Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[S:3].Cl[CH2:10][C:11]#[C:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].CN(C=O)C.N12CCCCC1C=NCCC2>CCOC(C)=O.O>[NH2:6][C:5]1[CH:7]=[CH:8][N:1]=[C:2]([S:3][CH2:10][C:11]#[C:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[N:4]=1
Reactant: O=C1c2ccccc2C(=O)N1CC#CCCl
Reactant: Nc1cc[nH]c(=S)n1
Agent: C1=NCCCN2CCCCC12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccnc(SCC#CCN2C(=O)c3ccccc3C2=O)n1
Reaction time: 2 h
Yield: 94.1 %

Procedure:
A mixture of thiocytosine (0.5 g.), N-(4-chlorobut-2-ynyl)phthalimide (1.03 g.), DMF (5 ml.) and 1,5-diazabicyclo[5,4,0]undec-5-ene (0.67 g.) was stirred for 2 hours. The solution was treated with water (20 ml.) and EtOAc (10 ml.) and the insoluble solid collected to give 4-amino-2-(4-phthalimidobut-2-ynylthio)pyrimidine (1.2 g.) m.p. 197°-202° (decomp.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].ClCCl.O1CCOCC1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:17]1([S:23]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1CNCCN1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=C1CN(S(=O)(=O)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-piperazinone was suspended in a mixed solvent of dichloromethane and dioxane and then pyridine and benzenesulfonyl chloride were added thereto. After stirring at room temperature for 16 hours, the solvent was removed by evaporation and the resulting solid was suspended in 1N hydrochloric acid, filtered, and washed with diisopropyl ether to obtain 4-(phenylsulfonyl)-2-piperazinone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([I:21])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[C:22](=[O:25])(O)[O-:23].[Na+]>O1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH:20][C:22](=[O:25])[O:23][C:4]([CH3:15])([CH3:5])[CH3:3])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([I:21])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: NC1=N[C@@]2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-3-Bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (2.31 g, 4.87 mmol, prepared as described in Method BB26) was dissolved in dioxane (24.36 mL). 25 mL of saturated sodium bicarbonate solution was added, followed by boc-anhydride (11.31 mL, 48.7 mmol). The reaction was stirred overnight at RT. The reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography on silica gel (0-25% EtOAc:Hex) to afford (S)-tert-butyl 3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate (2.614 g, 4.55 mmol) as a yellow solid. MS m/z=597.9 [M+H]+. Calculated for C19H17BrIN3O3S: 574.23.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][S:27]([C:30]1[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][N:31]=1)(=[O:29])=[O:28].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:36][C:34]3[CH:33]=[CH:32][N:31]=[C:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH:35]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CS(=O)(=O)c1cc(N)ccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccnc(S(C)(=O)=O)c3)nc12
Temperature: 150 °C
Yield: 87.2 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (120 mg, 281 μmol), 2-(methylsulfonyl)pyridin-4-amine (55 mg, 319 μmol), xantphos (48.7 mg, 84.2 μmol), Pd2(dba)3 (25.7 mg, 28.1 μmol) and cesium carbonate (183 mg, 562 μmol) in dioxane (2 mL) was heated in a microwave at 150° C. for 20 min. The mixture was cooled then filtered through a pad of celite. The filtrate was concentrated in vacuo then purified by chromatography (silica, 35-70% ethyl acetate in hexanes) to give N-tert-butyl-2-(2-(methylsulfonyl)pyridin-4-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (127 mg, 245 μmol, 87%) as a light yellow gum. (EI/CI) m/z: 519.1 [M+H].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:19][C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[C:21]=1[C:30]([OH:32])=[O:31])(=[O:18])=[O:17].C(O)(=O)C.[C:37]1(=O)[CH2:41][CH2:40][CH2:39][CH2:38]1.C([BH3-])#N>CN(C=O)C>[CH:37]1([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([NH:19][C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]=2[C:30]([OH:32])=[O:31])(=[O:18])=[O:17])[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2NCC[C@@H]2CCCCN2)ccc2c1CCCC2
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2NCCC2CCCCN2C2CCCC2)ccc2c1CCCC2
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
A solution of Example 401A (0.022 g, 0.044 mmol) in DMF (1.0 mL) was treated with acetic acid (0.05 mL) and cyclopentanone (0.005 mL, 0.06 mmol). The mixture was shaken at 50° C. for 20 minutes, treated with macroporous polystyrene bound cyanoborohydride resin (47 mg, 0.13 mmol), shaken at 70° C. for 15 hours, concentrated, and purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. MS (DCI) m/e 526 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 13.21 (br s, 1H), 7.54 (d, 1H), 7.40 (t, 1H), 6.93 (br s, 1H), 6.84 (d, 1H), 6.65 (t, 2H), 6.03 (br s, 1H), 4.02 (br s, 1H), 3.63 (br s, 1H), 3.35 (br s, 3H), 2.99 (br s, 1H), 2.70 (br s, 2H), 2.63 (br s, 2H), 2.00 (br s, 4H), 1.83 (br s, 3H), 1.65-1.54 (m, 13H).
Reaction SMILES: C[Si](C)(C)[O-:3].[K+].[F:7][C:8]1[C:16](F)=[C:15]([CH3:18])[CH:14]=[C:13]([N+:19]([O-:21])=[O:20])[C:9]=1[C:10]([OH:12])=[O:11]>CC1OCCC1>[F:7][C:8]1[C:16]([OH:3])=[C:15]([CH3:18])[CH:14]=[C:13]([N+:19]([O-:21])=[O:20])[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: C[Si](C)(C)[O-]
Reactant: Cc1cc([N+](=O)[O-])c(C(=O)O)c(F)c1F
Agent: C[Si](C)(C)O[K]
Agent: [K+]
Solvent: CC1CCCO1
Product: Cc1cc([N+](=O)[O-])c(C(=O)O)c(F)c1O
Temperature: 22.5 °C
Yield: 89.9 %

