Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH2:5]([O:7][C:8]([C:10]1[N:11]=[CH:12][C:13]2[NH:14][C:15]3[C:20]([C:21]=2[C:22]=1[CH3:23])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:9])[CH3:6].CCCCC.[C:29](Cl)([CH3:32])([CH3:31])[CH3:30]>>[CH2:5]([O:7][C:8]([C:10]1[N:11]=[CH:12][C:13]2[NH:14][C:15]3[C:20]([C:21]=2[C:22]=1[CH3:23])=[CH:19][C:18]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:17][CH:16]=3)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1ncc2[nH]c3ccccc3c2c1C
Reactant: CC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCC
Product: CCOC(=O)c1ncc2[nH]c3ccc(C(C)(C)C)cc3c2c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.2 g of aluminum trichloride is added to a suspension of 500 mg of 4-methyl-β-carboline-3-carboxylic acid ethyl ester in 15 ml of tert-butyl chloride. The mixture is stirred for 2 hours at room temperature and thereafter combined with 50 ml of pentane. The supernatant solution is removed by decanting, and the precipitate is combined with 10 ml of ethanol and 30 ml of water. After setting the pH at 3, the mixture is extracted repeatedly with ether. The collected organic phases are dried, filtered, and concentrated. Recrystallization from ether yields 250 mg of 6-tert-butyl-4-methyl-β-carboline-3-carboxylic acid ethyl ester, mp 201°-203° C. From the mother liquor, 100 mg of 6,8-di-tert-butyl-4-methyl-β-carboline-3-carboxylic acid ethyl ester can be isolated, mp 260°-263° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](O)=[O:4].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH2:25]([O:32][C:33](=[O:44])[C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39](=[O:43])[C@H:40]([CH3:42])[NH2:41])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[CH2:25]([O:32][C:33](=[O:44])[C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39](=[O:43])[C@H:40]([CH3:42])[NH:41][C:3](=[O:4])[C@@H:2]1[CH2:6][CH2:7][CH2:8][NH:1]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 2.5 h

Procedure:
Ac-L-proline (3.05 g, 19.41 mmol) was dissolved in drytetrahydrofuran (100 ml) under an argon atmosphere in a flask fitted with an overhead stirrer and an internal thermometer. The solution was cooled to -15° C. and N-methylmorpholine (2.13 ml, 19.41 mmol) was added followed by isobutylchloroformate (2.51 ml, 19.41 mmol) at such a rate as to maintain the internal reaction temperature at -10° to -15° C. Five minutes after the addition was completed, a solution of L-alanyl-L-proline benzyl ester hydrochloride (6.08 g, 19.41 mmol) in chloroform (70 ml) was added followed by a second portion of N-methylmorpholine (2.13 ml, 19.41 mmol) at such a rate as to maintain the internal reaction temperature at -10° to -15° C. The reaction mixture was then allowed to slowly warm to room temperatureand stirred at room temperature for 2.5 hours. Thereaction mixture was concentrated to a small residue on a rotary evaporator, diluted with chloroform (500 ml) and poured into a separatory funnel where it was washed with 0.2N hydrochloric acid (3×200 ml) and 5% sodium bicarbonate (200 ml). The organic layer was dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and chromatographed using methylene chloride-methanol as an eluent to give Ac-L-prolyl-L-alanyl-L-proline benzyl ester; Rf: 0.35 (CH3OH/CH2Cl2 --7:93).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][C:11]=1I)[CH2:2][CH2:3][CH3:4].[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][C:11]=1[C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][CH3:19])[CH:22]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCCCOc1cc(/C=C/C(=O)OC)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCCCOc1cc(/C=C/C(=O)OC)ccc1-c1cccc(NC)c1
Yield: 86.5 %

