Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:31]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:49].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:49][C:9]1[C:8]2[N:31]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[C:7]=2[C:16]2[CH:15]=[CH:14][C:13]([O:17][CH:18]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:22][CH2:23]3)=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c2n1CC(C)(C)O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c2n1CC(C)(C)O
Reaction time: 0.5 h

Procedure:
To a stirring solution of tert-butyl 4-{[2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate (3.32 g, 6.66 mmol) in chloroform (70 mL) was added 3-chloroperoxybenzoic acid (2.29 g, 6.66 mmol, based on 50% purity). After 30 minutes, concentrated ammonium hydroxide (35 mL) was added and the reaction was stirred for 15 minutes. p-Toluenesulfonyl chloride (1.27 g, 6.66 mmol) was added in one portion and stirring was continued for 16 additional hours. The layers were separated and the organic fraction was washed with water, then saturated aqueous sodium chloride. The organic fraction was evaporated under reduced pressure and the residue was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-28% CMA in chloroform), followed by recrystallization from acetonitrile to afford 0.630 g of tert-butyl 4-{[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate as a tan crystalline solid, mp 214-215° C., decomposition.
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1([CH2:15][OH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>S(=O)(=O)(O)O>[C:9]1([CH2:15][O:16][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1
Reactant: O=C1CCCCCO1
Agent: O=S(=O)(O)O
Product: O=C(CCCCCO)OCc1ccccc1
Temperature: 50 °C
Yield: 25.8 %

Procedure:
A mixture of 6-hexanolactone (40 g, 0.35 mol), phenylmethanol (70 g, 0.647 mol), and conc. sulfuric acid (40 drops) was heated at 50° C. overnight. The resulting mixture was purified by column chromatography (hexane, 5-30% ethyl acetate/hexane) and distilled to afford 20.1 g (26%) of 6-hydroxyhexanoic acid phenylmethyl ester, b.p. 70°-75° C./1 mm.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:14]=[C:13]([CH2:15]B2OCC(C)(C)CO2)[O:12][C:11]=1[CH3:24])(C)C)(C)(C)C.ClC1[N:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:24][C:11]1[O:12][C:13]([C:15]2[N:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:14][C:10]=1[CH2:9][OH:8]
Reactant: Cc1oc(CB2OCC(C)(C)CO2)cc1CO[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc(Cl)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2cc(CO)c(C)o2)nn1
Reaction time: 8 h
Yield: 31.6 %

Procedure:
A mixture of tert-butyl({5-[(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)methyl]-2-methylfuran-3-yl}methoxy)dimethylsilane (2.4 g), 3-chloro-6-methylpyridazine (1.5 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (7 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), 1N tetrabutylammonium fluoride in tetrahydrofuran (10 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (50% ethyl acetate/hexane to 100% ethyl acetate/hexane) to give the title compound (0.44 g, 31%) as a yellow crystal.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]Br)[CH:10]=2)[NH:5][C:4](=[O:18])[CH:3]=1.[SH:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH:10]=2)[NH:5][C:4](=[O:18])[CH:3]=1
Reactant: Sc1ccc2ccccc2n1
Reactant: Cc1cc(=O)[nH]c2ccc(OCCCCBr)cc12
Product: Cc1cc(=O)[nH]c2ccc(OCCCCSc3ccc4ccccc4n3)cc12

Procedure:
Prepared analogous to Example 122 from 4-methyl-6-(4-bromo-butoxy)-carbostyril and 2-mercapto-quinoline.
Reaction SMILES: [C@@H]1([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=O)[C:12]=3[N:11]=[CH:10]2)O[C@H](CO)[C@@H](O)C1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N)C[NH2:35]>N1C=CC=CC=1>[NH2:17][C:16]1[N:18]=[C:19]2[C:12]([NH:11][CH:10]=[N:9]2)=[C:13]([NH2:35])[N:15]=1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: NCCN
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Nc1nc(N)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To 2′-deoxyguanosine (2 mmol), dried by coevaporation with pyridine, suspended in 40 mL of pyridine and cooled in an ice bath under an argon atmosphere, trifluoroacetic anhydride (16 mmol) is added following the procedure of Kung and Jones (Tetraheron Lett., 32, 3919, 1991). After 40 minutes, ethylenediamine (30 mmol) is added and stirred for 24 h at room temperature. The reaction mixture is concentrated and purified by silica column chromatography. The product is guanylated with reagent 5 as in Example 8 and protected at N2-position with an isobutyryl group by treating with isobutyric anhydride, 5′-dimethoxytritylated at the 5′-position and purified. The resulting compound is treated with benzoic anhydride (N6 protection) and then phosphitylated following the procedures described above to afford the 2,6-diaminopurine derivative functionalized at the 6-position (35).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[CH2:10]Cl>>[CH3:10][CH:5]1[CH2:6][CH2:7][CH2:8][CH:3]([CH:2]=[O:1])[CH2:4]1
Reactant: OCC1CCCCC1
Reactant: ClCCl
Product: CC1CCCC(C=O)C1
Reaction time: 1 h

