Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4].[Br:9][CH2:10]CC(O)=O>>[Br:9][CH2:10][CH2:2][C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4]
Reactant: CON(C)C(=O)CBr
Reactant: O=C(O)CCBr
Product: CON(C)C(=O)CCBr

Procedure:
In analogy to the procedure described in intermediate 1D, 3-bromopropionic acid gave the title compound as a light yellow liquid. MS: 195.9 (MH+, 1Br).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[Na].[C:11]1([C:17]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([OH:23])[C:18](OCC)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:11]1([C:17]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([OH:23])[C:18]([O:9][CH:3]2[CH:4]3[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2]2)=[O:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OC1CN2CCC1CC2
Reactant: CCOC(=O)C(O)(C#Cc1ccccc1)c1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: O=C(OC1CN2CCC1CC2)C(O)(C#Cc1ccccc1)c1ccccc1

Procedure:
A suspension of 3-quinuclidinol (5.1 g. 0.04 mole) and Na (~0.05 g.) in 20 ml. of toluene was heated to reflux in a flask equipped with a reflux head and stirrer. After the sodium reacted completely (about 15 minutes of refluxing), ethyl α-phenyl-α-phenylethynyl-glycolate (7.0 g., 0.025 mole) dissolved in 20 ml. of toluene was added very slowly over a two hour period. Towards the end of the addition a temperature drop of 6° was noted in the head and 10 ml. of the toluene-ethanol azeotrope slowly was distilled over. The reaction mixture was refluxed for an additional hour, and an additional 10 ml. of distillate was subsequently collected over a thirty minute period. The reaction mixture was poured on ice and acidified with 6N HCl. The toluene layer was separated and washed with several portions of 6N HCl. The combined water layers were neutralized with 10% NaOH, basified with potassium carbonate and extracted with chloroform several times. The chloroform layer was dried and subsequently stripped of volatile material in vacuo to leave a tacky solid. The material was washed with hot ether to give 5.2 g. (58%) of an off-white solid, m.p. 150°-90°. Recrystallization from benzene and then isopropanol yielded analytically pure material, m.p. 205°-8°.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:44]=[C:45]([S:50](Cl)(=[O:52])=[O:51])[CH:46]=[CH:47][C:48]=1[Cl:49]>C(#N)C>[Cl:42][C:43]1[CH:44]=[C:45]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:52])[CH:46]=[CH:47][C:48]=1[Cl:49]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(Cl)c(Cl)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 28.2 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0322 g, 0.0698 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 3,4-dichlorobenzenesulfonyl chloride (0.0305 mL, 0.195 mmol) to obtain 4-(3,4-dichlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0132 g, yield 28%).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:6]=[C:7]([F:10])[C:8]=1[F:9])[NH2:5].[N:12]([O-])=O.[Na+].[F:16][B-:17]([F:20])([F:19])[F:18].[H+]>O>[F:16][B-:17]([F:20])([F:19])[F:18].[Br:1][C:2]1[C:3]([Cl:11])=[C:4]([N+:5]#[N:12])[CH:6]=[C:7]([F:10])[C:8]=1[F:9]
Reactant: Nc1cc(F)c(F)c(Br)c1Cl
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: N#[N+]c1cc(F)c(F)c(Br)c1Cl

Procedure:
To a suspension of 3-bromo-2-chloro-4,5-difluoroaniline (30.1 g) in 42% fluoroboric acid (180 ml) with stirring vigorously was added sodium nitrite (12 g) in water (30 ml) at -9° to 1° C. for 40 minutes. After stirred for 1.5 hours, the resulting precipitate was collected by filtration and washed with 42% fluoroboric acid and then with ether to give the title compound (35.6 g) as light yellow needles, mp>300° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH:15]=O.C([O-])(=O)C.[NH2+]1CCCCC1>C1C=CC=CC=1>[F:11][C:12]1[CH:13]=[C:14]([CH:15]=[C:5]([C:4](=[O:10])[CH2:3][O:2][CH3:1])[C:6]([O:8][CH3:9])=[O:7])[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: COCC(=O)CC(=O)OC
Reactant: O=Cc1ccc(F)c(F)c1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: COCC(=O)C(=Cc1ccc(F)c(F)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 42970.2 %

