Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:4][C@@H:3]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>C(O)C.C(OCC)(=O)C>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][C@@H:2]([F:1])[C@H:3]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@@H]1F
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2N)CC[C@H]1F
Yield: 99 %

Procedure:
Following method 1, tert-butyl (3S,4S)-4-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate in ethanol and ethyl acetate (1:1, 0.1 M solution) was reduced yielding tert-butyl (3R,4R)-1-(3-aminopyridin-4-yl)-4-fluoropiperidin-3-ylcarbamate, (>99%). LCMS (m/z): 311.2 (MH+); LC Rt=2.14 min.
Reaction SMILES: Cl[C:2]1[N:3]2[C:8]([CH:9]=[CH:10][CH:11]=1)=[C:7]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19])[C:6](=[O:20])[CH:5]=[CH:4]2.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:7]1[C:6](=[O:20])[CH:5]=[CH:4][N:3]2[C:8]=1[CH:9]=[CH:10][CH:11]=[C:2]2[N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=c1ccn2c(Cl)cccc2c1-c1c(Cl)cccc1Cl
Reactant: C1CCNC1
Product: O=c1ccn2c(N3CCCC3)cccc2c1-c1c(Cl)cccc1Cl
Temperature: 90 °C

Procedure:
A mixture of 6-chloro-1-(2,6-dichlorophenyl)-2H-quinolizin-2-one (Example 1, 15 mg) in pyrrolidine (0.5 mL) was heated to 90° C. for 2½ hr and then concentrated. The residue was purified by silica gel (methylene chloride/acetone=3/1) to give title compound as a yellow solid (12 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][OH:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:18][CH2:17][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](COS(C)(=O)=O)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of N-tert-butoxycarbonyl-D-Phenylalaninol (754 mg) and TEA (0.5 ml) in dichloromethane was added methanesulfonyl chloride (0.28 ml) at 0°~5° C. The reaction mixture was stirred at 0°~5° C. for 30 min, quenched with water, and extracted with dichloromethane. The organic layer was washed with 10% citric acid and sat. NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane=1/2 to afford the product (931 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]#[N:9])[CH2:4][CH2:3]1.N1C(C)=CC=CC=1C.[Si:18](OS(C(F)(F)F)(=O)=O)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>ClCCl>[C:21]([Si:18]([CH3:20])([CH3:19])[O:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]#[N:9])[CH2:4][CH2:3]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: N#CC1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OC1CCC(C#N)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
6.4 g (51.1 mmol) of 4-hydroxy-cyclohexanecarbonitrile (121) were dissolved in 120 mL of dichloromethane, cooled to 0° C. and 14.9 mL (13.7 g, 128 mmol) of 2,6-lutidine and 15.4 mL (14.9 g, 56.2 mmol) of tert-butyldimethylsilyltrifluoromethanesulfonate were added. The reaction mixture was stirred for 16 h at room temperature, then additional 5.0 mL of tert-butyldimethylsilyltrifluoromethanesulfonate were added and stirring continued for 1 h. The reaction mixture was diluted with 100 mL of dichloromethane and washed with 100 mL of water, 80 mL of saturated aqueous sodium bicarbonate solution and 50 mL of brine. The organic phase was dried over magnesium sulphate, filtered, concentrated in vacuo and purified by silica gel chromatography (heptanes:ethyl acetate) to give 9.76 g of the desired product. Rt=0.95 min (Method 18). Detected mass: 240.1 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.Cl[CH2:18]Cl.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[OH:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([O:7][CH3:18])=[O:6])=[CH:3][C:2]=1[I:1]
Reactant: O=C(O)c1ccc(O)c(I)c1
Reactant: ClCCl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(O)c(I)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
A solution of 3-iodo-4-Hydroxybenzoic acid (7.25 g, 27.4 mmol) and sulfuric acid (1.9 ml, 36 mmol) in methanol is stirred at 55° C. for 6 hours. TLC (dichloromethane): 30% of starting material. The solution is stirred 12 h at room temperature. TLC (dichloromethane): 10% of starting material and stirred at 55° C. for 2 h. After cooling, ethyl acetate (200 mL) was added and the mixture was adjusted to pH 3 using sodium bicarbonate. The organic layer was washed two times with water and then dried over MgSO4. Filtration and rotary evaporation at 40° C. afforded a white solid. The solid was triturated with hexane, filtered off and dried under reduced pressure. M=4.47 g. Yield: 59%.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C@H:8]1[C:16]2[C:11](=[C:12]([C:17]3[N:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([C:32]#[N:33])[CH:23]=4)[O:19][N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)(=[O:3])[CH3:2].[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][N:7]([C@H:8]1[C:16]2[C:11](=[C:12]([C:17]3[N:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([C:32]#[N:33])[CH:23]=4)[O:19][N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[S:35]([CH3:34])(=[O:37])=[O:36])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCN[C@@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCN([C@@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 109.6 %

