Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2](=[NH:7])([O:4][CH2:5][CH3:6])[CH3:3].C(N(CC)CC)C.[C:15](Cl)(=[O:17])[CH3:16].CCOCC>C(Cl)Cl>[C:15]([N:7]=[C:2]([O:4][CH2:5][CH3:6])[CH3:3])(=[O:17])[CH3:16]
Reactant: CCOC(C)=N
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(C)=NC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A slurry of 50.0 gm (405 mmol) of ethyl acetimidate hydrochloride in 500 ml of methylene chloride was mechanically stirred and treated dropwise with 81.9 gm (809 mmol) of triethylamine while keeping the temperature at less than 25° C. The resulting slurry was then treated dropwise with 31.8 gm (405 mmol) of acetyl chloride while keeping the temperature at less than 30° C. The white slurry was stirred for one hour at room temperature, after which the methylene chloride was removed in vacuo. The white, oily mass obtained was then stirred with 400 ml of ether and filtered. The white solid obtained was washed with additional ether and the combined filtrate was concentrated in vacuo to afford 48.6 gm (93 percent) of a pale, yellow oil. IR and NMR spectra were consistent with the assigned structure.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]4[C:19](=[O:20])[NH:18][C:17](=[O:21])[C:16]4=[C:11]3[CH:10]=[N:9]2)=CC=1.[CH2:24](O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.FC(F)(F)C(O)=O>[CH2:24]([N:18]1[C:19](=[O:20])[C:15]2[C:16](=[C:11]3[CH:10]=[N:9][NH:8][C:12]3=[N:13][CH:14]=2)[C:17]1=[O:21])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)C(=O)NC4=O)cc1
Reactant: OCCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2cnc3[nH]ncc3c2C(=O)N1CCc1ccccc1
Temperature: 65 °C
Reaction time: 6 h
Yield: 12.8 %

Procedure:
A solution of 3-(4-methoxybenzyl)pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (150 mg, 0.48 mmol), phenethylalcohol (70 μl, 0.58 mmol) and triphenylphosphine (191 mg, 0.73 mmol) in anhydrous tetrahydrofuran (6 ml) was treated with diisopropyl azodicarboxylate (141 μl, 0.73 mmol) at room temperature and stirred for 6 hours. The mixture was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a brown oil. The oil was dissolved in trifluoroacetic acid (7 ml) and heated to 65° C. for 24 hours. The mixture was concentrated under reduced pressure and the product was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate (50 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford a brown solid which was purified by flash column chromatography (12 g SiO2, 30% ethyl acetate in hexanes). Fractions containing the product were concentrated under reduced pressure. The solid was triturated in ethyl acetate, cooled to 0° C. and filtered to afford 7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione as a white solid (18 mg, 13%). M.p.=237-239° C.; 400 MHz 1H NMR (DMSO-d6) δ: 9.00 (s, 1H), 8.51 (s, 1H), 7.23 (m, 6H), 3.85 (t, J=7.2 Hz, 2H), 2.95 (t, J=7.6 Hz, 2H); LCMS: 293 [M+H].
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[OH:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:27])=[C:17]2[C:25]=1[C:24](=[O:26])[CH:23]1[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]1>C(O)(=O)C>[OH:12][C:13]1[C:14]([N+:8]([O-:11])=[O:9])=[CH:15][C:16]([CH3:27])=[C:17]2[C:25]=1[C:24](=[O:26])[CH:23]1[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)c2c1C1CCCCC1C2=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])c(O)c2c1C1CCCCC1C2=O
Temperature: 15 °C
Reaction time: 1 h

