Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH2:18]Cl)[CH:12]=2)[CH:3]=1.[CH3:20][NH2:21].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C(O)C.CO>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([CH2:18][NH:21][CH3:20])[CH:12]=2)[CH:3]=1
Reactant: CN
Reactant: N#Cc1ccc(Cl)cc1Oc1ccc(F)c(CCl)c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCO
Product: CNCc1cc(Oc2cc(Cl)ccc2C#N)ccc1F
Temperature: 25 °C
Reaction time: 240 h
Yield: 104.6 %

Procedure:
To a solution of 4-chloro-2-(3-chloromethyl-4-fluorophenoxy)-benzonitrile (0.14 g, 0.47 mmol) in ethanol (15 mL) was added methylamine (33% in ethanol, 4.0 mL, 32 mmol), and the reaction mixture stirred for 10 days at ambient temperature. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and a solution of fumaric acid (50 mg, 0.43 mmol) in methanol (3 mL) was added. After the solvent was removed in vacuo, the residue was triturated with diethyl ether overnight, collected by filtration, and dried to give 4-chloro-2-(4-fluoro-3-methylaminomethyl-phenoxy)-benzonitrile fumarate (183 mg, 95%) as a white solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[CH:2]2[CH:3]=[CH:4][CH2:5]1.[OH2:11].[OH2:12].C[N+]([O-])(C)C.[O-][Si]([O-])=O.[Mg+2].S([O-])(O)=O.[Na+]>ClCCl.C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.[Os](=O)(=O)(=O)=O.N1C=CC=CC=1.CC(C)=O.O>[CH:1]12[CH2:10][CH:7]([CH:8]([OH:12])[CH:9]1[OH:11])[CH:6]1[CH:2]2[CH:3]=[CH:4][CH2:5]1
Reactant: O
Reactant: C1=CC2C3C=CC(C3)C2C1
Agent: O=[Os](=O)(=O)=O
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: OC1C(O)C2CC1C1C=CCC12
Reaction time: 72 h
Yield: 19.6 %

Procedure:
A slurry of tricyclo[5.2.1.02,6]deca-3,8-diene (26.5 g, 0.2 mol), trimethylamine N-oxide dihydrate (22.3 g, 0.2 mol) and osmium tetroxide (2.5 wt % solution in 2-methyl-2-propanol, 2 □l) in dichloromethane (200 ml) was stirred for 18 h. A further portion of osmium tetroxide (2.5 wt % solution in 2-methyl-2-propanol, ca. 2 □l) was added, water (25 ml) and acetone (50 ml) was added and the reaction mixture was stirred for a further 72 h. Pyridine (0.5 ml) and tetrabutylammonium acetate (0.5 g) were added. Florisil (10 g) and aqueous sodium hydrogensulfite solution was added and the reaction mixture was stirred for 20 min. The reaction mixture was filtered and the product was extracted with dichloromethane (3 times). The combined organic extracts were washed with water, brine and then concentrated to give an oil. The crude oil was purified by flash chromatography eluting with ethyl acetate:hexane (10:90) and then ethyl acetate, to give a waxy solid (6.5 g, 19%).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]2[N:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=2)=[O:10])[CH2:3][CH2:2]1.[N:18]1([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH:1]1([CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]2[N:12]=[N:13][C:14]([N:21]3[CH2:22][CH2:23][N:18]([C:24](=[O:25])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:35])([F:33])[F:34])[CH2:19][CH2:20]3)=[CH:15][CH:16]=2)=[O:10])[CH2:3][CH2:2]1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(NCCCCC1CC1)c1ccc(Cl)nn1
Product: O=C(NCCCCC1CC1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (4-cyclopropylbutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (3-cyclobutylpopyl)amide to react with piperazin-1-yl-(2-trifluoromethyl-phenyl)methanone, the title compound was obtained as a white powder (21% yield). 1H NMR (300 MHz, CDCl3) δ 8.03, 7.86, 7.72, 7.58, 7.34, 6.98, 4.05, 3.89-3.62, 3.48-3.31, 1.64-1.41, 1.20, 0.60, 0.39-0.30, −0.04. 13C NMR (75 MHz, CDCl3) δ 167.6, 162.9, 160.0, 145.4, 134.3, 132.4, 129.5, 127.2, 126.9, 126.7, 125.4, 121.8, 112.6, 46.4, 44.6, 44.4, 41.2, 39.5, 34.4, 29.4, 27.0, 10.7, 4.4. MS (ES+) m/z 476.1 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[C:12]([O:16][C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(C1C=CC(Br)=CC=1)CC.C[Si](C#C)(C)C.Cl>O>[C:12]([O:16][C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:11]#[C:10][C:7]2[CH:6]=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:9][CH:8]=2)=[CH:22][CH:21]=1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: C#Cc1ccc(CCC)cc1
Reactant: CC(C)(C)OC(=O)Oc1ccc(Br)cc1
Agent: C#C[Si](C)(C)C
Agent: CCCc1ccc(Br)cc1
Agent: Cl
Solvent: O
Product: CCCc1ccc(C#Cc2ccc(OC(=O)OC(C)(C)C)cc2)cc1