Procedure:
In a manner similar to that of Example (18d), by reaction of 28 mg (1 mol %) of palladium acetate, 88 mg (2 mol %) of dicyclohexylbiphenylphosphine, 4.5 g (12.5 mmol, 1.0 eq) of methyl (E)-3-(3-butoxy-4-iodophenyl)acrylate and 3.79 g (16.2 mmol, 1.3 eq) of methyl[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]amine (prepared in Example 7a) in 72 mL of a mixture of dimethylformamide/2M potassium phosphate solution (5/1) at 90° C. for 2 hours, 3.67 g of methyl (E)-3-(2-butoxy-3′-methylaminobiphenyl-4-yl)acrylate are obtained in the form of crystals. Yield=86%
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3].[I-].[K+].Cl[CH2:30][C:31]1[C:32]([CH3:37])=[N:33][O:34][C:35]=1[CH3:36]>>[C:2]([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:30][C:31]3[C:32]([CH3:37])=[N:33][O:34][C:35]=3[CH3:36])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=[O:4])[CH3:3]
Reactant: Cc1noc(C)c1CCl
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Agent: Cl
Agent: [I-]
Agent: [K+]
Product: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1c(C)noc1C
Yield: 71.6 %

Procedure:
Using an analogous procedure to that described for the starting material in Example 1, 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (400 mg) was reacted in the presence of potassium iodide (16 mg) with 4-chloromethyl-3,5-dimethylisoxazole (177 mg) to give 4-(3-acetoxy-4-methylanilino)-7-(3,5-dimethylisoxazol-4-ylmethoxy)-6-methoxyquinazoline (342 mg, 72%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[Br:5][C:6]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([CH3:16])[C:7]=1[NH2:8].CC(O)=O>O>[Br:5][C:6]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:7]=1[NH:8][N:1]=[CH:16]2
Reactant: Cc1cc([N+](=O)[O-])cc(Br)c1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(Br)c2[nH]ncc2c1
Reaction time: 1 h
Yield: 72 %