Procedure:
A mixture of 15 ml of acetic anhydride and 50 ml of acetic acid was ice-cooled and thereto was added dropwise 10 ml of nitric acid (d=1.38). After stirring for 1 hour, thereto was added dropwise an acetic acid solution containing 10 g of 8-hydroxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone in 100 ml of acetic acid. After stirring for 30 minutes, the ice bath was removed and the solution was warmed to an inner temperature of 15° C. To this solution was added 150 ml of diethyl ether, followed by stirring under ice-cooling. The resulting precipitate was collected by filtration to obtain 8 g of 8-hydroxy-5-methyl-7-nitro-1,2,3,4,4a,9a-hexahydro-9-fluorenone of yellowish green powdery crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:63]1[CH2:68][CH2:67][NH:66][CH2:65][C:64]1=[O:69]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:66]1[CH2:67][CH2:68][NH:63][C:64](=[O:69])[CH2:65]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: O=C1CNCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCNC(=O)C3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and piperazinone in DMSO at ambient temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([N:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]([NH:24][CH3:25])[CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][OH:32]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([C@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]3[CH:17]=[CH:18][C:19]([CH:22]([NH:24][CH2:25][CH2:29][CH2:30][CH2:31][OH:32])[CH3:23])=[CH:20][CH:21]=3)[CH2:14][CH2:15]2)[CH3:9])=[O:7])=[CH:26][CH:27]=1
Reactant: OCCCBr
Reactant: CNC(C)c1ccc([C@H]2CC[C@H](N(C)C(=O)c3ccc(Cl)cc3)CC2)cc1
Product: CC(NCCCCO)c1ccc([C@H]2CC[C@H](N(C)C(=O)c3ccc(Cl)cc3)CC2)cc1

Procedure:
from trans-N-(4-chlorobenzoyl)-N-methyl-4-[4-(1-methylaminoethyl)phenyl]cyclohexylamine and 3-bromo-1-propanol. Melting point: 88°-90° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([N:5]1[CH2:10][CH:9]2[C:7]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]4=[O:27])=[CH:13][CH:12]=3)([CH2:8]2)[CH2:6]1)=[O:4].C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>C1COCC1.O>[CH2:39]([O:38][C:36](=[O:37])[O:1][CH2:2][C:3]([N:5]1[CH2:10][CH:9]2[C:7]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]4=[O:27])=[CH:13][CH:12]=3)([CH2:8]2)[CH2:6]1)=[O:4])[CH3:40]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CC3CN(C(=O)CO)C4)cc2)C(=O)O1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)OCC(=O)N1CC2CC2(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2)C1
Yield: 29.9 %

Procedure:
To a solution of N-(3-{4-[3-(2-hydroxy-acetyl)-3-aza-bicyclo[3.1.0]hex-1-yl]-phenyl}-2-oxo-oxazolidin-5(S)-ylmethyl)-acetamide (Example X) (200 mg, 0.54 mmol) in THF (5 mL) were added triethylamine (0.19 mL, 1.35 mmol) and ethyl chloroformate (0.07 mL, 0.7 mmol) at 0° C. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (2×20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.3:9.7 MeOH:CHCl3) to provide the title compound (72 mg, 30%) as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1.[Br:11]N1C(=O)CCC1=O.[OH-].[Na+]>CN(C)C=O.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([Br:11])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc(N)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Br)cnc(N)c1C#N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A stirred solution of 8.3 grams (0.063 mole) of 2-amino-3-cyano-4-methylpyridine in 125 mL of N,N-dimethylformamide is cooled in an ice bath, and a solution of 11.2 grams (0.063 mole) of N-bromosuccinimide in 125 mL of N,N-dimethylformamide is added dropwise during a 30 minute period, while maintaining the reaction mixture temperature at about 15°-25° C. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about 20 hours. After this time, the reaction mixture is poured into 1 liter of aqueous 3N sodium hydroxide. The mixture is then diluted to a volume of about 1700 mL with distilled water. A solid precipitate is collected by filtration and dried under reduced pressure, yielding 2-amino-5-bromo-3-cyano-4-methylpyridine.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>C1COCC1>[CH2:1]([O:8][C:12]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1cccc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cccc(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Benzyl alcohol (5.51 mL) was added dropwise over 20 min to a stirred suspension of sodium hydride (2.128 g of a 60% dispersion in mineral oil) and 2,3-difluorobenzonitrile (7.4 g) in THF (100 mL) with external ice bath cooling to maintain temperature around 25° C. After addition was complete, the reaction mixture was stirred at room temperature for 24 h, quenched with water (200 mL) and extracted into ethyl acetate (3×120 mL), combined organics were dried (MgSO4) and evaporated. The residual oil was purified (SiO2 chromatography eluting with 20% ether in isohexane) to give the subtitle compound as an oil (9.70 g).
Reaction SMILES: [O:1]1[CH:5]([CH2:6]O)[CH2:4][C:3]2[CH:8]=[CH:9][C:10]3[CH2:11][CH2:12][CH2:13][C:14]=3[C:2]1=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[O:1]1[CH:5]([CH2:6][N:38]2[C:34](=[O:44])[C:35]3[C:36](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:37]2=[O:39])[CH2:4][C:3]2[CH:8]=[CH:9][C:10]3[CH2:11][CH2:12][CH2:13][C:14]=3[C:2]1=2
Reactant: OCC1Cc2ccc3c(c2O1)CCC3
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC1Cc2ccc3c(c2O1)CCC3
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.4 %