Procedure:
To a solution of methyl 4-methoxyacetoacetate (84.32 g, 0.577 mol), 3,4-difluorobenzaldehyde (82 g, 0.577 mmol), and piperidinium acetate (5.86 g, 0.068 mol) in benzene (1.5 L) were added molecular sieves (400 g) and the mixture was stirred at room temperature for 48 h. The molecular sieves were removed by filtration and the solvent was evaporated from the filtrate under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (100:3) to get the product as an oil (67 g, 47%). This product was a mixture of cis and trans isomers.
Reaction SMILES: C1CO[C:3]2([C:9]3[CH:10]=[CH:11][C:12]([CH:14]([CH3:18])[C:15](N)=[O:16])=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]3[CH:19]=[CH:20][CH:21]=[CH:22][C:4]2=3)[O:2]1.Cl.C(O)(=[O:28])C>>[CH:13]1[C:8]2[CH:7]=[CH:6][C:5]3[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=3[C:3](=[O:2])[C:9]=2[CH:10]=[CH:11][C:12]=1[CH:14]([CH3:18])[C:15]([OH:16])=[O:28]
Reactant: CC(=O)O
Reactant: CC(C(N)=O)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Agent: Cl
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Yield: 70 %

Procedure:
11.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionamide is refluxed for 2 hours in 70 ml. of acetic acid and 105 ml. of concentrated hydrochloric acid. The mixture is cooled and diluted, then extracted with ether. The ethereal solution is extracted with aqueous sodium carbonate and the extract acidified and extracted with ethyl acetate to afford a 70% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid., m.p. (chloroform-hexane) 138°-139° C.; m.p. (acetone-hexane) 113°-115° C. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetamide gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5° C.
Reaction SMILES: [CH3:1][C:2]([CH:4]=[CH2:5])=[O:3].[CH:6]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:11](=[C:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:10]=2[CH:9]=[CH:8][CH:7]=1.C1C2CCC3C=CC=CC=3C(=C3CCN(C)CC3)C=2C=CC=1>C(O)C>[CH:6]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[C:11](=[C:21]3[CH2:22][CH2:23][N:24]([CH2:5][CH2:4][C:2](=[O:3])[CH3:1])[CH2:25][CH2:26]3)[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: C=CC(C)=O
Reactant: c1ccc2c(c1)CCc1ccccc1C2=C1CCNCC1
Agent: CN1CCC(=C2c3ccccc3CCc3ccccc32)CC1
Solvent: CCO
Product: CC(=O)CCN1CCC(=C2c3ccccc3CCc3ccccc32)CC1

Procedure:
5.1 g of methylvinylketone are added dropwise at 70° to a solution of 10 g of 4-(10,11-dihydro-5-dibenzo[a,d]cycloheptenylidene)piperidine [M.P. 113°-114°, produced in a manner analogous to that described in Example 4 (a), from 4-(10,11-dihydro-5-dibenzo[a,d]cycloheptenylidene)-1-methylpiperidine] in 100 cc of ethanol, and the mixture is boiled at reflux for 11/2 hours. The reaction mixture is then concentrated by evaporation in a vacuum, the residue is dissolved in acetone, the solution is made acid with hydrogen chloride in ether, is again concentrated by evaporation, and the residue is crystallized first from acetone/ether and then from isopropanol/ether. The hydrochloride of the title compound has an M.P. over 300°.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[Cl:16]Cl>>[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]([Cl:16])=[O:11]
Reactant: O=Cc1ccccc1Cl
Reactant: ClCl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=C(Cl)c1ccccc1Cl
Temperature: 160 °C

Procedure:
Phosphorus pentachloride (41.5 g, 0.2 mole) was added to 2-chlorobenzaldehyde (289.7 g, 2.0 mole, 97%). After the ensuing exotherm had subsided, the resulting red solution was heated to 160° C. A stream of chlorine was introduced through a sparge tube into the solution for a period of six hours. (Gas chromatography indicated 96.5% conversion.) The solution was then cooled and distilled under reduced pressure giving 325.4 grams of 2-chlorobenzoyl chloride which boiled at 135° to 140° C. at 16 millimeters of mercury. The yield of the desired product was 93% (98.5% pure).
Reaction SMILES: [CH2:1]([S:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25]CC)=[O:24])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].[Li+].[OH-].Cl>C(O)C.O>[CH2:1]([S:21][C:22]([CH3:28])([CH3:29])[C:23]([OH:25])=[O:24])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCSC(C)(C)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCSC(C)(C)C(=O)O
Temperature: 70 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
Ethyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenylthio)-2-methylpropanoate (209 mg, 0.50 mmol) was dissolved in ethanol (2.5 mL) and added to a solution of LiOH×H2O (168 mg, 4.0 mmol) in water (2.5 mL). The resulting turbid solution was stirred at 70° C. under inert atmosphere for 2 hours, cooled and added water (10 mL) and 1 M HCl (5 mL) to pH=1-2. The mixture was extracted three times with heptane (3×20 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to give 101 mg of the title compound as crude oil. Purification by flash chromatography on silica gel using gradient elution (starting with pure heptane and increasing stepwise to heptane:EtOAc (with 5% HOAc) 80:20) afforded 78 mg (40%) of the title compound as oil.
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CN(C=O)C>[CH2:21]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH2:11][CH3:12])=[O:9])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: CCOC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccccc1C(=O)OCC
Yield: 98.3 %

