Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]2[C:21]([CH:22]=1)=[N:20][C:19]1[C:14](=[CH:15][CH:16]=[C:17]([NH2:23])[CH:18]=1)[CH:13]=2.[CH2:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].O>CN1C(=O)N(C)CC1>[CH2:24]([NH:23][C:17]1[CH:16]=[CH:15][C:14]2[C:19]([CH:18]=1)=[N:20][C:21]1[C:12](=[CH:11][CH:10]=[C:9]([NH:8][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])[CH:22]=1)[CH:13]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: Nc1ccc2cc3ccc(N)cc3nc2c1
Reactant: CCCCCCCCCCCCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: CCCCCCCCCCCCCCCCCCCCNc1ccc2cc3ccc(NCCCCCCCCCCCCCCCCCCCC)cc3nc2c1
Temperature: 50 °C
Reaction time: 86 h

Procedure:
2.53 g of anhydrous potassium carbonate are added to a solution of 2.5 g of 3,6-diaminoacridine hydrochloride and 2.95 g of 1-eicosyl bromide in 20 ml of N,N'-dimethylethyleneurea, and the mixture is stirred at 50° C. for 86 hours. The cooled reaction mixture is subsequently poured into water, and the orange-brown suspension is extracted with methylene chloride. The organic phase is washed with water and dried over sodium sulfate. After evaporation, 2N HCl is added to the brown oil. The red precipitate formed is filtered off, washed with water and then dried in a high vacuum. The resultant red-brown crystals are taken up in methylene chloride/methanol (10:1) and chromatographed on silica gel. After evaporation, the residue is taken up in diethyl ether/methanol (10:1) and re-chromatographed on silica gel, giving the title compound as red crystals, absorption spectrum (ethanol): λmax =472 nm; ε=42 200.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[OH-].[Na+].Cl.[CH2:14]([OH:16])C>>[CH3:14][O:16][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(=O)O)cn1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 6-methylnicotinic acid (35 mg) in ethanol (1 mL) was added 2N sodium hydroxide solution (0.14 mL) and the mixture was stirred at 60° C. for 2 hours. After cooling to room temperature, to the reaction mixture was added 5N HCl (0.06 mL) and the mixture was evaporated in vacuo to give 6-methyloxynicotinic acid. The product was treated in the same manner as described in Example 3 to give (3R)-1-[bis-(4-chlorophenyl)methyl]-3-[(6-methoxynicotinoyl)amino]pyrrolidine (28.0 mg; yield: 61%) as a powder.
Reaction SMILES: [Cl:1][CH:2]=[C:3](Cl)Cl.[C:6]1([O:12][CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(=O)(=O)(O)O>C(O)(=O)C>[CH3:13][O:12][C:6]1[CH:11]=[CH:10][C:9]([CH:3]([C:9]2[CH:10]=[CH:11][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[CH2:2][Cl:1])=[CH:8][CH:7]=1
Reactant: ClC=C(Cl)Cl
Reactant: COc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(C(CCl)c2ccc(OC)cc2)cc1
Temperature: 15 °C

Procedure:
To a 500-milliliter jacketed flask equipped with a mechanical stirrer, thermometer, and dropping funnel, and cooled to approximately 2° C. with circulating trichloroethylene thermostated cooling liquid, was charged 43.2 grams (0.40 mole) of anisole and 30.6 grams (0.20 mole) of commercial chloroacetal. To the cooled and stirred solution was added a solution of 80.0 grams (0.82 mole) of concentrated sulfuric acid dissolved in 50 milliliters of glacial acetic acid over a 1.17-hour period (1 hour and 10 minutes) at a rate sufficient to maintain the temperature at less than 15° C. When the addition was complete, the solution was stirred an additional 10 minutes, allowed to warm to 15° C. and poured into 1 liter of an ice/water mixture. The mixture was extracted with three 150-milliliter portions of diethyl ether, washed successively with three 100-milliliter portions of saturated aqueous sodium carbonate and three 100-milliliter portions of cold water, and dried over anhydrous sodium sulfate. Evaporation of the ether in vacuo yielded 55.0 grams (almost quantitative) of crude 1,1-bis(4-methoxyphenyl)-2-chloroethane as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[CH:18](Br)=[CH:19][C:20](=[CH2:22])[CH3:21].C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:7])=[O:8])[CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH3:2]
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(OC)cc1
Reactant: C=C(C)C=CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(CC=C(C)C)S(=O)(=O)c1ccc(OC)cc1

