H) 7.98-8.01 (m, 1H) 5.90 (s, 1H) 5.20 (dt, J=13.14, 6.57 Hz, 1H) 4.41 (br. s., 1H) 4.40 (br. s., 1H) 2.22 (s, 3H) 2.13 (s, 3H) 1.53 (s, 3H) 1.51 (s, 3H). LC-MS (ES) m/z=484.1 [M+H]+
Reaction SMILES: [C:1]1([C:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[C:19]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[CH:18][N:17]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[N:16]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:49])C=1>C(COC)OC>[C:35]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[C:19]([C:20]4[CH:25]=[CH:24][N+:23]([O-:49])=[CH:22][CH:21]=4)=[CH:18][N:17]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[N:16]=3)[CH:10]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COc1ccc(Cn2cc(-c3ccncc3)c(-c3cccc(N=C(c4ccccc4)c4ccccc4)c3)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: COCCOC
Product: COc1ccc(Cn2cc(-c3cc[n+]([O-])cc3)c(-c3cccc(N=C(c4ccccc4)c4ccccc4)c3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
100 mg (0.19 mmol) of N-(diphenylmethylidene)-3-[1-(4-methoxybenzyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]aniline were reacted with 36 mg (0.21 mmol) of m-chloroperbenzoic acid in 4 ml of dimethoxyethane. The solution was stirred at room temperature overnight. The reaction mixture was partitioned between dichloromethane and aqueous NaHCO3, the organic layer dried over Na2SO4 and the solvent removed under reduced pressure. The residue was triturated with diethylether and collected by filtration giving 80 mg (78%) of the title compound.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.C(C1C=C2C(=CC=1)NC(=O)/C/2=C\C1NC=CC=1)#C.IC1C=CC=CC=1.C(N(CC)CC)C>[Cu]I.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.CN(C=O)C>[C:5]1([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Solvent: CCN(CC)CC
Solvent: Ic1ccccc1
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(C#Cc3ccccc3)cc2/C1=C/c1ccc[nH]1

Procedure:
This compound was prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one in Example 83 above. In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (90 mg, 0.38 mmol) (from Example 82) was coupled with iodobenzene (219 mg, 1.07 mmol) (Aldrich) using CuI (8 mg, 0.042 mmol) (Aldrich) and (Ph3P)2PdCl2 (14 mg, 0.020 mmol) (Aldrich) as catalyst in 1 mL DMF and 2 mL triethylamine at 70° C. for 15 hours to give (Z)-1,3-dihydro-5-phenylethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a yellow powder. (Yield 92 mg, 78%)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:4]=1[C:10]1[C:14]([C:15](Cl)=[O:16])=[C:13]([CH3:18])[O:12][N:11]=1.C([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])C.[C:26](O)(=O)[CH3:27]>>[C:24]1([NH:21][CH2:22][CH2:23][C@@H:27]2[CH2:26][CH2:3][CH2:4][C@H:10]([NH:11][C:15]([C:14]3[C:10]([C:4]4[C:5]([F:9])=[CH:6][CH:7]=[CH:8][C:3]=4[Cl:2])=[N:11][O:12][C:13]=3[CH3:18])=[O:16])[CH2:14]2)[CH:25]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: CCN(CC)CC
Reactant: CC(=O)O
Agent: Cl
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)N[C@H]1CCC[C@@H](CCNc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A compound from preparation 91 (53 mg; 0.166 mmol) was dissolved in excess, neat acetic acid saturated with HCl(g) (2 mL). After 30 min of stirring at room temperature, in air, the solution was concentrated to dryness by rotary evaporation. Acetic acid was removed from the resultant solid by consecutive dissolution in, and drying from, acetonitrile (thrice) and then diethyl ether (twice). The resulting white powder was dissolved in anhydrous dichloromethane (8 mL) under a nitrogen atmosphere. First was added 3-(2-chloro-6-fluoro-phenyl)-5-methylisoxazole-4-carbonyl chloride (50.2 mg; 0.183 mmol; 1.1 equiv), and then 4-N,N-dimethylaminopyridine (2 mg; 0.017 mmol; 0.1 equiv) and finally triethylamine (94 μL; 0.667 mmol; 4 equiv). The reaction solution was stirred overnight, then quenched with saturated NaHCO3(aq), then extracted with dichloromethane (twice). The organic layer was washed with saturated NaCl(aq) (once), dried with Na2SO4(s), filtered, and concentrated to dryness by rotary evaporation. The resulting product was dissolved in dichloromethane and purified by radial chromatography on a 2 mm thick silica gel rotor. A dichloromethane mobile phase was followed by a 5% tetrahydrofuran/dichloromethane (v/v) mobile phase. An off-white solid (66 mg; 87%) was obtained. TOF-MS(ES) calc'd: [M+H]+=456.1854 m/z.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][OH:7])=[CH:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Cl)[N:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[N:12]=1
Reactant: OCc1ccsc1
Reactant: Clc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cccc(OCc2ccsc2)n1