Procedure:
To a solution of (±)-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-ylmethanol (0.500 g, 2.63 mmol) in tetrahydrofuran (25 mL) was added triphenylphoshine (1.03 g, 3.94 mmol), phthalimide (0.58 g, 3.94 mmol) followed by diethylazodicarboxylate (0.687 g, 3.94 mmol) and the reaction mixture was allowed to stir at room temperature for 12 h. The reaction was quenched by the addition of water (5 mL) and the solvent was removed in vacuo. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:3) provided 0.65 g of (±)-2-(3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-ylmethyl)-1H-isoindole-1,3(2H)-dione as a white solid (mp 131-135° C.). The solid was re-dissolved in methanol (10 mL) and hydrazine monohydrate (0.153 g, 3.06 mmol) was added to the reaction mixture. The reaction mixture was heated at reflux for 12 h, concentrated hydrogen chloride (12.1 M, 3 mL) was added and heating was continued for an additional 1 h. The reaction mixture was cooled to room temperature and diluted with water (150 mL) and aqueous sodium hydroxide (2.5 N, 10 mL). The reaction mixture was extracted with ethyl acetate (2×75 mL) and the combined organic layers were dried (magnesium sulfate) and the solvent was removed in vacuo. Purification by flash column chromatography (silica, 10% aqueous ammonium hydroxide/methanol:ethyl acetate 1:19) provided a colorless oil. The oil was re-dissolved in isopropanol (1 mL) and hydrogen chloride (1.0 N in diethyl ether, 5 mL) was added. The resulting precipitate was filtered, washed (diethyl ether), and dried to afford 0.42 g (71%) of (±)-1-(3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. mp>230° C. (dec); Anal. calcd. for C12H15NOHCl: C, 63.85; H, 7.14; N, 6.21. Found: C, 63.64; H, 7.25; N, 6.02.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[CH:21][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=O.[C:29]([CH2:32][C:33](=O)[CH3:34])(=[O:31])[CH3:30]>C(O)(=O)C>[C:29]([C:32]1[C:33]([CH3:34])=[N:6][C:7]2[C:8]([C:9]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=[CH:21][C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)(=[O:31])[CH3:30]
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: CC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(-c2c(C(C)=O)c(C)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 81.4 %

Procedure:
Conc. sulfuric acid (0.185 ml ) was added to a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (10.0 g), acetylacetone (3.78 g) and acetic acid (75 ml), and the mixture was stirred at 100° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was poured into water and made alkaline with 2N sodium hydroxide, and extracted with chloroform. The chloroform layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethanol (20:1, v/v) gave 3-acetyl-4-(3,4-dimethoxyphenyl )-6,7-dimethoxy-2-methyl-quinoline (9.78 g, 82%). This compound was recrystallized from dichloromethane-ethanol to give colorless prisms, mp. 210°-211° C.
Reaction SMILES: O.[ClH:2].Cl.[O:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][NH:12][CH2:13][C:14]2([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:17][CH2:16][CH2:15]2)[CH2:6][CH2:5]1.[CH2:26]=O.[OH-].[Na+]>C(O)=O>[ClH:24].[ClH:2].[CH3:26][N:12]([CH2:13][C:14]1([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH2:15][CH2:16][CH2:17]1)[CH2:11][CH2:10][N:7]1[CH2:6][CH2:5][O:4][CH2:9][CH2:8]1
Reactant: Clc1ccc(C2(CNCCN3CCOCC3)CCC2)cc1Cl
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: CN(CCN1CCOCC1)CC1(c2ccc(Cl)c(Cl)c2)CCC1