Procedure:
To a solution of ethyl salicylate (100 g, 0.602 mol) in DMF (400 ml) was added K2CO3 (150 g), followed by the dropwise addition of allyl bromide (87.5 g, 0.723 mol). The reaction mixture was then heated on a steam bath for 2 hours, the K2CO3 was removed by filtration and the reaction mixture was poured into water and extracted with ethyl acetate (3×300 ml). The organic layer was washed with brine, and dried over MgSO4, and the solvent was removed to afford 122 g (98%) of ethyl 2-(2-propenyloxy)benzoate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:20][O:21][CH:22]([O:39][CH3:40])[CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33]OS(C)(=O)=O)=[CH:28][CH:27]=1.[I-].[Na+]>CN(C)C=O.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[N:16]([CH2:33][CH2:32][C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][CH:22]([O:39][CH3:40])[O:21][CH3:20])=[CH:31][CH:30]=1)[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2cccc3cc[nH]c23)cc1
Reactant: COC(CCOc1ccc(CCOS(C)(=O)=O)cc1)OC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCOc1ccc(CCn2ccc3cccc(OCc4ccccc4)c32)cc1)OC
Reaction time: 0.17 h

Procedure:
A mixture of 4-(2-hydroxyethyl)phenol (1 g), 3-bromopropionaldehyde dimethyl acetal (1.02 mL), cesium carbonate (2.83 g) and a catalytic amount of sodium iodide in acetone (15 mL) was stirred at room temperature overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on aminopropylated silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 3-[4-(2-hydroxy-ethyl)phenyloxy]propionaldehyde dimethyl acetal (1.22 g). This material was dissolved in methylene chloride (15 mL). To the solution were added triethylamine (0.85 mL) and methanesulfonyl chloride (0.43 mL) under ice-cooling, and the mixture was stirred for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with 0.5 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 3-[4-(2-methanesulfonyloxyethyl)-phenyloxy]propionaldehyde dimethyl acetal (1.49 g). To a solution of 7-benzyloxy-1H-indole (1.04 g) in N,N-dimethyl-formamide (10 mL) was added sodium hydride (55% 0.25 g) under ice-cooling, and the mixture was stirred for 10 minutes. To the reaction mixture were added the above 3-[4-(2-methane-sulfonyloxyethyl)phenyloxy]propionaldehyde dimethyl acetal (1.49 g) and a catalytic amount of sodium iodide, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1-5/1) to give 7-benzyloxy-1-{2-[4-(3,3-dimethoxypropoxy)phenyl]ethyl}-1H-indole. This material was dissolved in tetrahydrofuran (10 mL). To the solution was added 10% palladium-carbon powder (0.5 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (1.57 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N+:5]([C:8]([N+:12]([O-:14])=[O:13])([CH3:11])CO)([O-:7])=[O:6].[O:15]1[CH2:20]CCOO1.[Al].Cl[CH2:23][Cl:24]>>[N+:5]([CH:8]([N+:12]([O-:14])=[O:13])[CH2:11][CH2:20][O:15][CH2:23][Cl:24])([O-:7])=[O:6]
Reactant: CC(CO)([N+](=O)[O-])[N+](=O)[O-]
Reactant: C1COOOC1
Reactant: ClCCl
Agent: [Al+3]
Agent: [Al]
Agent: [Cl-]
Product: O=[N+]([O-])C(CCOCCl)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
8.8 grams of aluminum chloride was added rapidly to an ice-cooled solution of 9.9 g 2,2-dinitropropanol and 2.0 g trioxane in 50 ml dry dichloromethane under a nitrogen atmosphere. The mixture was stirred 2 days at room temperature, then it was poured onto crushed ice and the mixture stirred vigorously until all aluminum precipitates had dissolved (addition of some sulfuric acid may be required). The product solution was separated, the aqueous phase extracted with dichloromethane, and the extracts washed rapidly with a near saturated, ice cold sodium hydrogen carbonate solution. After drying (MgSO4) the solvent was evaporated in vacuo to give 12.0 g (92%) crude chloromethyl dinitropropyl ether, purity 98% by gas-liquid phase chromatography (GLPC). 1H NMR (CDCl3): δ2.18, s (3H); 4.49 (2, 2H); 5.44 (s,2H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][C:23]([OH:25])=O)([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC)=O.[N-:32]=[N+:33]=[N-:34].[Na+]>CC(C)=O.O>[O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][C:23]([N:32]=[N+:33]=[N-:34])=[O:25])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)CC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of 2-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetic acid (6A: 97 mg, 0.287 mmol) in acetone (1 mL) at 0° C. was added TEA (0.064 mL, 0.459 mmol), followed by ethyl chloroformate (0.044 mL, 0.459 mmol) dropwise. The mixture was stirred at 0° C. for 30 min. A solution of NaN3 (37.3 mg, 0.573 mmol) in 0.5 mL water was added slowly and the mixture was stirred at 0° C. for another 1 h. The reaction mixture was then poured into ice-water (5 mL) and extracted with diethyl ether (3×2 mL). The combined extracts were washed successively with water (5 mL), saturated aqueous NaHCO3 (5 mL) and water (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound (104 mg, 100% yield). LCMS, [M+Na]+=386.1.
Reaction SMILES: C(OC(N1CCN(C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)CC1)=O)(C)(C)C.[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42]([CH2:45][CH2:46][CH2:47]OS(C)(=O)=O)=[CH:41][C:40]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:39]2)[CH2:36][CH2:35]1.[NH:62]([CH2:66][CH2:67][OH:68])[CH2:63][CH2:64][OH:65]>>[OH:65][CH2:64][CH2:63][N:62]([CH2:47][CH2:46][CH2:45][C:42]1[C:43](=[O:44])[N:38]([CH2:37][CH:34]2[CH2:35][CH2:36]2)[N:39]=[C:40]([C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=2)[CH:41]=1)[CH2:66][CH2:67][OH:68]
Reactant: OCCNCCO
Reactant: COc1ccc(-c2cc(CCCOS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Agent: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Product: COc1ccc(-c2cc(CCCN(CCO)CCO)c(=O)n(CC3CC3)n2)cc1F
Yield: 13.1 %