Procedure:
To a solution containing 3-thiophenemethanol (1.17 g, 0.010×1.0 mol) and sodium hydride (0.39 g, (ca.60% in mineral oil), 0.010×1.0 mol) in tetrahydrofuran, 2,6-dichloropyridine (1.5 g, 0.010 mol) was added and the resultant solution was refluxed for about 2 hours.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8]O)[CH:2]([CH3:4])[CH3:3].[ClH:14]>>[ClH:14].[CH2:1]([NH:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][Cl:14])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNc1ccccc1CO
Agent: Cl
Product: CC(C)CNc1ccccc1CCl
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
In 190 ml of conc. hydrochloric acid was dissolved 19.1 g of 2-(isobutylamino)benzyl alcohol, and the solution was heated in a sealed tube at 100° C. for 40 min. The reaction mixture was stirred for 30 min. under chilling with ice and the precipitated crystals were collected by filtration. The collected crystals were washed successively with hydrochloric acid and acetone and dried to give 16.9 g (yield: 68%) of 2-(isobutylamino)benzyl chloride hydrochloride as a white crystalline product.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CO.[BH4-].[K+]>[OH:13][CH:12]1[C:11]2[C:10](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:18])[N:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccccc1
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C1c2ccccc2C(O)N1Cc1ccccc1
Temperature: 20 °C
Reaction time: 20 h
Yield: 92.4 %

Procedure:
3-Hydroxy-2-benzyl-2,3-dihydroisoindol-1-one is prepared as described in Example 1, starting with 10.2 g of N-benzylphthalimide in 100 cm3 of methanol and 2.6 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours and is then cooled to a temperature in the region of 0° C. and 50 cm3 of distilled water are added dropwise. The methanol is then partially evaporated off under reduced pressure (2 kPa) at a temperature in the region of 40° C., followed by addition of a further 50 cm3 of distilled water. The aqueous phase is extracted 3 times with 50 cm3 of ethyl acetate. The organic extracts are combined, washed with 50 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 9.5 g of 3-hydroxy-2-benzyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a white powder. (Rf=0.20, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:47]([CH3:48])=[CH:46][C:39]([O:40][C:41]([CH3:45])([CH3:44])[C:42]#[N:43])=[CH:38][C:37]=1[CH3:49]>>[C:42]([C:41]([O:40][C:39]1[CH:38]=[C:37]([CH3:49])[C:36]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:47]([CH3:48])[CH:46]=1)([CH3:45])[CH3:44])#[N:43]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(OC(C)(C)C#N)cc(C)c1Br
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OC(C)(C)C#N)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 2-(4-bromo-3,5-dimethylphenoxy)-2-methylpropanenitrile following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.25 min; Mass spectrum (ESI+): m/z=530 [M+H]+.
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:21])[CH2:15][CH2:16][O:17][CH2:18][CH2:19]O>>[C:1]([O:12][CH2:19][CH2:18][O:17][CH2:16][CH2:15][N:14]([CH3:21])[CH3:13])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CN(C)CCOCCO
Product: CCCCCCC/C=C/C(=O)OCCOCCN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 2-(2-(dimethylamino)ethoxy)ethanol as starting materials to give the aimed compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]3=[CH:15][S:16][CH:17]=[C:13]3[CH:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([O:24]COC)=[CH:20][CH:19]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].Cl.[OH-].[Na+]>C(O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:14]3=[CH:15][S:16][CH:17]=[C:13]3[CH:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(OCOC)cc3)cc3cscc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN1CCN(c2nc(-c3ccc(O)cc3)cc3cscc23)CC1
Yield: 11.4 %