Procedure:
To a 500 mL glass reactor equipped with mechanical stirrer, addition funnel, thermocouple, reflux condenser and nitrogen inlet is charged potassium trimethylsilanolate (TMSOK, 61.2 g, 0.48 mol, 3.2 eq) and 2-methyl tetrahydrofuran (240 mL) to form a suspension. The suspension is stirred at 20-25° C. 2,3-difluoro-4-methyl-6-nitrobenzoic acid (32.5 g, 0.15 mol, 1 eq) is dissolved in 2-MeTHF (75 mL). To the TMSOK suspension, the solution of 2,3-difluoro-4-methyl-6-nitrobenzoic acid is added. The addition is exothermic and the temperature of the reaction mixture rises to 40-50° C. during addition. After charging is complete, the jacket temperature is set at 65-70° C. The suspension is stirred for 2-3 hour, until HPLC sample shows complete conversion. The mixture is cooled down to room temp. The reaction is quenched with water (100 mL), and acidified to pH 1 with HCl aqueous solution (6M, 90 mL). The layers are separated. The upper organic layer is washed with water (150 mL), and distilled under vacuum to minimum volume. The dark brown residue is stirred in 200 mL of mixed solvent of toluene/methylcyclohexane (v/v, 2:1) to give a suspension. The slurry is filtered. The solid is dried under vacuum to provide the desired product, 2-fluoro-3-hydroxy-4-methyl-6-nitrobenzoic acid (29 g, 90% yield).
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][C:18]=1[F:30])=O)(C)(C)C.C([O-])(O)=O.[Na+]>ClCCl>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH2:15])=[C:18]([F:30])[CH:19]=1)=[O:29]
Reactant: CC(C)(C)CC(=O)c1ccc(CNC(=O)OC(C)(C)C)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)CC(=O)c1ccc(CN)c(F)c1
Reaction time: 6.5 h
Yield: 101.7 %

Procedure:
Add 4N hydrogen chloride in dioxane (5.5 mL, 22 mmol) to a solution of N-(tert-butoxycarbonyl)-4-(3,3-dimethyl-butyryl)-2-fluoro-benzylamine (600 mg, 1.85 mmol) in dichloromethane (22 mL) and stir for 6.5 h. Concentrate in vacuo and wash the solid obtained with diethyl ether. Suspend the solid into saturated aqueous NaHCO3 and stir for 30 min. Extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the title compound as an oil (420 mg, 99%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28]Br>CC(C)=O>[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:18]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: O=C(Nc1ccc(F)cc1F)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(F)cc1F)c1ccccc1OCc1ccc(F)cc1F
Temperature: 25 °C

Procedure:
To a solution of compound 3a (0.50 g, 2 mmole) in anhydrous acetone (10 mL) were added potassium carbonate (0.69 g, 5 mmole) and 2,4-difluorobenzyl bromide (0.56 mL, 4.4 mmole) and refluxed 8 hr. After cooled to room temperature, the reaction mixture was filtered through Celite and concentrated. The residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, then concentrated and recrystallized with hot methanol.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]CC)=[O:26])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[K+].C(O)C.O.Cl>O>[CH2:1]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)OCC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)O)cc1