Procedure:
NaNO2 (65.00 g, 942.0 mmol) in H2O (140 mL) was added via addition funnel to a 5 L 3-neck round bottom flask, equipped with a mechanical stirrer and a thermometer, containing a mixture of crude 2-bromo-6-methyl-4-nitroaniline (145.0 g, 627.6 mmol) and glacial HOAc (2.5 L). During the addition, the reaction mixture was cooled with an ice bath to to maintain the internal reaction temperature below 25° C. About 1 hour after the addition was complete, additional NaNO2 (21.65 g, 313.8 mmol) in H2O (50 mL) was added to the reaction mixture relatively rapidly (<5 min) with no evidence of an exotherm. After an additional 1 hour, the reaction mixture was concentrated under reduced pressure. The resulting solid was triturated with MeOH/H2O (1:1, 1 L) then filtered, washed with additional MeOH/H2O (1:1, 500 mL), and dried in a vacuum oven at about 50-60° C. for about 16 hours to give 7-bromo-5-nitro-1H-indazole (109.4 g, 72%, 90% pure by HPLC); 1H NMR (DMSO-d6, 400 MHz) 14.28 (br s, 1H), 8.87 (d, J=1.9 Hz, 1H), 8.57 (s, 1H), 8.40 (d, J=1.9 Hz, 1H); LC/MS (Table 1, Method e) Rt 1.75 min; m/z (ESI−) 241.7.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[I:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].[Al+3].[Cl-].[Cl-].[Cl-].CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[S:3][C:4]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([I:12])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1ccsc1Br
Reactant: O=C(Cl)c1ccc(I)c([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)Cc1cc(C(=O)c2ccc(I)c([N+](=O)[O-])c2)sc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To a stirred solution of 230 mg (1 mmol) methyl (2-bromothiophene-3-yl)acetate and 310 mg (1 mmol) 4-iodo-3-nitrobenzoyl chloride in 15 mL of dry CH2Cl2 was added 432 mg of AlCl3 (4 mmol) in four portions at room temperature. The resulting mixture was stirred overnight. The reaction mixture was slowly poured onto 5 g of ice and allowed to warm to room temperature. The organic layer was dried over MgSO4, filtered, and then concentrated in vacuo. The residue was purified by flash chromatography. (Hex/EtOAc=1:5) to give 310 mg of product as a light yellow solid (yield 60%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.C[Si]([C:14]#[CH:15])(C)C.C(N(CC)C(C)C)(C)C>[Cu]I.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.CN1CCCC1=O>[C:14]([C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=1)#[CH:15]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc(F)cc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C#Cc1cc(F)cnc1N
Temperature: 70 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To a mixture of 5-fluoro-3-iodo-pyridin-2-ylamine (751 mg, 3.16 mmol) described in Manufacturing Example 173-1-1, trimethylsilylacetylene (874 μL, 6.32 mmol), copper (I) iodide (60.2 mg, 0.32 mmol), N,N-diisopropylethylamine (1.07 mL, 6.32 mmol), and N-methylpyrrolidinone (15 mL) was added tetrakis(triphenylphosphine)palladium (0) (183 mg, 0.16 mmol), which was stirred for 3 hours under nitrogen atmosphere at 70° C. This reaction solution was cooled to room temperature, and then partitioned into ethyl acetate and water. 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 thus obtained was purified by NH silica gel column chromatography and then silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (129 mg, 30%).
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[CH:26]=[C:25]([CH3:27])[C:21]2[N:22]=[CH:23][NH:24][C:20]=2[C:19]=1[CH2:28][CH3:29]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C.CO>[CH2:28]([C:19]1[C:20]2[NH:24][CH:23]=[N:22][C:21]=2[C:25]([CH3:27])=[CH:26][C:18]=1[N:17]=[C:8]=[S:9])[CH3:29]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: CCc1c(N)cc(C)c2nc[nH]c12
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1c(N=C=S)cc(C)c2nc[nH]c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of di-2-pyridyl thionocarbonate (0.72 g, 3.11 mmol) and 4-dimethylaminopyridine (0.02 g) in ethyl acetate (50 mL) is added dropwise a solution of 5-amino-4-ethyl-7-methylbenzimidazole (0.42 g, 2.39 mmol) in ethyl acetate (20 mL) and methanol (5 mL). The mixture is stirred at room temperature for 3 hours, then rotary evaporated. The residue is purified by filtration on a short pad of silica gel, eluting with ethyl acetate, to afford 4-ethyl-5-isothiocyanato-7-methylbenzimidazole as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1ccc(C2CCCN2)cc1F
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccc(F)c(F)c2)cc1

Procedure:
The title compound, white solid, m.p. 127° C. and MS: m/e=338.2 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-(3,4-difluoro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[C:26]([CH3:27])=[CH:25][C:5]2[N:6]([C:19](=[O:24])[CH2:20][N:21]([CH3:23])[CH3:22])[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[NH:12][N:13]=3)[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:30][N:31]([CH3:36])[CH2:32][CH2:33][CH2:34]Cl>CN(C)C=O.C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[C:26]([CH3:27])=[CH:25][C:5]2[N:6]([C:19](=[O:24])[CH2:20][N:21]([CH3:23])[CH3:22])[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[N:12]([CH2:34][CH2:33][CH2:32][N:31]([CH3:36])[CH3:30])[N:13]=3)[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1C)-n1c(n[nH]c1=O)-c1cccnc1N2C(=O)CN(C)C
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1C)-n1c(nn(CCCN(C)C)c1=O)-c1cccnc1N2C(=O)CN(C)C
Reaction time: 22 h