Procedure:
4-(4-Ethylpiperazin-1-yl)-6-[4-(methoxymethoxy)phenyl]thieno[3,4-c]-pyridine (695 mg) was dissolved in ethanol (10 ml), followed by the addition of a 5N aqueous solution of hydrochloric acid (1 ml), and the mixture was reacted for 1 hr with heating under reflux. The reaction solution was neutralized with a 1N aqueous solution of sodium hydroxide and then extracted with ethyl acetate. The organic layer was washed with brine, dried and evaporated, and then purified by silica gel column chromatography (dichloromethane/methanol system), to give 4-(4-ethylpiperazin-1-yl)-6-(4-hydroxyphenyl)thieno[3,4-c]pyridine as a yellow oil (70 mg, yield; 11%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH3:17])=[CH:4][CH:3]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:18][S:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH3:17])=[CH:6][CH:7]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(N)cc2)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(C)c(-c2ccc(NS(C)(=O)=O)cc2)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-[5-(4-Amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide (0.05 g, 0.20 mmol) is dissolved in dimethylformamide (1 ml) and treated by a solution of methylsulfonyl chloride (0.0232 g, 0.20 mmol) in dry dimethylformamide (1 ml) followed by 2M aqueous sodium carbonate solution (0.20 ml, 0.40 mmol). The reaction mixture is stirred at room temperature for 18 hours. The solvent is removed in vacuo and the residue is purified by chromatography to give the title compound. MH+ (ESMS): 326.1
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14].CC(O)=O>N1C=CC=CC=1.CCCCCC>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]3)(=[O:24])=[O:23])=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cccc2ccc(O)cc12
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2cccc3ccc(O)cc23)cc1
Temperature: 0 °C
Yield: 46.5 %

Procedure:
A mixture of 8-amino-2-hydroxynapthalene (50 g, 0.3 mole) and 4-nitrobenzenesulfonyl chloride (55 g, 0.25 mole) in pyridine (500 ml) was heated under reflux for 2.5 hours then allowed to stand O/N. The mixture was poured in ice water and acidified with HOAc. The precipitated product was boiled in hexane and then recrystallized from ethyl acetate-hexane to give 40 g of green product (47%). This material was used in Part B.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:28])[C:10](=[O:27])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][C:23](O)=[O:24])[C:16](=[O:26])[C:12]3=2)[C:7]1=[O:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:52]([CH3:54])[CH3:53])C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CNC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:28])[C:10](=[O:27])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][C:23]([N:52]([CH3:54])[CH3:53])=[O:24])[C:16](=[O:26])[C:12]3=2)[C:7]1=[O:29]
Reactant: O=C(O)CN1CCCCn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CN1CCCCn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O

Procedure:
A solution of [11-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8,10-trioxo-1,3,4,5,6,8,10,11,12,13-deca-hydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridin-2-yl]acetic acid (25 mg, 0.05 mmol), BOP (28 mg, 0.06 mmol), diisopropylethylamine (7 mg, 0.07 mmol) and dimethylamine (0.11 mL, 2M in THF) in DMF (0.5 mL) was stirred at room temperature overnight. The product mixture was concentrated under vacuum. The residue was subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and lyophilization of appropriate fractions afforded the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]>C(O)C.[Pd]>[NH2:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([F:1])=[C:3]([C:12](=[O:14])[CH3:13])[CH:4]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(C)cc1F
Agent: [Pd]
Solvent: CCO
Product: CC(=O)c1cc(N)c(C)cc1F
Yield: 60.5 %

Procedure:
1-(2-Fluoro-4-methyl-5-nitro-phenyl)-ethanone (3.17 g) in ethanol (10 ml) was hydrogenated over Pd/C (200 mg) under balloon pressure over night. The mixture was filtered and the filtrate was concentrated under reduced pressure to a grey solid that was recrystallized (EtOAc Hexane) to give 1.625 g of 1-(5-amino-2-fluoro-4-methyl-phenyl)-ethanone as an off-white powder.