Procedure:
A mixture of 6.0 g. of ethyl (4-hexadecylaminophenyl)acetate, 7.0 g. of potassium hydroxide and 100 ml. of ethanol-water (9:1) is heated to reflux for 4 hours. While hot, the mixture is adjusted to pH 7 with conc. hydrochloric acid. The mixture is diluted with water cooled and filtered. Recrystallization of the precipitate yields (4-hexadecylaminophenyl)acetic acid.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:30])[C:5]2[S:10][C:9](=[S:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26]C(=O)C)[C@@H:18]([O:19]C(=O)C)[C@H:13]3[O:14]C(=O)C)[C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].CC(O)=O>CO>[NH2:1][C:2]1[NH:3][C:4](=[O:30])[C:5]2[S:10][C:9](=[S:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][OH:26])[C@@H:18]([OH:19])[C@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=S)sc3c(=O)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1nc2c(sc(=S)n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.3 %

Procedure:
Nucleoside triester 32 (100 mg, 0.21 mmol) and K2CO3 (42.7 mg, 0.31 mmol) were dissolved in MeOH (5 mL) and stirred for 16 h at ambient temperature. To this mixture was added HOAc (37 mg, 0.62 mmol) and the solvent was removed via rotary evaporation. The residue were then submitted to HPLC purification (MeCN—H2O) yielding 47 mg (66%) of a solid: 1H NMR (400 MHz, d6-DMSO) δ 11.66 (s, 1H), 6.91 (br s, 2H), 6.47 (s, 1H), 5.31 (d, J=5.2, 1H), 4.94 (s, 1H), 4.78 (s, 2H), 4.27 (d, J=8.0, 1H), 3.78 (m, 1H), 3.69 (m, 1H), 3.52 (m, 1H); [M+H]+ m/z 333. Analysis calc'd for C10H12N4O5S2.0.5TFA•0.75H2O.0.25MeCN: C, 33.43; H, 3.60; N, 14.41. Found: C, 33.11; H, 3.73; N, 14.80.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([C:14](Cl)=[O:15])=[CH:7][C:6]=1[O:17][CH2:18][CH3:19])[CH3:2].[S].N1C2C(=CC=CC=2)C=CC=1.[H][H]>[Pd]>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([CH:14]=[O:15])=[CH:7][C:6]=1[O:17][CH2:18][CH3:19])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(OCC)cc(C(=O)Cl)cc1OCC
Agent: [Pd]
Agent: [S]
Solvent: c1ccc2ncccc2c1
Product: CCOC(=O)c1c(OCC)cc(C=O)cc1OCC

Procedure:
A mixture of 12 g. of 4-(chloroformyl)-2,6-diethoxy-benzoic ethyl ester, 1.4 g. of palladium/barium sulfate catalyst (5%) and 0.2 ml. of quinoline sulfur regulator are heated under an atmosphere of nitrogen at 120° with stirring. Thereafter, hydrogen is passed through the reaction mixture at 120° until 90% of the theoretical amount of acid salt is freed. The reduction is stopped, and the suspension under an atmosphere of nitrogen is cooled to 25°. The catalyst is removed by filtration and the filtrate is evaporated to dryness under vacuum, whereby there is obtained 2,6-diethoxy-4-formylbenzoic acid ethyl ester as a colorless oil. A sample after recrystallization from low boiling petroleum ether yields pure 2,6-diethoxy-4-formylbenzoic acid ethyl ester having a m.p. of 45°-46°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:27]([CH:24]4[CH2:26][CH2:25]4)(=[O:29])=[O:28])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2cc(CN3CCNCC3)sc2n1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C1CC1)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C

Procedure:
To 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[2,3-d]pyrimidine (187 mg) in anhydrous DCM (5 ml) and triethylamine (111 ul) was added cyclopropanesulfonyl chloride (65 ul) at 0° C. The reaction mixture was allowed to warm up to room temperature over 4 hours. Aqueous work-up and purification on silica gave 2-chloro-4-morpholin-4-yl-6-[4-(cyclopropane-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[2,3-d]pyrimidine (159 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4](O)=[O:5].B.C1COCC1>O1CCCC1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[CH2:4][OH:5]
Reactant: Cc1cccc([N+](=O)[O-])c1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: Cc1cccc([N+](=O)[O-])c1CO
Yield: 107.3 %