Procedure:
The product of Example 74 in the form of its free base (0.55 g) 98% formic acid (4 ml) and 37-40% aqueous formaldehyde were heated at 70°-80° C. for four hours. The reaction mixture was cooled and basified with aqueous sodium hydroxide solution. The mixture was then extracted with ether and the ether extract washed and dried. Hydrogen chloride gas was passed through the extract to give N-methyl-N-(2-morpholinoethyl)-[1-(3,4-dichlorophenyl)cyclobutyl]methylamine dihydrochloride (m.p. 233°-235° C.).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=3[S:9][C:8]=2[CH:17]=1)=[O:3].[N+:18](=[CH2:20])=[N-:19]>CCOCC>[N+:18](=[CH:20][C:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=3[S:9][C:8]=2[CH:17]=1)=[O:3])=[N-:19]
Reactant: C=[N+]=[N-]
Reactant: Cc1ccc2sc3cc(C(=O)Cl)ccc3c2c1
Solvent: CCOCC
Product: Cc1ccc2sc3cc(C(=O)C=[N+]=[N-])ccc3c2c1
Reaction time: 8 h

Procedure:
A solution of 2.5 g. of 3-chlorocarbonyl-8-methyldibenzothiophene in 75 ml. of ether was added dropwise to a solution of 0.81 g. of diazomethane in 100 ml. of ether in an ice bath. The solution was stirred overnight, and the ether was removed on the steam bath. The crude product (2.5 g.), 3-diazomethylcarbonyl-8-methyldibenzothiophene, was used directly in the next step.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:3]=1.C([Li])CCC.[CH:20](=[O:22])[CH3:21].O>O1CCCC1.CCCCCC>[C:4]12([CH2:14][CH2:13][CH2:12][CH2:11]1)[C:5]1[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]([CH:20]([OH:22])[CH3:21])=[CH:3]2
Reactant: BrC1=CC2(CCCC2)c2ccccc21
Reactant: CC=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)C1=CC2(CCCC2)c2ccccc21
Temperature: -70 °C
Reaction time: 2 h

Procedure:
3'-Bromospiro(cyclopentane-1,1'-indene) (23 g) is dissolved in tetrahydrofuran (200 ml) and cooled to -70° C. While stirring under nitrogen, n-butyllithium (75 ml of a 2 M solution in hexane) is added followed after 30 minutes by acetaldehyde (14 g) in one portion. Stirring and cooling is maintained for 30 minutes whereupon the mixture is allowed to come to about 20° C. and is kept there for 2 hours. Water (600 ml) is then added and the solution is extracted three times with diethyl ether. The ether extracts are washed, dried over sodium sulphate and the ether is distilled off. Distillation of the residual oil gives the title alcohol, b.p. 139° C./0.4 torr.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[CH2:16]([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(#N)C>[CH2:16]([N:23]1[CH:27]=[CH:26][N:25]=[C:24]1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[Br:1])=[O:6])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(Cn2ccnc2)cc1
Reactant: Cc1cccc(C(=O)O)c1Br
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: Cc1cccc(C(=O)c2nccn2Cc2ccccc2)c1Br
Temperature: 60 °C
Yield: 102.3 %

Procedure:
A solution of 2-bromo-3-methylbenzoic acid (2.0 g, 9.3 mmol) in thionyl chloride (4.75 ml, 65.1 mmol) was heated at 65° C., under nitrogen, for 3 h. The mixture was concentrated in vacuo and to the residue was added acetonitrile (25 ml). This solution was concentrated in vacuo and the process was repeated. To the final residue was added acetonitrile (25 ml), 1-benzylimidazole (1.62 g, 10.2 mmol) and triethylamine (1.44 ml, 10.2 mmol) and the reaction mixture was heated at 60° C., under nitrogen, for 18 h. The mixture was concentrated in vacuo and to the residue was added ethyl acetate (80 ml). The solution was washed with water (40 ml) and saturated aqueous sodium hydrogen carbonate solution (40 ml), dried (MgSO4) and concentrated in vacuo to give the title compound (3.38 g).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=O)[CH3:5].[CH2:8]1[CH2:13][CH2:12][C:11]([CH2:18][NH2:19])([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH2:9]1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CO>[CH3:5][C:4]([NH:19][CH2:18][C:11]1([CH2:14][C:15]([O-:17])=[O:16])[CH2:12][CH2:13][CH2:8][CH2:9][CH2:10]1)=[CH:3][C:2](=[O:7])[CH3:1].[NH2+:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(=O)CC(C)=O
Reactant: NCC1(CC(=O)O)CCCCC1
Reactant: C1CCNCC1
Solvent: CO
Product: C1CC[NH2+]CC1
Product: CC(=O)C=C(C)NCC1(CC(=O)[O-])CCCCC1

