Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[C:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([NH:27][NH2:28])(=O)=O)=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[C:2]1([C:1]2[C:8]3[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]=3[NH:27][N:28]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: O=C1C(=Cc2ccccc2)Cc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reaction time: 18 h

Procedure:
A mixture of 2-benzylidene-indan-1-one (3.99 g), p-toluenesulphonyl hydrazine (4.0 g), p-toluenesulphonic acid hydrate (0.7 g) and ethanol (60 ml) was boiled under reflux for 1.5 hours and then left to stand for 18 hours at ambient temperature. The mixture was boiled under reflux for a further 74 hours and then left to stand at ambient temperature for 74 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (100 ml) and 2M sodium hydroxide solution (50 ml). The organic layer was separated, dried over magnesium sulfate and filtered. The magnesium sulfate was washed with ethyl acetate and filtered. The ethyl acetate filtrate was evaporated to dryness to give a solid which was recrystallized from ethanol to give 3-phenyl-1,4-dihydroindeno[1,2-c]pyrazole, m.p. 234-236° C.
Reaction SMILES: [Cl-:1].[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([C:11]2[CH:16]=[CH:15][C:14]([N+]([O-])=O)=[CH:13][C:12]=2[N+]([O-])=O)=[CH:7][CH:6]=1)(=[O:4])[NH2:3].[CH3:23][O:24]C1C=CC=CC=1N>CO>[Cl-:1].[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:24][CH3:23])=[CH:7][CH:6]=1)(=[O:4])[NH2:3]
Reactant: COc1ccccc1N
Reactant: NC(=O)c1cc[n+](-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: CO
Product: COc1ccccc1-[n+]1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-carbamoyl-1-(2,4-dinitrophenyl)-pyridinium chloride (13.6 g), 2-methoxyaniline (10 ml) and methanol (500 ml) was stirred at ambient temperature for 16 hours and the solvent was removed in vacuo. Ether containing a small amount of acetone was added and the mixture heated under reflux until solidification of the product was complete. The product was collected by filtration to give 4-carbamoyl-1-(2-methoxyphenyl)-pyridinium chloride as a yellow solid (11.5 g), m.p. 229°-230° C. (dec).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>C1COCC1.O>[CH:1]1([C:18]2([OH:20])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:11][C:10]3[C:19]2=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:3][CH2:2]1
Reactant: O=c1c2ccccc2sc2ccccc12
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: OC1(C2CC2)c2ccccc2Sc2ccccc21

Procedure:
A solution of cyclopropylmagnesium bromide in dry THF (prepared from cyclopropylbromide (18.2 g, 0.15 mol), magnesium turnings (2.9 g, 0.12 mol) and dry THF (80 ml)) was placed under an atmosphere of nitrogen. A solution of thioxanthen-9-one (12.7 g, 0.06 mol) in dry THF (70 ml) was added dropwise and when addition was complete the mixture was heated at reflux for 20 minutes. The reaction mixture was cooled on an ice-bath and saturated ammonium chloride (70 ml) was carefully added. The mixture was diluted with water (100 ml) and extracted with diethyl ether (2×100 ml). The combined organic extracts were washed with water, dried (Na2SO4) and the solvent was evaporated in vacuo to give 25.2 g of crude 9-cyclopropyl-9H-thioxanthen-9-ol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([OH:14])=[C:12]([C:15](=O)[CH3:16])[C:11]([C:18]([F:21])([F:20])[F:19])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH:22][C:23]1[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:24]=1[C:25]([NH:27][NH2:28])=[O:26]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[C:15]([NH:28][NH:27][C:25](=[O:26])[C:24]3[CH:29]=[CH:30][C:31]([OH:33])=[CH:32][C:23]=3[OH:22])[CH3:16])[C:11]([C:18]([F:20])([F:21])[F:19])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(=O)c1c(C(F)(F)F)nn(-c2ccc(C)c(C)c2)c1O
Reactant: NNC(=O)c1ccc(O)cc1O
Solvent: CCO
Product: CC(NNC(=O)c1ccc(O)cc1O)=C1C(=O)N(c2ccc(C)c(C)c2)N=C1C(F)(F)F
Yield: 87 %