Procedure:
To a solution of 1-hydroxymethylcyclohexane (6.8 g, 0.053 mole) in 150 ml dichloromethane was added pcc (22.9 g, 0.106 mole) under nitrogen. Stirring continued for 1 hour at room temperature. The solids were removed by filtration through Florisil and the filtrate was concentrated to give 8 g of the title compound. The NMR spectrum showed 0.90, 0.95 (d, 3H, J=8 Hz), 0.86-2.32 (m, 10H), and 9.68, 9.70 (d, 1H, J=2 Hz).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.C([Li])CCC.[CH:21]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22]1.[F:31][C:32]1([F:39])[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1>C1COCC1>[F:31][C:32]1([F:39])[CH2:37][CH2:36][C:35]([C:21]2([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22]2)([OH:38])[CH2:34][CH2:33]1
Reactant: O=C1CCC(F)(F)CC1
Reactant: CC(C)(C)OC(=O)C1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(C2(O)CCC(F)(F)CC2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
A solution of LDA prepared from diisopropylamine (304 mg, 3.00 mmol) and butyllithium (1.20 mL, 3.00 mmol) in THF was added to a cold (−78° C.) solution of tert-butyl cyclopropanecarboxylate (427 mg, 3.00 mmol) in THF (2 mL), and the mixture was stirred at −78° C. for 1 h. A solution of 4,4-difluorocyclohexanone (268 mg, 2 mmol) in THF (0.5 mL) was added dropwise and the mixture was stirred at −78° C. for 2 h and allowed to warm to rt overnight. The crude product was purified by silica gel FCC (DCM) to afford tert-butyl 1-(4,4-difluoro-1-hydroxycyclohexyl)cyclopropanecarboxylate as a clear oil (0.273 g). 1H NMR (500 MHz, CDCl3) δ ppm 2.12-2.30 (2H, m), 1.79-1.96 (4H, m), 1.48-1.53 (2H, m), 1.41-1.47 (9H, m), 1.21-1.34 (1H, m), 1.11-1.17 (2H, m), 0.90-0.97 (2H, m).
Reaction SMILES: [CH:1]([CH:19]1[CH2:24][C:23](=[O:25])[O:22][C:20]1=O)=[CH: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][CH2:16][CH2:17][CH3:18].[CH2:26]([CH2:28][NH2:29])[OH:27]>>[OH:27][CH2:26][CH2:28][N:29]1[C:23](=[O:25])[CH2:24][CH:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:20]1=[O:22]
Reactant: NCCO
Reactant: CCCCCCCCCCCCCCCCC=CC1CC(=O)OC1=O
Product: CCCCCCCCC=CCCCCCCCCC1CC(=O)N(CCO)C1=O
Yield: 75.3 %

Procedure:
A 50 mL reaction flask was charged with 35.1 g of octadecenyl succinic anhydride (manufactured by Tokyo Chemical Industry Co., Ltd.) and 6.1 g of ethanolamine (manufactured by Tokyo Chemical Industry Co., Ltd.), and the resulting mixture was reacted at 110° C. for 6 hours under continuous nitrogen purging and with vigorous stirring. The reaction product was purified by silica gel column chromatography (mobile phase: ethyl acetate/hexane), yielding 29.6 g of N-(2-hydroxyethyl)-9-octadecenyl succinimide (yield: 75.3%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][OH:24])[CH:19]=[CH:20][C:21]=1[F:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:23][O:24][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1ccc(F)c(Cl)c1
Product: CN1c2cc(OCc3ccc(F)c(Cl)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3-chloro-4-fluorophenyl)methanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1.[C:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)#[N:15].C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C.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>[OH:13][CH2:12][CH2:11][C@H:9]1[CH2:10][C@@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:19]2[CH:20]=[CH:21][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)=[CH:3][CH:4]=1
Reactant: OCC[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: N#Cc1ccc(-c2ccc([C@H]3C[C@@H]3CCO)cc2)cc1