Procedure:
In the manner given in Example 25, to 6,7-dimethyl-2,9-dihydro-9-[(dimethylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react to about 95° C. for 40 minutes and after cooling [3-(dimethylamino)-propyl]chloride in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 25 to give 6,7-dimethyl-2,9-dihydro-2-[3-(dimethylamino)propyl]-9-[(dimethylamino)-acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.C([O:21][C:22](=O)[C:23]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Cl:36])[CH:30]=2)[C:26]([O:37][CH2:38][CH2:39][OH:40])=[C:25]([Br:41])[CH:24]=1)C>C1COCC1.O.Cl>[CH2:1]([NH:13][C:22](=[O:21])[C:23]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Cl:36])[CH:30]=2)[C:26]([O:37][CH2:38][CH2:39][OH:40])=[C:25]([Br:41])[CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)c1cc(Br)c(OCCO)c(-c2ccc(F)c(Cl)c2)c1
Reactant: CCCCCCCCCCCCN
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCO)c(-c2ccc(F)c(Cl)c2)c1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
Into a flamed dried round bottom flask charged with n-dodecylamine (586 mg, 3.16 mmol) in 7 mL THF at −20° C. was added n-BuLi (1.8 mL, 3.6 mmol) as a solution in hexanes. After the addition, the reaction was warmed up to room temperature and stirred for one-half hour. Then the solution was cooled to −20° C. and was added to a solution of 3-bromo-4-(2-hydroxyethoxy)-5-(3-chloro-4-fluorophenyl)benzoic acid ethyl ester (400 mg, 0.957 mmol) in 8 mL THF that had been previously cooled to −40° C. The resulting mixture was stirred at −40° C. for 5 min after which point the reaction mixture was allowed to warm up to room temperature. The reaction was diluted with water and 2N HCl then extracted with EtOAc three times. The combined organic extracts were washed with sat NaHCO3 then dried over Na2SO4. After filtering and removal of solvent in vacuo, there yielded a yellow oil that was subjected to column chromatography on silica gel (10% EtOAc: 90% Hexanes followed by 25% EtOAc: 75% Hexanes). There resulted 300 mg, 58% of the amide as a yellow oil. 1H NMR (CDCl3) 0.868 (t, J=8.13 Hz, t); 1.20–1.40 (m, 18H); 1.48–1.67 (m, 2H); 1.895–2.00 (bs, 1H); 3.427 (q, J=8.13 Hz, 2H); 3.636–7.71 (m, 4H); 6.014 (m, 1H); 7.20–7.24 (m, 1H); 7.40–7.454 (m, 1H); 7.586–7.668 (m, 2H); 7.868 (d, J=2.04 Hz, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])=S.[N:17]#[C:18][NH2:19].[Pb]>>[C:18]([NH:19][C:3]([NH:2][CH3:1])=[N:5][CH2:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])#[N:17]
Reactant: CNC(=S)NCCCSCc1[nH]cnc1C
Reactant: N#CN
Agent: [Pb]
Product: CNC(=NCCCSCc1[nH]cnc1C)NC#N
Yield: 15 %