Procedure:
2,4-pentanedione (103 μL, 1 mmol), gabapentin (171 mg, 1 mmol), and piperidine (99 μL, 1 mmol) were mixed in anhydrous methanol (10 mL). The resulting mixture was heated under reflux for 4 h. Removal of the solvent under reduced pressure gave the title compound with purity greater than 90%. 1H NMR (CDCl3, 400 MHz): δ 1.34-1.62 (m, 12H), 1.71 (m, 4H), 1.94 (s, 3H), 1.96 (s, 3H), 2.26 (s, 2H), 2.98 (m, 4H), 3.38 (d, J=6 Hz, 2H), 4.90 (s, 1H), 5.20 (s, br, 2H), 8.64 (t, J=6 Hz, 1H). MS (ESI) m/z 252.35 (M−H−).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1COCC1.[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([CH:20]([C:22]3[C:23]([O:39][CH3:40])=[C:24]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([C:36](O)=[O:37])[CH:31]=4)[C:25]([CH3:29])=[C:26]([Cl:28])[CH:27]=3)[CH3:21])[N:17]=[C:18]([CH3:19])[C:11]=12.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[NH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([CH:20]([C:22]3[C:23]([O:39][CH3:40])=[C:24]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([C:36]([N:2]([CH3:3])[CH3:1])=[O:37])[CH:31]=4)[C:25]([CH3:29])=[C:26]([Cl:28])[CH:27]=3)[CH3:21])[N:17]=[C:18]([CH3:19])[C:11]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C(=O)O)c1
Reactant: CNC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C(=O)N(C)C)c1
Reaction time: 1 h

Procedure:
2.0 M Dimethylamine in THF (0.14 mL, 0.28 mmol) was added to a solution of 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridine-2-carboxylic acid (9.6 mg, 0.021 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (10 mg, 0.03 mmol) in N,N-dimethylformamide (0.7 mL) at room temperature followed by addition of triethylamine (8.8 μL, 0.064 mmol). The reaction was stirred for 1 hour. The crude mixture was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C24H27ClN7O2 (M+H)+: m/z=480.2; Found: 480.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.C([O-])([O-])=O.[Na+].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](OB(O)O)=[CH:22][CH:21]=1>O1CCOCC1.CO>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]3)=[CH:22][CH:21]=1
Reactant: O=c1ccc2cc(Br)ccc2[nH]1
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: O=c1ccc2cc(-c3ccc(Cl)cc3)ccc2[nH]1
Temperature: 110 °C

Procedure:
A solution of 22.7 g (0.101 mol) 6-bromo-1H-quinolin-2-one in 380 mL 1,4-dioxane and 380 mL MeOH is combined with 141.5 ml (0.283 ml) 2 M Na2CO3 solution and saturated with argon. Then 3.735 g (3.23 mmol) tetrakis-triphenyl-phosphane-palladium and 4-chlorophenylboric acid are added successively. The reaction mixture is heated to 110° C. for four hours and then evaporated down to a volume of 300 mL. 1.2 L water are added and the precipitate is filtered off. The solid is dried at 55° C. in the drying cupboard, washed with diisopropylether and dried again.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[NH:12][C:11]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][O:33][CH2:34][CH2:35][NH:36][CH2:37][CH3:38])=[C:10]1[C:39]([O:41][CH3:42])=[O:40].[C:43](=O)([O:49]C(C)(C)C)[O:44][C:45]([CH3:48])([CH3:47])[CH3:46].C(N(CC)CC)C>ClCCl>[CH3:42][O:41][C:39]([C:10]1[CH:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[NH:12][C:11]=1[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][O:33][CH2:34][CH2:35][N:36]([C:43]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:49])[CH2:37][CH3:38])=[O:40]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CCNCCOCc1ccccc1CCC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CC(=O)OC)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CCOCc1ccccc1CCC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CC(=O)OC)N1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To an ice-cooled stirred solution of dimethyl 4-(2,6-dichlorophenyl)-2-[2-(2-{[2-(ethylamino)ethoxy]methyl}phenyl)ethyl]-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate (700 mg/1.13 mmol) in dichloromethane (50 ml) was added di-t-butyl carbonate (297 mg/1.36 mmol) and triethylamine (172 mg/1.70 mmol). The reaction mixture was warmed to room temperature and stirred for 1.5 h. The reaction mixture was quenched with water. The separated organic layer was washed with water, dried over MgSO4, filtered and concentrated to give a crude mixture. This crude was purified by column chromatography on silica gel (CH2Cl2:MeOH=40:1) to afford a yellow amorphous (813 mg/quant.).