Procedure:
A solution of the product of Example 28E (2-[(1R,2S)-2-(4-bromophenyl)cycloprop-1-yl]ethanol), 4-cyanophenylboronic acid [CAS 126747-14-6] (2 equivalents), Pd(PPh3)2Cl2, and Cs2CO3 in isopropanol under N2 was stirred at reflux overnight. The mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with saturated aqueous NaHCO3 and then with brine. The organic layer was then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by chromatography on silica gel eluted with 4:1 hexanes/ethyl acetate to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:19][O:20][CH3:21])=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:30]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:14][CH2:15][N:16]([CH2:23][CH2:24][C:25]4[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([S:31]([NH2:34])(=[O:32])=[O:33])[CH:30]=4)[CH2:17][CH2:18]3)=[N:10][C:9]=2[CH2:19][O:20][CH3:21])=[CH:4][CH:3]=1
Reactant: COCc1nc(C2CCNCC2)oc1-c1ccc(F)cc1
Reactant: COc1ccc(CCCl)cc1S(N)(=O)=O
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COCc1nc(C2CCN(CCc3ccc(OC)c(S(N)(=O)=O)c3)CC2)oc1-c1ccc(F)cc1
Reaction time: 16 h
Yield: 38.6 %

Procedure:
A solution of 4-[5-(4-fluoro-phenyl)-4-methoxymethyl-oxazol-2-yl]-piperidine (0.3 g; 1.03 mmol) in dry dioxane (7 ml) is treated with 5-(2-chloroethyl)-2-methoxy-benzenesulfonamide (0.52 g; 2.06 mmol), sodium iodide (0.31 g; 2.06 mmol) and diisopropylethylamine (0.72 ml; 4.12 mmol) and heated to 100 C. for 16 hours. The reaction mixture is partitioned between ethyl acetate (50 ml) and dilute sodium bicarbonate (20 ml). The aqueous phase is washed with ethyl acetate (20 ml). The combined organic phases are washed with saturated brine (10 ml), dried over sodium sulfate and concentrated to dryness. Purification by radial chromatography on silica gel using a methanol/ethyl acetate gradient (5%-20%) is followed by a second chromatography using a methanol/dichloromethane gradient (5%-15%). Crystallization from dichloromethane/ethyl acetate afforded the product as a white solid (0.20 g; 40%). HNMR (CDCl3): 7.72 (d, 1H, J=2.1 Hz), 7.62 (m, 2H), 7.35 (dd, 1H, J=8.6; 2.1 Hz), 7.13 (t, 21H, J=8.6 Hz), 6.96 (d, 1H, J=8.6 Hz), 5.64 (broad s, 2H), 4.44 (s, 2H), 3.97 (s, 3H), 3.44 (s, 3H), 2.96 (m, 2H), 2.80 (m, 1H), 2.75 (m, 2H), 2.53 (m, 2H), 2.10 (m, 4H), 1.90 (m, 2H). Mass spectrum: m/e calculated (MH+)=504; observed (MH+)=504.
Reaction SMILES: [NH2:1][C:2]1([C:12]([OH:14])=[O:13])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[CH:15]1[C:24]2[C:19](=[C:20]([N:25]3[C:29]([C:30]4[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:31]=4[O:38][CH3:39])=[CH:28][C:27]([C:40](Cl)=[O:41])=[N:26]3)[CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1>N1C=CC=CC=1.ClCCl>[CH:15]1[C:24]2[C:19](=[C:20]([N:25]3[C:29]([C:30]4[C:31]([O:38][CH3:39])=[CH:32][CH:33]=[CH:34][C:35]=4[O:36][CH3:37])=[CH:28][C:27]([C:40]([NH:1][C:2]4([C:12]([OH:14])=[O:13])[CH:9]5[CH2:8][CH:7]6[CH2:6][CH:5]([CH2:4][CH:3]4[CH2:11]6)[CH2:10]5)=[O:41])=[N:26]3)[CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1
Reactant: NC1(C(=O)O)C2CC3CC(C2)CC1C3
Reactant: COc1cccc(OC)c1-c1cc(C(=O)Cl)nn1-c1cccc2cnccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(OC)c1-c1cc(C(=O)NC2(C(=O)O)C3CC4CC(C3)CC2C4)nn1-c1cccc2cnccc12
Reaction time: 8 h