Procedure:
The reaction was carried out in the same manner as in the step (i), except for using 4-n-propylphenylacetylene synthesized in the step (ii) and 1-(tert-butoxycarbonyloxy)-4-bromobenzene synthesized in the Example 4 instead of 1-n-propyl-4-bromobenzene and trimethylsilylacetylene, respectively. After completion of the reaction, the reaction solution was poured into an iced water, and the resultant solution was acidified by adding hydrochloric acid. After the resultant solid was collected by filtration, the collected solid was washed with water, dried, and recrystallized successively from hexane and ethanol to provide 4.1 g (12.1 mmol) of 1-[4-(tert-butoxycarbonyloxy)phenyl]-2-(4-n-propylphenyl)acetylene.
Reaction SMILES: O.[NH:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[CH3:15][C:16]([N+:22]([O-:24])=[O:23])([CH3:21])[CH2:17][CH2:18][CH:19]=[O:20]>C(O)(C)C>[OH:20][C:19](=[C:8]1[NH:2][C:3](=[O:4])[NH:5][C:6]1=[O:7])[CH2:18][CH2:17][C:16]([CH3:21])([N+:22]([O-:24])=[O:23])[CH3:15]
Reactant: O=C1CNC(=O)N1
Reactant: CC(C)(CCC=O)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(CCC(O)=C1NC(=O)NC1=O)[N+](=O)[O-]
Temperature: 85 °C
Yield: 80.2 %

Procedure:
Water (70 ml) was added to hydantoin (20.8 g, 210 mmol) and sodium carbonate (7.2 g, 70 mmol) and the mixture was dissolved by heating to 85° C. 4-Methyl-4-nitropentanal (20.0 g, 140 mmol) was dissolved in isopropyl alcohol (130 ml) and added. The mixture was refluxed under heating for 2 h and isopropyl alcohol was evaporated under reduced pressure. Water (20 ml) and concentrated hydrochloric acid were added to adjust its pH to 8. The precipitated crystals were separated and dried to give 5-(1-hydroxy-4-methyl-4-nitropentylidene)hydantoin (27.3 g). This compound (19.4 g, 78.9 mmol) was dissolved in pyridine (60 ml) and methanesulfonyl chloride (7.9 ml, 102.6 mmol) was added under ice-cooling. The mixture was stirred at room temperature for 3 h. Water (50 ml) was added and the mixture was extracted three times with ethyl acetate (50 ml). The extract solutions were combined and washed 4 times with 1 mol hydrochloric acid (50 ml). After separation of layers, the organic layer was concentrated to dryness to give 5-(1-methanesulfonyloxy-4-methyl-4-nitropentylidene)hydantoin (20.5 g). To this compound (5.74 g, 17.8 mmol) were added tetrahydrofuran (80 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.7 ml, 17.8 mmol) and the mixture was stirred at room temperature for 4 h. Tetrahydrofuran was concentrated under reduced pressure and the residue was extracted with ethyl acetate (50 ml) and 0.5 M hydrochloric acid (80 ml). After separation of layers, ethyl acetate was concentrated to dryness to give 5-(4-methyl-4-nitropentylidene)hydantoin (4.0 g, 17.6 mmol, yield 61.6%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8][CH2:7]1)=[O:4].[NH3:13]>CO>[NH2:13][CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8][CH2:7]1)=[O:4]
Reactant: N
Reactant: O=C(CCl)N[C@H]1CC[C@H](O)CC1
Solvent: CO
Product: NCC(=O)N[C@H]1CC[C@H](O)CC1

Procedure:
11.5 g. (0.06 mole) trans-2-chloro-N-(4-hydroxycyclohexyl)-acetamide are dissolved in 100 ml. methanol and shaken with 200 ml. liquid ammonia for 20 hours at 50° C. in an autoclave. After concentration of the solvent, suction filtration is carried out. There are obtained 9.7 g. of the title compound, i.e. 94% of theory; m.p. 110°-114° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].O=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:14][C:15](OCC)=[O:16]>C(O)(=O)C>[OH:16][C:15]1[N:6]2[N:5]=[CH:4][C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[N:1]=[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CCOC(=O)c1cn[nH]c1N
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(O)cc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 34.2 %