Procedure:
To a stirred solution of (4-methoxy-benzenesulfonyl)acetic acid ethyl ester (5.16 g, 20 mmol), isoprenyl bromide (3.0 g, 20 mmol) and 18-Crown-6 (500 mg) in acetone (250 ml) was added K2CO3 (10 gms, excess) and the mixture refluxed foe 24 hours. At the end, the reaction mixture was filtered and the acetone layer was concentrated. The residue obtained was extracted with chloroform, washed well with water, dried over anhydrous MgSO4, filtered and concentrated. The product obtained was purified by silica-gel column chromatography, eluting with 30% ethy acetate: hexane. The product 2-(4-methoxy-benzenesulfonyl)-5-methyl-hex-4- enoic acid ethyl ester was isolated as a colourless oil. Yield: 3.0 g, 93%.
Reaction SMILES: C([NH:4][C:5]1[N:9]([C:10](=[N:19]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]([CH3:31])[CH:6]=1)(=O)C.[OH-].[Na+].Cl>CO>[CH3:31][C:7]1[CH:6]=[C:5]2[N:4]=[N:19][CH:10]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]2[N:8]=1
Reactant: CC(=O)Nc1cc(C)nn1C(CCc1ccccc1)=NOS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2n(n1)C(CCc1ccccc1)N=N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
1 g (2.27 mmol) of 5-acetamido-3-methyl-1-(3-phenyl-O-tosyl-propanehydroximoyl)-pyrazole mixed with 15 ml of methanol and 4 ml of 2N sodium hydroxide solution is stirred for 30 minutes at room temperature, when a clear solution is produced. The mixture is then adjusted to be weakly acid with conc. hydrochloric acid and the methanol is distilled off under vacuum, when a white precipitate is formed. The product may be recrystallised from nitromethane. 420 mg (82%) of 6-methyl-3-(2-phenyl-ethyl)pyrazolo[5,1-c][1,2,4]triazole with a m. pt. of 84°-185° C. are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:24])[CH:7]=1)[CH3:2].Br[C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:27]3[CH:28]=[N:29][N:30]([CH2:32][CH2:33][CH3:34])[CH:31]=3)[C:14]=2[CH3:24])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Reactant: CCCn1cc(Br)cn1
Product: CCCn1cc(-n2c(C)c(Sc3cccc(CC(=O)OCC)c3)c3ccc(Cl)c(F)c32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: [3-(6-Chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid ethyl ester and 4-bromo-1-propyl-1H-pyrazole.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][S:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:16][C:17]1[N:25]([C:26]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[O:27])[C:24]2[CH:23]=[CH:22][C:21]([O:35][CH3:36])=[CH:20][C:19]=2[C:18]=1[CH2:37][C:38](O)=[O:39].CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:26]([N:25]2[C:24]3[C:19](=[CH:20][C:21]([O:35][CH3:36])=[CH:22][CH:23]=3)[C:18]([CH2:37][C:38]([NH:1][CH2:2][CH2:3][S:4][S:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:39])=[C:17]2[CH3:16])=[O:27])=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)NCCSSCCN
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: COc1ccc2c(c1)c(CC(=O)NCCSSCCNC(=O)OC(C)(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
tert-Butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (150 mg, 0.595 mmol) was taken up in CH2C22 (10 mL) along with indomethacin (213 mg, 0.595 mmol) and EDCI (125 mg, 0.65 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and diluted with CH2Cl2. The organic layer was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography (CH2Cl2) to afford 312 mg of tert-butyl 2-(2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethyl)disulfanyl)ethylcarbamate (89% yield).
Reaction SMILES: C([O:3][C:4](=[O:49])[CH2:5][CH2:6][CH2:7][N:8]([C:17]1[CH:22]=[C:21]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:24])[CH:20]=[C:19]([C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:37])[CH:18]=1)[CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])C.[OH-].[Na+]>CO>[CH2:26]([NH:25][C:23]([C:21]1[CH:22]=[C:17]([N:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:49])=[O:3])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:18]=[C:19]([C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:37])[CH:20]=1)=[O:24])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCNC(=O)c1cc(C(=O)NCCCCCCCCCC)cc(N(CCCC(=O)OCC)CCCC(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCNC(=O)c1cc(C(=O)NCCCCCCCCCC)cc(N(CCCC(=O)O)CCCC(=O)O)c1
Yield: 52 %