Procedure:
1-(1-(3,4-Dimethylphenyl)-5-hydroxy-3-trifluoromethyl-1H-pyrazol-4-yl)-ethanone (0.173 mmol, 51.5 mg) and 2,4-dihydroxybenzoic hydrazide (0.173 mmol, 30.6 mg) were stirred in ethanol (5 ml) at 80° C. for 19 hours. After the solvent was removed by evaporation, the residue was dried with a vacuum pump and filtered with chloroform, and the filtrate was concentrated and resolved by silica gel thin layer chromatography (CHCl3/MeOH=10/1) to obtain 2,4-dihydroxybenzoic N′-(1-(1-(3,4-dimethylphenyl)-3-trifluoromethyl-5-oxo-1,5-dihydropyrazol-4-ylidene)-ethyl)-hydrazide as a pale yellow solid (67 mg, yield 87%, purity 80.7%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:21])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:28](I)[CH3:29]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:21][CH2:28][CH3:29])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccco2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccco2)c1OCC
Reaction time: 10 h

Procedure:
300 g of 4-hydroxy-1-(2-furyl)methyl-1H-pyrazolo[3,4-b]-pyridine-5-carboxylic acid ethyl ester (1.05 mol) is dissolved in 1 liter of dimethylformamide. 210 g of potassium carbonate (1.5 mol) and 233 g of ethyl iodide are added. The mixture is heated at 60° with continuous stirring for 10 hours. The excess potassium carbonate is filtered off. On addition of 500 ml of water, 4-ethoxy-1-(2-furyl)methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester precipitates and is recrystallized from methanol, yield 280 g (85%), m.p. 93°-96°.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[N:12]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](/[CH:21]=[CH:22]/[C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][C:27]([Cl:33])=[CH:28][CH:29]=4)[N:24]=3)[CH:16]=1)[CH2:11][CH2:10]2)#[N:2].C(#N)C.C(O)(=O)C.C1COCC1.C([Sn]([N:59]=[N+:60]=[N-:61])(CCCC)CCCC)CCC>>[Cl:33][C:27]1[CH:26]=[C:25]2[C:30]([CH:31]=[CH:32][C:23](/[CH:22]=[CH:21]/[C:17]3[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=3)[CH2:14][N:12]3[C:13]4[C:9](=[CH:8][CH:7]=[CH:6][C:5]=4[CH2:4][CH2:3][C:1]4[NH:61][N:60]=[N:59][N:2]=4)[CH2:10][CH2:11]3)=[N:24]2)=[CH:29][CH:28]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#CCCc1cccc2c1N(Cc1cccc(/C=C/c3ccc4ccc(Cl)cc4n3)c1)CC2
Solvent: CC(=O)O
Solvent: CC#N
Solvent: C1CCOC1
Product: Clc1ccc2ccc(/C=C/c3cccc(CN4CCc5cccc(CCc6nnn[nH]6)c54)c3)nc2c1
Reaction time: 3.5 h
Yield: 36 %

Procedure:
A solution of 7-(2-cyanoethyl)-1-[3-[2-E-(7-chloroquinolin-2-yl)ethenyl]benzyl]-2,3-dihydroindole (600 mg) in tri-n-butyltin azide (2.0 mL) was heated in an oil bath at 95° C. for 23 hours. To the cooled solution was added acetonitrile (50 mL), acetic acid (20 mL), and THF (10 mL). The resulting solution was stirred for 3.5 hours and washed with hexane. The hexane layer was separated and discarded. The resulting mixture was concentrated in vacuo and the residue chromatographed (silica gel, 2% methanol/98% methylene chloride) to provide a solid that was recrystallized (ethyl acetate/ether) to provide 235 mg (36%) of the desired product: mp 141°-144° C. 1H-NMR (DMSO-d6) 8.48 (d, J=9 Hz, 1H), 8.08 (m, 2H), 7.85 (d, J=8 Hz, 1H), 7.75 (d, J=17 Hz, 1H), 7.59 (s, 1H), 7.54 (m, 2H), 7.33 (m, 3H), 7.07 (d, J=8 Hz, 1H), 6.95 (d, J=8 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 4.49 (s, 2H), 3.28 (t, 2H, J=7 Hz), 3.17 (m, 2H), 3.08 (m, 2H), 2.83 (t, J=7 Hz, 2H); MS-FD m/e (493, p).
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=2)[CH:4]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([S:34]([C:37]2[CH:38]=[C:39]([NH2:43])[CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[CH2:30][CH2:29]1>>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([S:34]([C:37]2[CH:38]=[C:39]([NH:43][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:26])[F:1])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[C:17]([CH3:25])[CH:16]=5)=[N:6][C:7]=34)=[O:14])[CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[CH2:30][CH2:29]1
Reactant: CN1CCN(S(=O)(=O)c2cccc(N)c2)CC1
Reactant: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)N5CCN(C)CC5)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.5) and 3-(4-methyl-piperazine-1-sulfonyl)-phenylamine [CAS 436095-35-1] according to general procedure II. Yellow solid. MS (ISP) 609.3 [(M+H)+]; mp 198° C.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[CH2:16][CH2:15][CH2:14]2)=[CH2:10].[C:22]1([C:28]2[C:32]([C:33]([F:36])([F:35])[F:34])=[C:31]([C:37](F)=[O:38])[O:30][N:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[C:22]1([C:28]2[C:32]([C:33]([F:36])([F:34])[F:35])=[C:31]([C:37]([CH:16]3[CH2:15][CH2:14][C:13]4[C:18](=[CH:19][CH:20]=[C:11]([CH:9]=[CH2:10])[CH:12]=4)[C:17]3=[O:21])=[O:38])[O:30][N:29]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C=Cc1ccc2c(c1)CCCC2=O
Reactant: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)CCC(C(=O)c1onc(-c3ccccc3)c1C(F)(F)F)C2=O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 35 %