Procedure:
0.75 g of 2-amino-2-adamantanecarboxylic acid is dissolved in 20 ml of pyridine. 1.4 g of 1-(5-isoquinolyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolecarbonyl chloride, dissolved in 20 ml of dichloromethane, are added and the reaction mixture is left overnight at room temperature. It is concentrated under vacuum, the residue is taken up with pH 2 buffer, the mixture is stirred and the precipitate is filtered off and rinsed with diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH2:13][C:14](=[O:20])[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Li+].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH:13]([CH3:22])[C:14](=[O:20])[CH2:15]3)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C1CC2CCCC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1C(=O)CC2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a stirring mixture of 9-(4-chloro-benzenesulfonyl)-9-aza-bicyclo[3.3.1]nonan-3-one (550 mg, 1.75 mmol) in THF (2 mL) at −78° C. was added LiHMDS in THF (2.62 mL, 1.0 M in THF, 2.62 mmol) dropwise over 15 min. The resulting mixture was allowed to stir at −78° C. for 30 min before the addition of MeI (1.24 g, 8.75 mmol). The reaction mixture was stirred at −78° C. for 2.5 h before it was allowed to warm up to room temperature for 15 min. The reaction mixture was quenched by the addition of a saturated aqueous NH4Cl solution (25 mL) and EtOAc (25 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude mixture was purified via silica gel chromatography to give 9-(4-chloro-benzenesulfonyl)-2-methyl-9-aza-bicyclo[3.3.1]nonan-3-one as a white solid. Retention time (min) 2.13 min, Method [1], MS (ESI) 350 (M+Na).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[C:14]([C:19]4[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:22]=[C:21]([CH:28]([CH3:30])[CH3:29])[C:20]=4[O:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:36]([CH3:41])=[CH:37][C:38]([OH:40])=[O:39])(=O)=O)C=CC=CC=1.[OH-].[K+].Cl>C(O)C.O1CCOCC1>[CH2:32]([O:31][C:20]1[C:21]([CH:28]([CH3:30])[CH3:29])=[CH:22][C:23]([CH:25]([CH3:26])[CH3:27])=[CH:24][C:19]=1[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[C:11]([C:36]([CH3:41])=[CH:37][C:38]([OH:40])=[O:39])[NH:10]2)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCOc1c(-c2cccc3c2cc(C(C)=CC(=O)O)n3S(=O)(=O)c2ccccc2)cc(C(C)C)cc1C(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: CCCCOc1c(-c2cccc3[nH]c(C(C)=CC(=O)O)cc23)cc(C(C)C)cc1C(C)C
Yield: 103 %