Procedure:
Prepared using General Procedure 12. To a stirred solution of (R)-2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)ethyl acetate (20 mg, 0.04 mmol) in DCM (1 mL) was added methanesulfonyl chloride (10.2 mg, 0.08 mmol) followed by triethylamine (9.08 mg, 0.08 mmol)) at 0° C. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with water (1 mL), extracted with DCM (2×1 mL), and the combined extracts were dried over MgSO4. The organic layers were concentrated to give 23 mg (50%) of (R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)methylsulfonamido)ethyl acetate which was used in the next step without purification. LCMS-ESI (m/z) calculated for C26H28N4O6S: 524.2. found 547.1 [M+Na]+, tR=3.82 min.
Reaction SMILES: CN(C)C=O.[C:6]([O:10][C:11]1[CH:12]=[C:13]([C:17]2[C:18]3[CH2:31][CH2:30][NH:29][C:19]=3[N:20]=[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:22]=2)[CH:14]=[CH:15][CH:16]=1)([CH3:9])([CH3:8])[CH3:7].[H-].[Na+].[S:34](Cl)([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)(=[O:36])=[O:35]>O>[C:6]([O:10][C:11]1[CH:12]=[C:13]([C:17]2[C:18]3[CH2:31][CH2:30][N:29]([S:34]([C:37]4[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=4)(=[O:36])=[O:35])[C:19]=3[N:20]=[C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:22]=2)[CH:14]=[CH:15][CH:16]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCc3c(-c4cccc(OC(C)(C)C)c4)nc(N4CCOCC4)nc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a dimethylformamide solution (1 ml) of 4-(3-t-butoxyphenyl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (11 mg), sodium hydride (60% mineral oil dispersion, 1.5 mg, 1.2 equivalents) was added with ice cooling, followed by stirring at room temperature for 30 minutes. With ice cooling, tosyl chloride (6.6 mg, 1.1 equivalents) was added, followed by stirring at room temperature for 10 hours. To the reaction mixture, water (5 ml) was added, followed by extraction with ethyl acetate (5 ml×2). The organic layer was washed with aqueous ammonium chloride solution and brine, followed by drying over sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative TLC (n-hexane/ethyl acetate=2/1), to obtain the desired compound as a colorless powder (11 mg, 70%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([OH:10])[CH:7]=2)[O:2]1.Br[CH:15]([CH2:20][CH2:21][CH2:22][Br:23])[C:16]([O:18][CH3:19])=[O:17]>>[Br:23][CH2:22][CH2:21][CH2:20][CH:15]([O:10][C:6]1[CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]2=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12])[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(Br)CCCBr
Reactant: O=[N+]([O-])c1cc2c(cc1O)OCO2
Product: COC(=O)C(CCCBr)Oc1cc2c(cc1[N+](=O)[O-])OCO2

Procedure:
In a manner similar to that of Reference Example 5, 4,5-methylenedioxy-2-nitrophenol was allowed to react with methyl 2,5-dibromovalerate to give methyl 5-bromo-2-(4,5-methylenedioxy-2-nitrophenoxy)valerate, which was then allowed to react, in a manner similar to that of Reference Example 8, with 1-(4-fluorophenyl)piperazine to obtain methyl 5-[4-(4-fluorophenyl)-1-piperazinyl]-2-(4,5-methylenedioxy-2-nitrophenoxy)valerate as crystals, m.p. 98°-99° C. The overall yield was 15.6%.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].C(N(CC)CC)C.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>ClCCl>[N:13]1([S:1]([Cl:5])(=[O:3])=[O:2])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=S(=O)(Cl)Cl
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Cl)N1CCOCC1
Reaction time: 2 h
Yield: 73.8 %