Procedure:
A solution of 0.099 g (0.14 mmol) of 4-[[3,5-bis[(decylamino)carbonyl]phenyl](4-ethoxy-4-oxobutyl)amino]butanoic acid ethyl ester and 0.6 ml (0.6 mmol) of 1N NaOH in 4 ml of methanol waskept at room temperature for 17 hours. The solvent was removed at reduced pressure and the residue was dissolved in water and acidified with 0.04 mlof acetic acid. The precipitate was filtered and recrystallized from methanol to give 0.046 g (51% yield, mp 154°-156°) of 4-[[3,5-bis[(decylamino)carbonyl]phenyl](4-hydroxy-4-oxobutyl)amino]butanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Br:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12](C(OC(C)(C)C)=O)[C:11]=1[Br:29])[NH:5][C:6](=[O:8])[CH3:7].FC(F)(F)C(O)=O.C(Cl)(Cl)Cl.CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Br:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[NH:12][C:11]=1[Br:29])[NH:5][C:6](=[O:8])[CH3:7]
Reactant: COC(=O)[C@H](Cc1c(Br)n(C(=O)OC(C)(C)C)c2cc(Br)c(OC)cc12)NC(C)=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1c(Br)[nH]c2cc(Br)c(OC)cc12)NC(C)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.6 %

Procedure:
To a solution containing 18.3 mg (0.03 mmol) of (S)-(+)-N-acetyl-2,6-dibromo-1-t-butoxycarbonyl-5-methoxytryptophan methyl ester (9) dissolved in 3.2 mL of chloroform, 0.8 mL of trifluoroacetic acid was added under ice cooling to prepare a 10% solution. Furthermore, the solution was stirred at room temperature for 12 hours. The reaction solution was charged with chloroform. The organic phase was washed with saturated sodium bicarbonate water. The resulting phase was further washed with a saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain colorless oil. Column chromatography using silica gel as a carrier and a chloroform-methanol (99:1, v/v) mixed solvent as an elution solvent was performed to obtain 10.3 mg (70%) of compound (2).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][C:15]([CH3:18])([CH3:17])[O:16][C:11]=2[CH:10]=[C:9]([NH2:26])[CH:8]=1>N1C=CC=CC=1>[F:6][C:7]1[C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][C:15]([CH3:18])([CH3:17])[O:16][C:11]=2[CH:10]=[C:9]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)N=C(c2ccc(F)cc2)c2c(F)cc(N)cc2O1
Solvent: c1ccncc1
Product: CC1(C)N=C(c2ccc(F)cc2)c2c(F)cc(NS(C)(=O)=O)cc2O1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Methanesulfonylchloride (93 μL) was added dropwise to a solution of 5-fluoro-4-(4-fluorophenyl)-2.2-dimethyl-2H-1,3-benzoxazin-7-amine (a compound of Reference Example 2, 87 mg) in pyridine (2 mL), and said mixture was stirred at 40° C. overnight. The reaction mixture was concentrated in vacuo, and the residue was dissolved in chloroform. The solution was washed successively with water, 10% hydrochloric acid and brine, filtered through a column of porous diatomite [Chem Elut (trade name), Varian Inc.], and the filtrate was concentrated in vacuo. The resulted residue was purified by column chromatography on silica gel (Solvent: n-hexane/ethyl acetate=85/15 to 30/70) to give the titled compound (21 mg) as a colorless powder.
Reaction SMILES: COC(=O)CC1(C2C=CC3OCOC=3C=2)C2C(=CC=CC=2)N(CCCCC)C1=O.[O:30]1[C:34]2[CH:35]=[CH:36][C:37]([C:39]3([CH2:54][CH2:55][C:56]([O:58]C)=[O:57])[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[N:41]([CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:40]3=[O:53])=[CH:38][C:33]=2[O:32][CH2:31]1>>[O:30]1[C:34]2[CH:35]=[CH:36][C:37]([C:39]3([CH2:54][CH2:55][C:56]([OH:58])=[O:57])[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[N:41]([CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:40]3=[O:53])=[CH:38][C:33]=2[O:32][CH2:31]1
Reactant: CCCCCN1C(=O)C(CCC(=O)OC)(c2ccc3c(c2)OCO3)c2ccccc21
Agent: CCCCCN1C(=O)C(CC(=O)OC)(c2ccc3c(c2)OCO3)c2ccccc21
Product: CCCCCN1C(=O)C(CCC(=O)O)(c2ccc3c(c2)OCO3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 11E, and making non-critical variations to replace methyl[3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]acetate with methyl 3-[3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]propanoate, the title compound was obtained (92%) as a colorless solid: MS (ES−) m/z 394.2 (M−1).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:7]([OH:9])=[O:8])[C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2.[N:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[C@@H:24](O)[CH2:23]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:7]([O:9][C@@H:24]2[CH:25]3[CH2:28][CH2:29][N:22]([CH2:27][CH2:26]3)[CH2:23]2)=[O:8])[C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2
Reactant: O=C(O)C(Nc1cccc(F)c1)c1csc2ccccc12
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1cccc(F)c1)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
A mixture of 2-(benzo[b]thiophen-3-yl)-2-(3-fluorophenylamino)acetic acid (I40) (677 mg, 2.25 mmol), (R)-quinuclidin-3-ol (343 mg, 2.70 mmol), HOBT (413 mg, 2.70 mmol), and DCC (556 mg, 2.70 mmol) in THF (20 ml) was stirred at room temperature overnight. THF was evaporated, and the crude product was partitioned between EtOAc and 1M K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by flash chromatography (DCM/MeOH=98/2 to 95/5) to obtain (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-3-yl)-2-(3-fluorophenylamino)acetate (421 mg, 45.6% yield over two steps).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](B(O)O)[CH:6]=[CH:5]2.Cl[C:16]1[N:21]=[N:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=1>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:16]1[N:21]=[N:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1)[CH:6]=[CH:5]2
Reactant: OB(O)c1ccc2cc(O)ccc2c1
Reactant: COC(=O)c1ccc(Cl)nn1
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3c2)nn1