Procedure:
Commercially available ethyl 5-amino-1H-pyrazole-4-carboxylate (5.0 g, 32 mmol) was taken into glacial acetic acid (3.2 mL) followed by addition of ethyl 3-oxo-3-phenylpropanoate (6.1 mL, 35 mmol) and the mixture was refluxed for 12 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The crude solid was recrystallized (ethanol) and collected to yield 3.1 g (61%) of crystalline ethyl 7-hydroxy-5-phenylpyrazolo[1,5-a]pyrimidine-3-carboxylate. 1H NMR (400 MHz, d6-DMSO): 11.75 (s, 1H), 8.28 (s, 1H), 7.80 (m, 2H), 7.61 (m, 3H), 6.28 (s, 1H), 4.31 (q, 2H), 1.34 (t, 3H).
Reaction SMILES: [N+]([O-])(O)=O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].CO.C[O-].[Na+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:28])([CH3:27])[C:23](OC)=O)=[CH:18][CH:17]=1>O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:28]2[NH:5][N:6]=[C:7]([NH2:9])[N:8]=2)([CH3:27])[CH3:23])=[CH:18][CH:17]=1
Reactant: N=C(N)NN
Reactant: COC(=O)C(C)(C)c1ccc(Br)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=[N+]([O-])O
Solvent: O
Product: CC(C)(c1ccc(Br)cc1)c1nc(N)n[nH]1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 30.1 %

Procedure:
To a stirred mixture of N-aminoguanidine nitrate (2.1 g, 15 mmol) and anhydrous methanol (18 mL) cooled to 0° C. was added sodium methoxide solution (25% in methanol, 3.4 mL, 15 mmol) dropwise. The resulting mixture was stirred at 0° C. for 10 min before methyl 2-(4-bromophenyl)-2-methylpropanoate (1.0 g, 3.9 mmol) was added. The mixture was then stirred at 0° C. for 10 min, RT for 10 min, and 75 ° C. for 6 days. The reaction mixture was cooled and diluted with 20 mL of water. Methanol was removed under vacuum and the aqueous solution was acidified to pH=3-4 with 3 N aqueous HCl solution and extracted with ethyl acetate. The ethyl acetate layer was dried (Na2SO4) and concentrated. Silica gel flash chromatography purification gave 330 mg (31% yield) of the title compound as a yellow solid. (M+H)+=281.14
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[C:9]1=[O:22])(C)(C)C.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[NH2:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[C:9]1=[O:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccnc(C#N)c2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(CN2CC[C@H](N)C2=O)ccn1
Reaction time: 18 h

Procedure:
To a solution of [1-(2-cyano-pyridin-4-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]carbamic acid tert-butyl ester (3.34 g, 10.6 mmol) in 50 mL of CH2Cl2 is added 5 mL of TFA. The reaction mixture is stirred for 18 hours and then concentrated to give the title compound (3.40 g, 10.3 mmol) as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](/[C:8](=[CH:18]/[N:19](C)C)/[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)=O)[CH:5]=[CH:4][N:3]=1.O.[NH2:23]N>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[N:23][NH:19][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)/C=C(\C(=O)c1cccc(Cl)c1)c1ccnc(Br)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Clc1cccc(-c2n[nH]cc2-c2ccnc(Br)c2)c1
Yield: 31.5 %

Procedure:
A solution of the product from step 2 (650 mg, 1.8 mmol) and hydrazine monohydrate (100 mg) in ethanol (10 ml) was refluxed for 24 hours. Solvent was evaporated and the residue was chromatographed on silica gel using mixtures of ethyl acetate and toluene as eluents to give 2-bromo-4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]pyridine (190 mg, 31%) as an oil: Anal. Calc'd for C14H9BrClN3: C, 50.25; H, 2.71; N, 12.56. Found: C, 50.10; H, 2.60; N, 12.40.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:4]([CH3:15])[C:3]=1[C:16](=[O:19])[CH2:17][CH3:18].C(O)C.[NH2:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]([CH3:15])[C:3]([C:16](=[O:19])[CH2:17][CH3:18])=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([S:24]([NH2:23])(=[O:26])=[O:25])=[CH:28][CH:29]=3)[C:6]=2[CH3:7])=[CH:9][CH:10]=1
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCC(=O)c1c(Br)c(C)c(-c2ccc(Cl)cc2)n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCC(=O)c1c(-c2ccc(S(N)(=O)=O)cc2)c(C)c(-c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Yield: 33.2 %