Procedure:
Under an ice-cooled, dichloromethane solution containing 12 ml (0.15 mol) of sulfurylchloride was cooled, dichloromethane solution containing 21 ml (0.15 mol) of triethylamine and 13 ml (0.15 mol) of morpholine was added dropwise over a period one hour. After stirring for 2 hour, the reaction mixture was washed cooled-0.1N hydrochloric acid and saturated brine and then was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue thus obtained was chromatographed on silica gel column for purification, whereby 20.54 g of morpholine-4-sulfonylchloride was obtained.
Reaction SMILES: COCCOC[O:7][C:8]1[CH:9]=[C:10]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][O:41]C3CCCCO3)=[CH:33][CH:32]=2)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24]C3CCCCO3)=[CH:16][CH:15]=2)[CH:13]=1.Cl>CO.O>[OH:41][CH2:40][CH2:39][CH2:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([C:10]2[CH:9]=[C:8]([OH:7])[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:16][CH:15]=3)[CH:11]=2)=[CH:36][CH:35]=1
Reactant: COCCOCOc1cc(-c2ccc(OCCCOC3CCCCO3)cc2)cc(-c2ccc(OCCCOC3CCCCO3)cc2)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: OCCCOc1ccc(-c2cc(O)cc(-c3ccc(OCCCO)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.90 g (12.1 mmol) 3′-[5′-(2-methoxy-ethoxymethoxy)-[1,1′:3′,1″-terphenyl]-4,4″-diylbis(oxy-3,1-propanediyloxy)]bis(tetrahydro-2H-pyrane) are dissolved in 60 ml methanol, and, after addition of 9 ml conc. hydrochloric acid, stirred overnight at RT. The mixture is diluted with water and extracted three times with MTB ether. The combined organic layers are washed with sat. aq. sodium chloride solution and dried over sodium sulfate. 4,4″-Bis-(3-hydroxy-propoxy)-[1,1′;3′,1″]terphenyl-5′-ol is obtained as a yellow oil.
Reaction SMILES: Cl.[NH2:2]N.[OH-].[Na+].C[N:7]([CH:9]=[C:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]1=O)C>CO>[NH:2]1[C:11]2[CH2:12][CH2:13][CH2:14][C:15](=[O:16])[C:10]=2[CH:9]=[N:7]1
Reactant: CN(C)C=C1C(=O)CCCC1=O
Reactant: NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCCc2[nH]ncc21
Yield: 87.6 %

Procedure:
According to Scheme 1 Step 2: A solution of hydrazine hydrochloride (41.9 mmol, 2.87 g), NaOH (6 M, 42 mmol, 7.0 mL) in MeOH (100 mL) was added, at 0° C., to a solution of 2-((dimethylamino)methylene)cyclohexane-1,3-dione (41.9 mmol, 7.00 g) and the reaction mixture was stirred under reflux for 3 hours. After evaporation, water was added and the aqueous phase was extracted with AcOEt at 50° C. The organic phase was dried over Na2SO4, was filtered and was concentrated under reduced pressure to yield 6,7-dihydro-1H-indazol-4(5H)-one (36.7 mmol, 5.00 g, 88%) as a yellow powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[OH-].[Na+].[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:15]=1)=[O:13].O>CN(C=O)C>[C:22]1([CH2:21][O:20][C:17]2[CH:16]=[CH:15][C:14]([C:12](=[O:13])[CH:11]=[CH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:19][CH:18]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=Cc1ccccn1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(C=Cc1ccccn1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.8 %