Procedure:
Followed the two step procedure described for Example 7 starting from 6-hydroxynaphthalen-2-ylboronic acid and methyl 6-chloropyridazine-3-carboxylate. 1H-NMR (DMSO-d6 500 MHz): 10.16 (s, 1H), 8.71 (d, J=5.0 Hz, 1H), 8.51-8.48 (m, 1H), 8.30-8.23 (m, 2H), 7.97-7.86 (m, 2H), 7.23-7.19 (m, 2H). MS (ESI): m/z 267.0 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[N:7]3[N:13]=[C:14]([CH3:16])[CH:15]=[C:6]3[NH:5][C:4]=2[CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[O:12])[N:7]3[N:13]=[C:14]([CH3:16])[CH:15]=[C:6]3[N:5]([CH3:17])[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2[nH]c3cc(Cl)ncc3c(=O)n2n1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc2n(C)c3cc(Cl)ncc3c(=O)n2n1
Reaction time: 24 h

Procedure:
23.5 g. of 6-chloro-2-methylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one of Example 3 are suspended in 200 ml. of dimethylformamide. 20 g. of potassium carbonate and 16 g. of methyl iodide are added. The mixture is stirred at 80° for 24 hours. After this time, the mixture is cooled and the precipitate filtered off. The crystalline product, 6-chloro-2,4-dimethylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one is washed several times with water and then recrystallized from dimethylformamide, yield: 18 g. (72%); m.p. >300°.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)CC1.[Cl:13][C:14]1[C:21]([CH3:22])=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:13][C:14]1[C:21]([CH3:22])=[C:20]([N:6]2[CH2:7][CH2:8][C@@:4]([OH:12])([CH3:1])[C@@H:5]2[CH2:9][CH3:11])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: Cc1c(F)ccc(C#N)c1Cl
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(Cl)c2C)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-ethyl-3-methylpyrrolidin-3-ol 0.5 oxalate (210 mg), 2-chloro-4-fluoro-3-methylbenzonitrile (300 mg) and lithium carbonate (215 mg), the title compound was obtained as pale-yellow oil (yield: 91.2 mg, yield: 27%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=[O:14])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)=[O:6].[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1B(O)O.C([O-])(O)=O.[Na+]>COCCOC>[F:1][C:2]([F:16])([F:15])[C:3](=[O:14])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:18]2[O:17][CH:21]=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)=[O:6]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Br)cc1
Reactant: OB(O)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: O=C(CC(=O)C(F)(F)F)c1ccc(-c2ccco2)cc1
Temperature: 25 °C
Yield: 61.3 %