Procedure:
To a solution of 1-(3-bromo-5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrol-2-yl)propan-1-one (compound 49b, 3.0 g, 8.81 mmol) in a mixture of toluene:ethanol (15 ml:45 ml) were added 4-aminosulfonylbenzene boronic acid (1.947 g, 9.69 mmol) and potassium carbonate (2.43 g, 17.61 mmol) at 25° C. in a sealed tube and a nitrogen gas was bubbled through it for 15 minutes. To the reaction mixture was the added tetrakis(triphenylphosphine)palladium(0) (0.51 g, 0.44 mmol) under nitrogen atmosphere and reaction mixture was heated at about 90 to about 95° C. for 18 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with 10% methanol in dichloromethane. The combined filtrate so obtained was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (1.22 g, 33.2%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:30]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:29])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:28])[C:13]=2[N:14]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21]C(=O)C(F)(F)F)[CH2:16][CH2:15]2)[N:6]=1.[C:38]1(B(O)O)[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]=1>>[NH2:30][C:4]1[S:3][C:2]([C:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]=2)=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:28])[C:13]=1[N:14]1[CH2:20][CH2:19][CH2:18][C@@H:17]([NH2:21])[CH2:16][CH2:15]1)=[O:29]
Reactant: OB(O)C1=CCCCC1
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Product: Cn1ncc(NC(=O)c2nc(C3=CCCCC3)sc2N)c1N1CCC[C@@H](N)CC1
Yield: 33 %

Procedure:
Following the procedure for Example 350 starting with (R)-tert-butyl 2-bromo-4-(1-methyl-5-(4-(2,2,2-trifluoroacetamido)-azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate and cyclohex-1-ene-1-boronic acid gave 338 as a white solid (17.1 mg, 33%). 1H NMR (400 MHz, d4-MeOD) δ 7.58 (s, 1H), 6.31 (t, J=4.1 Hz, 1H), 3.74 (s, 3H), 3.30-3.24 (m, 3H), 3.13-3.07 (m, 1H), 2.64-2.45 (m, 2H), 2.28-2.24 (m, 2H), 2.04-1.88 (m, 3H), 1.83-1.66 (m, 8H). LCMS (ES+) m/z 416 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:20][CH3:21])=[O:13])=[CH:7][CH:8]=1
Reactant: CCO
Reactant: COc1ccc(CCCC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCc1ccc(OC)cc1

Procedure:
After 4-(4-methoxyphenyl)butanoic acid (200 g) and then concentrated sulfuric acid (4 ml) were added to ethanol (400 ml), the resulting mixture was heated under reflux for 1 hour. About one-half of the solvent was distilled off under reduced pressure, and the residual reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate (1 L). The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain ethyl 4-(4-methoxyphenyl)butanoate quantitatively.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]([C:10]1[N:11]([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:12]2[C:17]([CH3:18])=[C:16]([CH3:19])[N:15]=[C:14](OC3C=CC=CC=3)[C:13]=2[N:27]=1)[CH2:7][CH2:8][CH3:9]>C(OCC)(=O)C>[CH2:6]([C:10]1[N:11]([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:12]2[C:17]([CH3:18])=[C:16]([CH3:19])[N:15]=[C:14]([NH2:5])[C:13]=2[N:27]=1)[CH2:7][CH2:8][CH3:9]
Reactant: [NH4+]
Reactant: CCCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCOc1ccccc1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: CCCCc1nc2c(N)nc(C)c(C)c2n1CCOc1ccccc1
Temperature: 150 °C

Procedure:
A sealed tube containing ammonium acetate (7.5 g) and 2-butyl-6,7-dimethyl-4-phenoxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]pyridine (0.75 g) from Part C was heated in an oil bath to 150° C. for 48hours. The reaction reached 70% completion and was allowed to cool to room temperature. The reaction mixture was then dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The product was passed through a silica gel column using 10/90 methanol/ethyl acetate as the eluant. To remove impurities, the product was recrystallized twice from acetonitrile with charcoal. The resulting white crystals were crushed and dried to yield 2-butyl-6,7-dimethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 130.0-132.0° C.
Reaction SMILES: [CH2:1]([CH:5]([CH:7]1[CH:12]([CH3:13])[CH2:11][C:10]([CH3:14])=[CH:9][CH2:8]1)[OH:6])[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.C(O)(C)C>O.C1(C)C=CC=CC=1>[CH2:1]([CH:5]1[CH:7]2[CH2:8][CH2:9][C:10]([CH3:14])([CH2:11][CH:12]2[CH3:13])[O:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(O)C1CC=C(C)CC1C
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: O
Product: CCCCC1OC2(C)CCC1C(C)C2
Yield: 70.2 %