Procedure:
A sample of a 42.4 g (0.4 mole) of pyridine-2-carboxaldehyde was added to a solution of 83.6 mL of 10% sodium hydroxide and 100 mL of DMF at 10° C. Then a solution of 47.2 g (0.21 mole) of 4-benzyloxyacetophenone in 300 mL of DMF was added slowly over a period of 1 hr to the mixture keeping the temperature of the reaction mixture at 5°-13° C. After 1.5 hr, the reaction mixture was allowed to warm to room temperature. Water was added, and the product precipitated out as a solid. The solid was crystallized from 95% ethanol to give 48.2 g (73% yield) of the title compound as a yellow solid, mp=131°-134° C. An additional 3.3 g (5% yield) of the product was obtained from the mother liquor, mp=131°-134° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13][C:14]1[C:19]([C:20]2[CH:25]=[C:24](S(C)=O)[N:23]=[CH:22][N:21]=2)=[N:18][CH:17]=[CH:16][N:15]=1.[NH3:29].CC(O)C>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13][C:14]1[C:19]([C:20]2[N:21]=[CH:22][N:23]=[C:24]([NH2:29])[CH:25]=2)=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: N
Reactant: COc1cc(OC)c(Cl)c(Nc2nccnc2-c2cc(S(C)=O)ncn2)c1Cl
Solvent: CC(C)O
Product: COc1cc(OC)c(Cl)c(Nc2nccnc2-c2cc(N)ncn2)c1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
(2,6-Dichloro-3,5-dimethoxy-phenyl)-[3-(6-methanesulfinyl-pyrimidin-4-yl)-pyrazin-2-yl]-amine 7 (200 mg, 0.414 mmol) is suspended in ammonia/2-propanol solution (2M, 3 mL, 6 mmol) in a sealed tube. After stirring at 100° C. overnight, the reaction is cooled to room temperature. The light yellow solid is collected by filtration, washed with water and 2-propanol, and dried to afford the desired product (6-[3-(2,6-dichloro-3,5-dimethoxy-phenylamino)-pyrazin-2-yl]-pyrimidin-4-ylamine (40). The filtrate can be used for further purification to give an additional product.
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH2:17][CH2:18][C:19](Cl)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([CH2:17][CH2:18][C:19]([N:9]2[CH2:10][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8]2)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(C2CNC2)cc1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)N1CC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.3 %

Procedure:
A solution of 3-phenylazetidine (266 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 3-phenylpropionyl chloride (421.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing 3-phenyl-1-(3-phenylazetidin-1-yl)propan-1-one are collected and the solvent is removed in vacuo to give 421 mg of colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH:12](=[N:1]/[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11])\[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc2c1COC2=O
Reactant: O=Cc1ccccc1
Solvent: CO
Product: O=C1OCc2c(/N=C/c3ccccc3)cccc21
Yield: 63.2 %

Procedure:
4-aminoisobenzofuran-1(3H)-one (600 mg, 4 mmol), benzaldehyde (427 mg, 4 mmol) were added to methanol (20 mL) and stirred under reflux overnight, then the mixture was evaporated under reduced pressure and the residue was dried in vacuum. 600 mg of crude product (E)-4-(benzylideneamino)isobenzofuran-1(3H)-one was obtained which was used for the next synthetic step without further purification.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH3:9][O:10][C:11]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:24])[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:24][C:16]([C:7]1[CH:8]=[C:1]([OH:2])[CH:3]=[CH:4][C:5]=1[OH:6])([CH2:15][CH2:14][CH2:13][C:11]([O:10][CH3:9])=[O:12])[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: Oc1ccc(O)cc1
Reactant: COC(=O)CCC=C(C)CCCC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)CCCC(C)(CCCC(=O)OC)c1cc(O)ccc1O

Procedure:
5.5 Parts of hydroquinone, 22,8 parts of 1,7-dimethoxycarbonyl-4-methylhept-3-ene and 1.0 parts of p-toluene sulphonic acid, are heated on a steam-bath for 3 days. After dilution with ether the reaction mixture is washed with sodium bicarbonate solution, water, evaporated and distilled to give dimethyl 5-methyl-5-(2,5-dihydroxyphenyl)-azelate, [formula (135)], b0.1 260°-269° C. with the following percentage composition by weight.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=1)=[O:25].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=2)=[O:25])[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: O=C(CBr)c1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 3.29 g (16.4 mmol) 4-benzyloxy-1H-pyridin-2-one in 16 mL DMF is added 13.3 g (40.9 mmol) cesium carbonate and the mixture is stirred 15 min at RT. Then 3.75 g (16.4 mmol) 2-bromo-1-(4-hydroxymethyl-phenyl)-ethanone (preparation 15a) is added and is stirred 2 h at RT. Water is added, the precipitate is collected, washed with water and dried.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:28]([NH:35][C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)=[O:2])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)NCc2ccccc2)c1
Temperature: 25 °C