Procedure:
The LDA solution was cooled to −78° C. and 6-vinyl-3,4-dihydronaphthalen-1(2H)-one (Intermediate I-1B, 0.299 g, 1.736 mmol) dissolved in 1 mL of THF was added dropwise over a period of 2 min. The pale yellow reaction mixture was stirred at −78° C. for 20 min. Then, 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride (Intermediate 4, 0.450 g, 1.736 mmol) dissolved in 1 mL of THF was added dropwise over a period of 2 min. The reaction mixture was stirred at −78° C. for 20 min, brought to room temperature, and stirred at room temperature for 10 min. The reaction mixture was quenched with 1N hydrochloric acid (5 mL) and extracted into ethyl acetate (20 mL). The aqueous layer was re-extracted with ethyl acetate (10 mL). The combined organic layers were dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (hexane/ethyl acetate). Fractions corresponding to the product were collected and concentrated to yield 2-(3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl)-6-vinyl-3,4-dihydronaphthalen-1(2H)-one (0.25 g, 0.608 mmol, 35.0% yield) as a yellow solid. LC/MS M+1=412.1.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([OH:13])=O)[CH:8]=2)[NH:3]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:34][CH2:35][C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=O.S(=O)(=O)(O)O>CN(C=O)C.CCOC(C)=O.O>[C:38]1([C:36]2[O:13][C:11]([C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2](=[O:1])[CH2:10]4)=[N:34][CH:35]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1Cc2cc(-c3ncc(-c4ccccc4)o3)ccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.4 %

Procedure:
To a solution of 2-oxoindoline-5-carboxylic acid (1.3 g, 7.3 mmol) in DMF (50 ml) was added iPr2NEt (3.8 ml, 22 mmol), HOBt (1.2 g, 8.8 mmol), WSCI (1.7 g, 8.8 mmol) and 2-amino-1-phenylethanone hydrochloride (1.3 g, 7.3 mmol). The reaction mixture was stirred for 2 h at room temperature. The mixture was poured into H2O and EtOAc. The resulting precipitate was removed by filtration, and the filtrate was separated. The organic layer was washed with sat. NaHCO3 solution, sat. NH4Cl solution and brine, and then dried over Na2SO4. The solvent was evaporated and the residue (0.73 g) was used for the next reaction without further purification. Sulfuric acid (5 ml) was added to the residue, and the mixture was heated for 2 h at 100° C. Ice was added, and the mixture was extracted with EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4 and evaporated. The residue was crystallized from EtOH to afford 5-(5-phenyloxazol-2-yl)indolin-2-one (0.27 g, 13%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][CH:5]([CH3:7])[N:6]=1.Br[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[N:14][CH:15]=1>C(#N)C>[Cl:16][C:13]1[N:14]=[CH:15][C:10]([CH2:9][N:6]2[C:5]([CH3:7])=[CH:4][S:3][C:2]2=[N:1][CH2:9][C:10]2[CH:15]=[N:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:11][CH:12]=1
Reactant: CC1CSC(N)=N1
Reactant: Clc1ccc(CBr)cn1
Solvent: CC#N
Product: Cc1csc(=NCc2ccc(Cl)nc2)n1Cc1ccc(Cl)nc1
Temperature: 90 °C
Yield: 42.4 %