Procedure:
3-[1-Benzenesulfonyl-4-(2-butoxy-3,5-diisopropyl-phenyl)-1H-indol-2-yl]-but-2-enoic acid (32 mg, 0.056 mmol) was dissolved in ethanol (1 mL)/dioxane (1 mL) and treated with 2.5N KOH (1 mL, 1 mmol) at 70-75° C. for 24 h. The reaction was neutralized with 1N HCl and extracted with ethyl acetate (3×10 mL). The organic portions were washed with water (10 mL), brine (10 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 25 mg of a residue. The material was purified using radial chromatography with a gradient of hexane/ethyl acetate to provide 13 mg (53%) of a yellow amorphous foam. 1H NMR (250 MHz, CDCl3): δ 8.26 (bs, 1H), 7.26-7.15 (m, 3H), 7.06 (m, 2H), 6.83 (s, 1H), 6.11 (s, 1H), 3.37 (m, 1H), 3.22 (t, 2H, J=6.3), 2.86 (m, 1H), 2.55 (s, 3H), 1.23 (m, 14H), 0.95 (m, 2H), 0.54 (t, 3H, J=7.2). MS [EI+] 434, (M+H)+, [EI−] 432 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:12]3[CH:11]=[CH:15][N:14]=[CH:13]3)=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2cccc(Cl)c2C1=O
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2c(C(=O)n3ccnc3)ncn2-c2cccc(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.3 g (25 mmol) of 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid are suspended in 50 ml of N,N-dimethylformamide, whereupon the suspension is treated with 5.67 g (34 mmol) of 1,1'-carbonyldiimazole and the mixture is stirred at room temperature for a further 0.75 hour and subsequently at 60° for 2 hours. The mixture is then poured into 100 ml of water, the product is filtered off under suction after 1 hour, rinsed with water and dried at 80° in a high vacuum. There is obtained 1-[[7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl]carbonyl]imidazole of decomposition point 242°-244°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:18])=[CH:4][C:5]2[C:6]3[CH:15](O)[O:14][C:13](=O)[C:7]=3[C:8]([OH:12])=[N:9][C:10]=2[CH:11]=1.O.[NH2:20][NH2:21]>CS(C)=O>[Cl:1][C:2]1[C:3]([Cl:18])=[CH:4][C:5]2[C:6]3[CH:15]=[N:21][NH:20][C:13](=[O:14])[C:7]=3[C:8]([OH:12])=[N:9][C:10]=2[CH:11]=1
Reactant: NN
Reactant: O=C1OC(O)c2c1c(O)nc1cc(Cl)c(Cl)cc21
Solvent: CS(C)=O
Solvent: O
Product: O=c1[nH]ncc2c1c(O)nc1cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 42 h

Procedure:
1.76 g (0.0062 mol) of (RS)-7,8-dichloro-1,4-dihydroxy-1,3-dihydro-furo[3,4-c]quinolin-3-one were dissolved in 18 ml of dimethyl sulphoxide while gassing with argon. 0.31 g (0.0062 mol) of hydrazine hydrate was added thereto and the mixture was stirred at room temperature for 42 hrs. The suspension obtained was suction filtered and rinsed with ethyl acetate. Yield: 0.32 g (18%) of 8,9-dichloro-5-hydroxy-3,4-dihydro-pyridazino[4,5-c]quinolin-4-one as yellow crystals; m.p. >350° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](OS(C2C=CC(C)=CC=2)(=O)=O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([C:34]#[CH:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCCCCCC.C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:35]#[C:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2nn(Cc3ccccc3)c3ccccc23)cc1
Reactant: C#Cc1ccccc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: C(#Cc1nn(Cc2ccccc2)c2ccccc12)c1ccccc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-benzyl-1H-indazol-3-yl ester and phenylacetylene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (9.25 mg, 6%); 1H NMR δ (CDCl3): 7.92 (d, J=7.92 Hz, 1H), 7.4-7.17 (m, 13H), 5.5 (s, 2H); LCMS m/z: 308.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:13]([O-:15])=[O:14])=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].S(Cl)(Cl)=O.[CH3:20]O>>[CH3:1][O:2][C:3]1[C:4]([N+:13]([O-:15])=[O:14])=[CH:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([O:10][CH3:20])=[O:9]
Reactant: CO
Reactant: COc1cc(C(=O)O)c(C)cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1C
Yield: 82 %

Procedure:
To 5-methoxy-2-methyl-4-nitrobenzoic acid (1.27 g, 6 mmol) in methanol (15 mL) was added thionyl chloride (0.44 mL, 6 mmol) dropwise. The mixture was heated to reflux for 3 h and then allowed to cool. The solvent was removed in vacuo and the residue was partitioned between DCM (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification of the residue via silica gel column chromatography (0-100% EtOAc in iso-hexane) gave methyl 5-methoxy-2-methyl-4-nitrobenzoate (1.11 g, 82%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]+=226 at 3.92 min. 1H NMR (400 MHz, CDCl3): δ 7.68 (s, 1H), 7.60 (s, 1H), 3.98 (s, 3H), 3.95 (s, 3H), 2.55 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=2)[C:11]2[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([Cl:29])[CH:22]=3)[C:11]3[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(C)c23)cc1Cl
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc(C)c(C)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6-dimethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6-dimethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.