Procedure:
To a stirred solution of 4,4,4-trifluoro-1-(4-bromophenyl)butane-1,3-dione (1 g, 3.39 mmol, J.Med.Chem., 1997, 40, 1347) in DME (40 mL) was added furan-2-boronic acid (0.455 g, 4.07 mmol), bis(triphenylphosphine) palladium( )chloride (0.271 g, 0.386 mmol) and saturated NaHCO3 solution (12 mL) at room temperature under nitrogen. The mixture was heated at reflux temperature for 5 hours, and cooled down to room temperature. The reaction mixture was filtered through celite, the filtrate was poured into water and the whole was extracted with ethyl acetate (30 mL×3). The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo . The residue was purified by flash chromatography eluting with hexane/ethyl acetate (3/1) to give the subtitle compound (0.586 g, 61.2% yield).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]([CH3:19])[CH2:11][CH2:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]([CH3:19])[CH2:11][CH2:12][CH:13]([OH:18])[CH2:14][CH2:15][CH2:16][CH3:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCC(=O)CCN(C)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCC(O)CCN(C)Cc1ccccc1
Yield: 94.3 %

Procedure:
Add sodium borohydride (1.29 g, 34.1 mmol) to a stirred solution of 1-(benzyl-methyl-amino)-heptan-3-one (2.41 g, 10 mmol) and methanol (45ml) at 0° C. under N2. Stir the reaction for 1 hr at 0° C. Quench the reaction with water at 0° C. and concentrate under reduced pressure. Dissolve the residue in ethyl acetate, wash with brine and dry over sodium sulfate. Filter off and concentrate to give the crude compound. Purify the compound by flash chromatography, eluting with 5% ethanol/0.5% ammonium hydroxide/chloroform to yield 2.22 g (91%) of 1-(benzyl-methyl-amino)-heptan-3-ol: mass spectrum (ion spray) m/z=236 (M+1); 1H NMR (CDCl3) δ 7.3-7.23 (m, 5H), 3.76-3.72 (m, 1H), 3.53 (dd, 2H), 2.80-2.73 (m, 1H), 2.59-2.53 (m, 1H), 2.21 (s, 3H), 1.68-1.62 (m, 1H), 1.57-1.29 (m, 7H), 0.91 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:21])=[C:4]([CH3:20])[C:5]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7][C:6]=2[CH:19]=1.[C:22](OC)(OC)(OC)[CH2:23][CH3:24].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C>[CH2:23]([C:24]1[O:21][C:3]2[C:2]([N:1]=1)=[CH:19][C:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:10][CH2:11][C:5]=1[C:4]=2[CH3:20])[CH3:22]
Reactant: CCC(OC)(OC)OC
Reactant: Cc1c(O)c(N)cc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CCc1nc2cc3c(c(C)c2o1)CCN(C(=O)OC(C)(C)C)CC3
Yield: 95 %

Procedure:
1,1-Dimethylethyl 8-amino-7-hydroxy-6-methyl-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (1.1 g) was treated with trimethyl orthopropionate (0.802 ml) and pyridinium p-toluenesulfonate (0.1 eq) in dry DMF (19 ml) at 60° C. for 1.5 hours. Volatiles were evaporated under reduced pressure and the residue was purified on silica gel (ethyl acetate/petroleum ether: 1/4) providing the title compound as white solid (1.18 g, 95% yield).
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[N:7]3[CH2:16][CH2:17][CH2:18][C@H:6]3[C:5]=12.[Cl:19]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:19][C:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[N:7]3[CH2:16][CH2:17][CH2:18][C@H:6]3[C:5]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1c2ccccc2-n2cncc2[C@@H]2CCCN12
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-n2cnc(Cl)c2[C@@H]2CCCN12

Procedure:
2.5 g (10.4 mmol) of (S)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 20 ml of dimethylformamide are stirred at room temperature for 1 hour and at 75° for 20 minutes with 1.40 g (10.4 mmol) of N-chlorosuccinimide. The solution is poured into water and extracted with chloroform. The chloroform extracts are washed several times with water, dried over magnesium sulphate and evaporated. By chromatography of the residue on a silica gel column there is obtained (S)-1-chloro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 233°-234.5°.