Procedure:
A mixture of 228 mg (2 mmol) of 2-amino-4-methylthiazoline and 1.03 g (5 mmol) of 5-bromomethyl-2-chloropyridine in 30 ml of acetonitrile was heated for 8 hours at 90° C. under refluxing. Then, the reaction mixture was cooled to the room temperature, and the solvent was removed under reduced pressure. The resulting residue was mixed with dichloromethane and saturated sodium hydrogen carbonate aqueous solution, and the organic layer was separated. The water layer was extracted with dichloromethane, and combined organic layer was dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel 60 (Merck Co., Ltd.) column chromatography (eluent; dichloromethane:ethyl acetate=from 9:1 to 4:1) to give 600 mg (yield; 82.1%) of crude product as yellow oil. Then, this crude product was purified again by aminopropyl-coated silica gel (Chromatorex NH-type; Fuji Silysia Chemical Ltd.) column chromatography (eluent; dichloromethane), and the eluted product was crystallized by treatment with ether-isopropyl ether to give 310 mg (yield; 42.4%) of 3-(6-chloro-3-pyridyl)methyl-2-[(6-chloro-3-pyridyl)methyl]imino-4-methyl-2,3-dihydrothiazole as milky white crystalline. 200 mg (0.548 mmol) of this product was dissolved in methanol and to this solution was added 64 mg (0.551 mmol) of fumaric acid, and the mixture was concentrated under reduced pressure. The resulting residue was treated with acetonitrile to give crystalline. The crystalline was collected by filtration and dried in vacuum to give 213 mg of fumarate of the title Compound 9.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])([O-:20])=[O:19]
Reactant: O=C(O)c1ccccc1S
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1Sc1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
In 300 ml of N,N-dimethylformamide were suspended 30.8 g of thiosalicylic acid, 28.2 g of 2-fluoronitrobenzene and 69.0 g of potassium carbonate, and the mixture was stirred at 100° C. for 2 hours. After cooling, water was added and acidified with hydrochloric acid and the crystals separated out therefrom were collected by filtration and washed with water. The crystals were then dissolved in ethyl acetate and the solution was dried over magnesium sulfate and filtered. The filtrate was concentrated and the crystals separated out therefrom were collected by filtration and dried to give 42.6 g of the title compound as yellow prisms, m.p. 169°-171° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](O)=[C:6](OC)[CH:5]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].COCCl>>[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: COc1cc(C(C)=O)ccc1O
Agent: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)c1ccccc1

Procedure:
Analogs in series 3, which contain a 3-carbon spacer, were prepared as shown in Schemes 28-37. Analogs 45a and 45b contain two identical aryl rings separated by an unsaturated 3-carbon spacer having a single carbonyl and were designed to test the importance of the length of the spacer. Analog 45a was prepared as shown in Scheme 28 following the procedures described by Masuda (Masuda et al., Phytochemistry 32(6), 1557-1560 (1993)) and by Kohler and Chadwell (Kohler et al., Org. Synth., Coll. Vol. 1 78-80 (1932)). 4-Hydroxy-3-methoxyacetophenone (44a) was reacted with potassium carbonate and chloromethyl methyl ether (18) in a substitution reaction to give compound 44j. The formation of the product was verified by proton NMR by the appearance of signals at 3.33 ppm and 5.12 ppm for the protons of the protecting group. Compound 1j, prepared as shown in Scheme 12, was reacted with compound 44j and barium hydroxide in an aldol reaction to give compound 45j. The formation of the product was verified by proton NMR by the appearance of a pair of doublets in the aromatic region with J values of 15.5 Hz for the alkene protons on the spacer. Also observed in the proton NMR was the loss of a signal at 2.38 ppm for the methyl protons of the starting acetophenone (44j) and the loss of a signal at 9.75 ppm for the aldehyde proton of the starting benzaldehyde (1j). Compound 45j was then reacted with a catalytic amount of concentrated hydrochloric acid to give the phenol, analog 45a. The formation of the product was verified by proton NMR by the appearance of signals at 6.00 ppm and 6.19 ppm for the phenolic protons. Also observed in the proton NMR was the loss of signals at 3.50 ppm, 5.25 ppm
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Cl)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:15]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH2:8])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1N
Reactant: ClCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccccc1NCC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
3.24 g of ortho-phenylenediamine was dissolved in 30 ml of dimethylformamide, to the solution were added 2.07 g of potassium carbonate and 1.52 g of cinnamyl chloride, and the mixture was stirred overnight at a room temperature. After adding 100 ml of water, the reaction mixture was extracted twice with 100 ml and 50 ml of chloroform, and the extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated to remove the solvent under a reduced pressure. The resulting residue was applied to a silica gel column and eluted with chloroform, to obtain 2.0 g of the title compound as light brown crystals.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]([CH2:34][CH3:35])([OH:33])[CH2:31][CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])[CH:12]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:40])=[O:4])[CH:8]=[N:9][CH:10]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]([CH2:31][CH3:32])([OH:33])[CH2:34][CH3:35])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)OC)c3)c(C)c2)cc1C)CC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)O)c3)c(C)c2)cc1C)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.098 mL, 0.098 mmol) was added to a solution of [5-(4-{1-ethyl-1-[4-(3-ethyl-3-hydroxy-1-pentynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 151-(2); 16.7 mg, 0.033 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (7.8 mg, 47%).
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:11]([N:13]2[CH2:17][CH2:16][C@@H:15]([CH2:18][O:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:14]2)=[O:12])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3].FC(F)(F)C([O-])=O.N>O>[NH:1]([C:5]1[S:6][C:7]([C:11]([N:13]2[CH2:17][CH2:16][C@@H:15]([CH2:18][O:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:14]2)=[O:12])=[C:8]([CH3:10])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: Cc1nc(NC(=N)N)sc1C(=O)N1CC[C@@H](COCC(=O)OC(C)(C)C)C1
Agent: N
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: Cc1nc(NC(=N)N)sc1C(=O)N1CC[C@@H](COCC(=O)O)C1
Yield: 82.3 %