Procedure:
Following the procedure of Example 1 (10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and diethanolamine were reacted to yield the title compound as a yellow oil (yield: 13.1%).
Reaction SMILES: N[C:2]1[CH:6]=[C:5]([C:7]([CH3:10])(C)C)O[N:3]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.N[C:24]([NH2:26])=O.[CH3:27][NH:28]N>C(#N)C>[CH3:27][N:28]1[C:6]2[CH:5]=[CH:7][CH:10]=[N:3][C:2]=2[CH:24]=[N:26]1
Reactant: CC(C)(C)c1cc(N)no1
Reactant: NC(N)=O
Reactant: CNN
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC#N
Product: Cn1ncc2ncccc21
Yield: 30 %

Procedure:
In analogy to GP 4b, 3-amino-5-tert-butylisoxazole (88.45 mg, 0.63 mmol, 1.23 eq.) was treated with triphosgene (59.44 mg, 0.2 mmol, 0.4 eq.) and Intermediate 3.1 (200 mg, 0.5 mmol, 1 eq.) in 10 mL acetonitril. The crude urea was subsequently cyclized with 48 μL methylhydrazine (0.91 mmol, 1.8 eq.) in 10 mL 1-PrOH to yield 80 mg of the N1-methyl-pyrazolopyridine (0.15 mmol, 30% yield over 2 steps).
Reaction SMILES: [CH3:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[N:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[O:15][C:3]=12.[Cl:20][CH2:21][CH2:22][CH2:23][S:24][C:25]1[N:26]([CH3:41])[C:27]([C:30]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:31]=2[CH:32]=[CH:33][C:34]([CH3:40])=[N:35]3)=[N:28][N:29]=1>>[ClH:20].[CH3:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH2:21][CH2:22][CH2:23][S:24][C:25]3[N:26]([CH3:41])[C:27]([C:30]4[CH:39]=[CH:38][CH:37]=[C:36]5[C:31]=4[CH:32]=[CH:33][C:34]([CH3:40])=[N:35]5)=[N:28][N:29]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]2[N:13]=[C:14]([C:16]([F:19])([F:17])[F:18])[O:15][C:3]=12
Reactant: Cc1c2c(cc3nc(C(F)(F)F)oc13)CCNCC2
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Product: Cc1ccc2c(-c3nnc(SCCCN4CCc5cc6nc(C(F)(F)F)oc6c(C)c5CC4)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 10-methyl-2-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (120 mg) was reacted with 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline (212 mg) and was obtained as a colourless slightly hygroscopic solid (115 mg).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10](OC)=[CH:11][C:12]=3[C@@:13]32[N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)=[CH:4][CH:3]=1.[F:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1.[F:35][C:36]1([F:42])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:35][C:36]1([F:42])[CH2:41][CH2:40][N:39]([C:10]2[CH:9]=[C:8]([F:24])[C:7]3[O:6][C:5]4[C:14](=[CH:15][C:2]([C:31]5[C:26]([F:25])=[N:27][CH:28]=[CH:29][CH:30]=5)=[CH:3][CH:4]=4)[C@:13]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:12]=3[CH:11]=2)[CH2:38][CH2:37]1