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (22.6 mg) and benzylamine (7.5 μL) were mixed in CH2Cl2 under nitrogen. Triethylamine (26 μL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (approx. 18 mg) and 4-dimethylaminopyridine (approx. 1 mg) were added and the mixture stirred at room temperature. After approximately 1.5 h another portion of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.5 mg) was added. One hour later the mixture was eluted directly on silica gel (95:5 CH2Cl2:MeOH) to yield 17.8 mg of the title compound. 1H NMR (500 MHz, CDCl3, partial): δ 8.46 (br s, 1H); 8.38 (d, J=5.2 Hz, 1H); 7.94 (s, 1H); 7.81 (d, J=7.7 Hz); 7.67 (m, 1H); 7.59 (d, J=7.8 Hz, 1H); 7.44 (t, J=7.7 Hz, 1H); 6.78 (d, J=5.5 Hz, 1H); 6.44 (s, 1H); 5.77 (br s, 1H); 5.24 (br s, 1H); 4.65 (m, 2H); 1.65 (d, J=6.8 Hz, 3H). Mass Spectrum (ESI): m/e 449.2 (M+1).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][C@@H:14]1[CH2:18][CH2:17][C@H:16]([NH:19][C:20]2[C:21]3[N:22]([CH:29]=[CH:30][CH:31]=3)[N:23]=[CH:24][C:25]=2[C:26]([NH2:28])=[O:27])[C:15]1([CH3:33])[CH3:32]>ClCCl>[CH3:8][S:9]([O:13][C@H:14]1[CH2:18][CH2:17][C@@H:16]([NH:19][C:20]2[C:21]3[N:22]([CH:29]=[CH:30][CH:31]=3)[N:23]=[CH:24][C:25]=2[C:26](=[O:27])[NH2:28])[C:15]1([CH3:33])[CH3:32])(=[O:11])=[O:10]
Reactant: CC1(C)[C@H](O)CC[C@@H]1Nc1c(C(N)=O)cnn2cccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)[C@@H](OS(C)(=O)=O)CC[C@H]1Nc1c(C(N)=O)cnn2cccc12
Reaction time: 15 h

Procedure:
Triethylamine (0.131 mL, 0.936 mmol) and methanesulfonyl chloride (0.029 mL, 0.375 mmol) were added to a solution of 4-((cis-3-hydroxy-2,2-dimethylcyclopentyl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (90 mg, 0.312 mmol, from Intermediate 16) in dichloromethane (5 mL). After 15 h at room temperature, the mixture was diluted with dichloromethane (60 mL), washed with saturated sodium bicarbonate (5 mL), brine (5 mL), dried (MgSO4), filtered and concentrated to give crude cis-3-(3-carbamoylpyrrolo[1,2-b]pyridazin-4-ylamino)-2,2-dimethylcyclopentyl methanesulfonate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[C:8]([OH:15])[C:7]=1[CH2:16][CH2:17][CH3:18].[CH2:20]([CH:22]1[O:24][CH2:23]1)Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[C:8]([O:15][CH2:20][CH:22]2[CH2:23][O:24]2)[C:7]=1[CH2:16][CH2:17][CH3:18]
Reactant: BrCC1CO1
Reactant: CCCc1c(OCC(=O)OC)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCC(=O)OC)ccc(C(C)=O)c1OCC1CO1

Procedure:
A mixture of 7.75 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid methyl ester, 7.5 ml of epibromohydrin, 4.8 g of potassium iodide and 6.0 g of anhydrous potassium carbonate in 80 ml of anhydrous acetone and 40 ml of anhydrous dimethylformamide was stirred at reflux for 50 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was purified by high pressure liquid chromatography (HPLC) using 10% ethyl acetate-hexane to yield 6.16 g of [4-acetyl-3-(oxiranylmethoxy)-2-propylphenoxy]acetic acid methyl ester.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][C:12]([OH:14])=[O:13])[CH:2]=[CH2:3].Cl.[C:22](=O)(O)[O-].[Na+]>CO>[CH3:22][O:13][C:12](=[O:14])[CH2:11][N:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH:2]=[CH2:3]
Reactant: O=C([O-])O
Reactant: C=CCc1ccccc1N(CC(=O)O)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCc1ccccc1N(CC(=O)OC)c1ccccc1

Procedure:
A solution of 0.06 mol of N-(2-allylphenyl)phenylglycine, prepared as described by A. Padwa, H. L. Gingrich, and R. Lim in J. Org. Chem.,1982, 47, 2447-2456, and 0.066 mol of HCl in 100 mL of CH3OH is stirred at reflux for 8 hours. The solution is then cooled and treated with 0.066 mol of sodium bicarbonate. The solvent is removed by rotary evaporator, and the residue is dissolved in diethyl ether, filtered, dried over MgSO4, and filtered. The solvent is removed by rotary evaporator to give N-(2-allylphenyl)phenylglycine methyl ester.