Procedure:
140 mg of tert.-butyl (R)-[1-(2-guanidino-4-methyl-thiazole-5-carbonyl)-pyrrolidin-3-ylmethoxy]-acetate are reacted as in Example 6. The crude trifluoroacetate is dissolved in water, neutralized with dilute NH3, purified on Kieselgel 100 C18 -reverse phase and lyophilized from water. There are obtained 99 mg of (R)-[1-(2-guanidino-4-methyl-thiazole-5-carbonyl)-pyrrolidin-3-ylmethoxy]-acetic acid, m.p. 136° C. (sintering), [α]D =+14.2°, (H2O, c=0.5), MS: 342 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.Cl.[NH2:17]O.[OH-].[Na+]>O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C:10](=[O:11])[O:12][N:17]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccc(I)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1CC(c2ccc(I)cc2)=NO1
Reaction time: 1 h
Yield: 74.1 %

Procedure:
Ethyl 3-(4-iodophenyl)-3-oxopropanoate (3.0 g, 9.4 mmol) was added slowly to a solution of hydroxylamine hydrochloride (660 mg, 9.44 mmol), NaOH (795 mg, 19.8 mmol), and water (12 mL) at 0° C. The reaction mixture was kept at 0° C. for 1 h. The precipitate was collected by filtration, rinsed with water, and dried under vacuum to afford the title compound as white solid (2.0 g, 64%). 1H NMR (CDCl3, 400 MHz): δ 7.84 (d, 2H), 7.40 (d, 2H), 3.78 (s, 2H). 13C NMR (acetone-d6, 100 MHz): δ 176.1, 164.6, 139.1, 129.2, 129.0, 98.6, 34.4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][C:23]([NH2:26])([CH3:25])[CH3:24])[C:20]([CH2:27][O:28][CH2:29][CH3:30])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]([N:34]=[C:35]=[O:36])([CH3:33])[CH3:32]>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][C:23]([NH:26][C:35]([NH:34][CH:31]([CH3:33])[CH3:32])=[O:36])([CH3:24])[CH3:25])[C:20]([CH2:27][O:28][CH2:29][CH3:30])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)N
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
2-(7-Benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethylamine (1.88 g, 4.65 mmol) and dichloromethane (50 mL) were combined and cooled to 0° C. Isopropyl isocyanate (0.50 mL, 5.11 mmol) was added and the reaction was stirred for 30 minutes. The cooling bath was removed and the reaction was stirred overnight. The volatiles were removed under reduced pressure to give a brown solid. The solid was purified by flash column chromatography on silica gel (eluting with 6% methanol in dichloromethane) to yield 1.96 g of N-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-N′-isopropylurea as a cream colored solid.