Procedure:
A 100 mL round bottomed flask under dry argon was charged with 5 g of 2-methyl-6-nitrobenzoic acid which was dissolved in 60 mL of dry tetrahydrofuran. To this solution was added slowly with cooling and stirring, 64.17 mL of a 1M solution of BH3.THF in THF. The mixture was refluxed for 17 h then the reaction was slowly and carefully quenched with an excess of 10% aqueous hydrochloric acid. The THF was removed under vacuum and the residue was extracted with three 50 mL aliquots of methylene chloride. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and the solvent removed. The crude product was recrystallized from methylene chloride/pentane to give 4.95 g of yellowish crystals (97% yield).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][C:6]2=[O:11])[CH2:4][CH2:3][CH2:2]1.[C:12]1(=O)CCCC[CH2:13]1.BrCCCCBr.[NH4+].[Cl-].Cl>C1COCC1.C1(C)C=CC=CC=1>[C:12]([C:6]1([OH:11])[CH2:7][CH2:8][CH2:9][CH2:10][C:5]21[CH2:1][CH2:2][CH2:3][CH2:4]2)#[CH:13]
Reactant: O=C1CCCCC12CCCC2
Reactant: O=C1CCCCC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: BrCCCCBr
Solvent: C1CCOC1
Product: C#CC1(O)CCCCC12CCCC2
Temperature: 20 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
At 5° C., a solution of lithium acetylide ethylene diamine complex (200 g, 2.17 mol) in THF (1 l) was treated dropwise with a solution of spiro[4.5]decan-6-one (196 g, 1.29 mol, prepared from cyclohexanone and 1,4-dibromobutane in the presence of potassium tert.-butylate in toluene) in THF (0.8 l). The resulting mixture was stirred for 3 h at 20° C., poured into a saturated aqueous solution of NH4Cl, acidified with conc. HCl and extracted three time with MTBE (500 ml). The aqueous phase was extracted twice with MTBE (150 ml) and the combined organic phases were washed twice with water (500 ml), once with a saturated aqueous solution of NaCl, dried (MgSO4), and concentrated. Short-path Vigreux-distillation (0.08 mbar, bath temperature: 140° C., head temp.: 100-105° C.) of the crude product (257 g) gave 6-ethynylspiro[4.5]decan-6-ol (180.8 g, 79%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].[NH:22]1[C:30]2[C:25](=CC=C[CH:29]=2)[C:24]2(COC3C=C4C(=[CH:41][C:31]2=3)CCO4)C1=O.ClCC1C=NC(OC)=NC=1>>[N:22]1[CH:41]=[CH:31][CH:24]=[CH:25][C:30]=1[CH2:29][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: O=C1Nc2ccccc2[C@@]12COc1cc3c(cc12)CCO3
Agent: COc1ncc(CCl)cn1
Product: O=C1N(Cc2ccccn2)c2ccccc2[C@@]12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using (3R)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and (2-bromomethyl)pyridine hydrobromide to replace 5-(chloromethyl)-2-methoxypyrimidine, (3R)-1′-(pyridin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (77%) as a colorless solid: mp 154-156° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ8.53-8.51 (m, 1H), 7.82-7.77 (m, 1H), 7.38-7.13 (m, 4H), 7.05-6.99 (m, 1H), 6.98-6.92 (m, 1H), 6.61 (s, 1H), 6.42 (s, 1H), 5.10 (d, J=16.4 Hz, 1H), 5.00 (d, J=16.4 Hz, 1H), 4.86 (d, J=9.3 Hz, 1H), 4.75 (d, J=9.3 Hz, 1H), 4.49 (t, J=8.7 Hz, 2H), 2.98 (t, J=8.7 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.0, 161.0, 160.4, 155.2, 149.2, 142.4, 137.0, 132.2, 128.5, 123.4, 122.8, 122.6, 121.5, 120.6, 119.7, 119.2, 109.2, 92.3, 79.7, 72.0, 56.8, 44.7, 28.2; MS (ES+) m/z 371.0 (M+1).
Reaction SMILES: Cl.[O:2]=[C:3]1[C:12]2[C:7]3[C:8](=[CH:13][CH:14]=[CH:15][C:6]=3[C:5](=[O:16])[N:4]1[CH2:17][CH2:18][CH2:19]CN1CCC(N(C3C=CC=CC=3)C(=O)CC)CC1)[CH:9]=[CH:10][CH:11]=2.[Br:38][CH2:39][CH2:40]CCCBr.BrCCCCBr>>[Br:38][CH2:39][CH2:40][CH2:19][CH2:18][CH2:17][N:4]1[C:5](=[O:16])[C:6]2[CH:15]=[CH:14][CH:13]=[C:10]3[C:11]=2[C:12](=[CH:7][CH:8]=[CH:9]3)[C:3]1=[O:2]
Reactant: BrCCCCCBr
Reactant: CCC(=O)N(c1ccccc1)C1CCN(CCCCN2C(=O)c3cccc4cccc(c34)C2=O)CC1
Agent: Cl
Solvent: BrCCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr

Procedure:
Following the procedure of part (a) of example 31 but substituting 1,5-dibromopentane for the 1,4-dibromobutane, one obtains 2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 113°-115°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:10]2[NH:11][C:12]([C:14]([O:16]C)=[O:15])=[CH:13][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:10]2[NH:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)C(Cc1cccc(Cl)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)C(Cc1cccc(Cl)c1)CC2

Procedure:
The title compound was synthesized from methyl 6-(3-chlorobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (140 mg, 0.48 mmol) and lithium hydroxide (188 mg, 4.50 mmol, in 1 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 50% EtOAc. 90 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.07-2.20 (m, 1H) 2.52-2.68 (m, 3H) 2.74-2.82 (m, 1H) 2.86-2.93 (m, 1H) 3.33-3.43 (m, 1H) 6.75 (d, J=1.61 Hz, 1H) 7.03-7.09 (m, 1H) 7.20-7.23 (m, 1H) 7.25-7.29 (m, 2H) 8.35 (br. s., 1H). LCMS m/e 276 (M+H). Purity>75% (HPLC).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[CH:24]=[CH:23][C:11]2[N:12]([CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:13](=[O:15])[NH:14][C:10]=2[CH:9]=1.IC.C([O-])(O)=O.[Na+]>CS(C)=O>[Br:7][C:8]1[CH:24]=[CH:23][C:11]2[N:12]([CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:13](=[O:15])[N:14]([CH3:1])[C:10]=2[CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: O=c1[nH]c2cc(Br)ccc2n1CCN1CCCC1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Product: Cn1c(=O)n(CCN2CCCC2)c2ccc(Br)cc21
Reaction time: 0.5 h

Procedure:
73 mg (0.65 mmol) potassium-tert-butoxide are added to a solution of 200 mg (0.65 mmol) 5-bromo-1-(2-pyrrolidin-1-yl-ethyl)-1,3-dihydro-benzimidazol-2-one in 4 mL DMSO at RT. The reaction solution is stirred for 30 min and then 40 μL (0.65 mmol) iodomethane are added and stirred for a further 30 min. The mixture is combined with semisaturated NaHCO3 solution and the aqueous phase is extracted twice with 30 mL EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.O=S(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C=O>[CH2:10]1[CH:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:14]2=[O:16])[C:12](=[O:13])[CH2:11]1
Reactant: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C1c2ccccc2CN2C(=O)CCC12
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a solution prepared from 11.68 g of (+)-N-benzylpyroglutamic acid (See E. Campaigne and D. P. Matthews, J. Het. Chem., 12, 391 (1975)), 100 ml of CH2Cl2 and a drop of dimethylformamide (DMF), 7.57 g of SOCl2 was added dropwise. The mixture was refluxed for five hours and allowed to stand overnight at ambient temperature. The reaction mixture was cooled in an ice-salt bath. Aluminum chloride (22.6 g) was added in portions with exclusion of moisture and vigorous stirring. The temperature did not exceed 10° C. during the addition. The mixture was stirred 1.5 hours and then ice was added gradually. The mixture was partitioned between water and CH2Cl2. The CH2Cl phase was washed with water, dried (Na2SO4), filtered and evaporated to give 10 g of a crude product. Recrystallization from toluene gave 7.45 g of crystals, m.p. 103°-105° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](Cl)=[O:6].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:6]
Reactant: C1CCNC1
Reactant: Cc1ccc(C(=O)Cl)cc1I
Product: Cc1ccc(C(=O)N2CCCC2)cc1I

Procedure:
By the reaction in the same manner as in Example 26-i) using 3-iodo-4-methylbenzoyl chloride (2.00 g) and pyrrolidine (3.5 ml), the title compound (1.62 g) was obtained as a pale-yellow oil.