Procedure:
A solution of 500 grams of alpha-n-butyl-4,6-dimethyl-3-cyclohexene methanol, 600 grams of sulfuric acid, 1400 grams of water and 500 grams of isopropyl alcohol is heated at reflux for 14 hours. The reaction mass is cooled, diluted with 1500 ml of H2O and 200 ml of toluene. The aqueous layer is discarded and the organic layer is washed twice with water, neutralizing with aqueous sodium hydroxide on the second wash. Distillation through a 1.5"×12" Goodloe column affords 351 grams of 3-n-butyl-1,5-dimethyl-2-oxabicyclo[2.2.2]octane (b.p. 90° C., 3 mm Hg pressure).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].C(N(CC)CC)C>>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:7]
Reactant: NCCC(=O)OCc1ccccc1
Reactant: O=C(Cl)c1cccc(CCl)c1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCN(CC)CC
Product: O=C(CCNC(=O)c1cccc(CCl)c1)OCc1ccccc1
Yield: 100.5 %

Procedure:
This compound was synthesized in a similar way as for I from 3-chloromethylbenzoyl chloride (3 mmol, 426 mL), benzyl 3-aminopropionate toluenesulfonic acid salt (3.2 mmol, 1.12 g) and triethylamine (7 mmol, 0.98 mL). Crystallization from ether-petroleum ether gave 1.0 g (100%) product. NMR (DMSO-d6): δ 8.62 (t, 1H); 7.88 (s, 1H); 7.78 (d, 1H); 7.46 (t, 1H); 7.32 (m, 5H); 5.10 (s, 2H); 4.80 (s, 2H); 3.52 (m, 2H); 3.65 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:17])C=1.C(=O)([O-])O.[Na+].[OH-].[Na+]>O.CO.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:17])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(Cl)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: OCc1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 17.8 %

Procedure:
To a mixture of 4-chloro-2-picoline (1.0 g, 7.84 mmol) and dichloromethane (20 mL), was added m-chloroperbenzoic acid (3.5 g, 13.2 mmol) on an ice bath, which was stirred for 1.5 hours at room temperature. Water and sodium hydrogencarbonate were added to the reaction, followed by extraction with dichloromethane. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. Acetic anhydride (20 mL) was added to the residue obtained by concentrating the filtrate under a reduced pressure, and this was stirred for 1 hour at 100° C. The reaction mixture was cooled to room temperature and concentrated under a reduced pressure. A 5 N aqueous sodium hydroxide solution (1.57 mL, 7.87 mmol) was added to a mixture of the resulting residue and methanol (20 mL) on an ice bath, which was stirred for 1.5 hours at room temperature. Water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=6:1) to obtain the title compound (200 mg, 18%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]=[CH:2]1.C([O-])(O)=[O:12].[Na+].ClC1C=CC=C(C(OO)=O)C=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[O:12]1[CH:8]2[CH:7]1[CH2:6][C:5]1[C:10]([CH2:9]2)=[CH:1][CH:2]=[CH:3][CH:4]=1
Reactant: O=C([O-])O
Reactant: C1=CCc2ccccc2C1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc2c(c1)CC1OC1C2
Reaction time: 1 h

Procedure:
1,4-Dihydronaphthalene (5 g) was dissolved in methylene chloride (250 ml) and saturated aqueous NaHCO3 (280 ml). The mixture was stirred vigorously at room temperature while meta-chloroperbenzoic acid (70%, 10.0 g) was added in portions. After 1 hour, an aqueous solution of Na2S2O3 (1M, 100 ml) and methylene chloride were added. The methylene chloride layer was separated, washed with water and brine, dried (MgSO4) and evaporated to give a brownish crude mixture, which was chromatographed on a flash column (silica gel; ether:hexane=1:6) to give 2,3-epoxy-1,2,3,4-tetrahydronaphthalene (3.45 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14]Br)([CH3:4])([CH3:3])[CH3:2].[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:17]=[N+:18]=[N-:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)Cc1ccccc1CBr
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cc1ccccc1CN=[N+]=[N-]
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a solution of crude 2-bromomethylphenylacetic acid t-butyl ester (0.349 mol) in 600 mL DMF was added 34.1 g (0.524 mol) sodium azide and the mixture stirred at 65° C. for 3 h. After cooling to ambient temperature, the mixture was diluted with 1.2 L ethyl acetate. The organic layer was washed with water (3×800 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the titled compound as a yellow oil. This material was used without further purification.