Reactant: FC1(F)CCNCC1
Reactant: OB(O)c1cccnc1F
Reactant: COc1cc(F)c2c(c1)[C@@]1(COCC(N)=N1)c1cc(Br)ccc1O2
Product: NC1=N[C@@]2(COC1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(N3CCC(F)(F)CC3)cc12

Procedure:
The title compound was synthesized by steps analogous to those described in method A6 above, but using intermediate 13A, 2-fluoropyridin-3-ylboronic acid and 4,4-difluoropiperidine. MS m/z=499.0 [M+H]+. Calculated for C26H22F4N4O2: 498.17
Reaction SMILES: C(OC[N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([OH:21])[CH3:20])[C:10](=[O:22])[N:9]([CH3:23])[C:8]=2[N:7]=[C:6]1[S:24][CH2:25][CH2:26][Cl:27])C.Cl>C(O)C>[Cl:27][CH2:26][CH2:25][S:24][C:6]1[NH:5][C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([OH:21])[CH3:20])[C:10](=[O:22])[N:9]([CH3:23])[C:8]=2[N:7]=1
Reactant: CCOCn1c(SCCCl)nc2c1c(=O)n(CCCC[C@@H](C)O)c(=O)n2C
Agent: Cl
Solvent: CCO
Product: C[C@@H](O)CCCCn1c(=O)c2[nH]c(SCCCl)nc2n(C)c1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
To a stirring slurry of (R)-7-ethoxymethyl-8-(2-chloroethylsulfanyl)-1-(5-hydroxyhexyl)-3-methylxanthine (150 mg, 0.322 mmol) in ethanol (9.0 ml) was added concentrated hydrochloric acid (1.0 ml). After stirring at 80° C. for 3 hours and concentrating under reduced pressure, (R)-8-(2-chloroethylsulfanyl)-1-(5-hydroxyhexyl)-3-methylxanthine (100 mg, 86 % yield) was obtained as a beige powder.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[CH:6]12[CH2:12][CH:9]([CH:10]=[CH:11]1)[CH:8]=[CH:7]2.[O:13]=O.[Cl-].[NH4+]>C(OCC)C.O>[CH:2]12[CH2:1][CH:9]([CH:10]=[CH:11]1)[CH:8]1[CH:3]2[CH:6]([CH2:12][OH:13])[CH2:7]1
Reactant: C1=CC2C=CC1C2
Reactant: C=CC[Mg]Br
Reactant: O=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: OCC1CC2C3C=CC(C3)C12
Temperature: 140 °C
Yield: 70 %

Procedure:
Allylmagnesium bromide (50 mmoles) and bicyclo[2.2.1]hepta-2,5-diene (50 mmoles) were reacted in diethyl ether in a sealed bomb by heating for 2.25 hours at 125° C. and one hour at 140° C. The reaction product was then oxidized at 0° C. by passing gaseous oxygen through the product for about 30 minutes. The resultant product was then hydrolyzed with water followed by aqueous ammonium chloride solution and then water. After drying the product over anhydrous magnesium sulfate, the diethyl ether solvent was removed using a steam bath. The product was vacuum distilled and the fraction boiling at 95°-101° C. at 2.5-3 mm Hg was collected. This product, tricyclo[4.2.1.02,5 ]non-7-en-3-ylmethanol, was isolated in a 70 percent yield and its structure was supported by the results of nuclear magnetic resonance studies. It may be depicted as follows: ##STR1##