Procedure:
The reaction of N-methyl-N'-[3-((4-methyl-5-imidazolyl)methylthio)propyl]thiourea (5.9 g.) with lead cyanamide (17.5 g.) by a procedure similar to that described in Example 3(b) afforded N-cyano-N'-methyl-N"-[3-((4-methyl-5-imidazolyl)methylthio)propyl]-guanidine (0.91 g.) m.p. 156°-158°, following chromatography on silica gel with successive elution by chloroformethyl acetate (1:1), ethyl acetate and ethyl acetate isopropyl alcohol (5:1) and final recrystallisation from isopropyl alcohol-ether. (Found: C, 49.5; H, b 7.0; S, 12.0. C11H18N6S requires: C, 49.6; H, 6.8; S. 12.0).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]=[CH:9][N:10](C)C)=[N:6][CH:7]=1.N1C=CC=CC=1.NOS(O)(=O)=O>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:10]=[CH:9][N:8]=2)[CH:7]=1
Reactant: CN(C)C=Nc1ccc(Br)cn1
Agent: NOS(=O)(=O)O
Solvent: CO
Solvent: c1ccncc1
Product: Brc1ccc2ncnn2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cooled, stirred solution of the crude product from Step A (3.94 g, 17.3 mmol) in methanol (30 mL) and pyridine (2.73 g, 35.6 mmol) was added hydroxylamine-O-sulfonic acid (2.54 g, 22.5 mmol). The reaction mixture was allowed to warm to room temperature and was stirred overnight. The volatiles were removed under reduced pressure, and the residue was partitioned between aqueous sodium bicarbonate solution and ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers were washed sequentially with water (100 mL) and saturated aqueous brine solution (100 mL), dried (magnesium sulfate) and concentrated in vacuo to yield a brown solid, which was recrystallized from dichloromethane to afford the title compound as an orange solid. LC/MS 197.9 and 199.9 (M+1).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[CH:23]([O:26][C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C@H:38]([O:41]C(=O)C(F)(F)F)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:25])[CH3:24].Br[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[Cl:56]>>[Cl:56][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=1[CH2:49][N:34]1[N:33]=[C:31]2[N:32]=[C:27]([O:26][CH:23]([CH3:24])[CH3:25])[N:28]=[C:29]([N:36]3[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37]3)[C:30]2=[N:35]1
Reactant: CC(C)Oc1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Reactant: Clc1ccccc1CBr
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC(C)Oc1nc(N2CC[C@H](O)C2)c2nn(Cc3ccccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-isopropoxy-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl ester and 1-(bromomethyl)-2-chlorobenzene. MS (m/e): 389.3 (MH+)
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:11][C:4]1[N:3]=[C:2]([N:22]2[CH2:23][CH2:24][CH:19]([CH3:18])[CH2:20][CH2:21]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1CCN(c2nc(Cl)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.9 %

Procedure:
A solution of 2,6-dichloro-3-nitro-pyridine (1.47 g, 7.61 mmol) in toluene (40 mL) was treated with, solid K2CO3 (1.26 g, 9.13 mmol) and 4-methyl-piperidine (0.90 mL, 7.6 mmol). The reaction was stirred at room temperature for 1.5 h, additional toluene (10 mL) was added, and the reaction was stirred an additional 5 h. The reaction was diluted with EtOAc and washed with water. The aqueous layer was further extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (2.00 g, 100%) as a waxy, bright yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 8.06 (d, 1H, J=4.0 Hz), 7.61 (d, 1H, J=4.0 Hz), 3.83-3.75 (m, 2H), 3.08-2.97 (m, 2H), 1.77-1.68 (m, 2H), 1.57 (br s, 1H), 1.37-1.23 (m, 2H), 0.98 (d, 3H, J=6.4 Hz). LC-MS (ESI, m/z): Calcd. for C11H14ClN3O2, 256.1 (M+H), found 256.1.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:5]([CH2:12][CH:13]=[CH2:14])=[C:6]([OH:11])[CH:7]=[C:8]([CH3:10])[CH:9]=1.S(C1C=CC(C)=CC=1)(O[CH2:19][C:20]([F:23])([F:22])[F:21])(=O)=O.Cl>CN1CCCC1=O.O>[F:21][C:20]([F:23])([F:22])[CH2:19][O:11][C:6]1[CH:7]=[C:8]([CH3:10])[CH:9]=[C:4]([CH3:3])[C:5]=1[CH2:12][CH:13]=[CH2:14]
Reactant: C=CCc1c(C)cc(C)cc1O
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: C=CCc1c(C)cc(C)cc1OCC(F)(F)F
Reaction time: 16 h

Procedure:
17 g of sodium hydroxide were metered into a mixture of 50 g of 3,5-dimethyl-2-(2-propen-1-yl)-phenol (C) and 86 g of 2,2,2-trifluoroethyl tosylate in 450 ml of N-methylpyrrolidone at 120° C. Stirring was continued for 16 hours at 120° C., and the mixture was subsequently poured into 2 l of water. The pH was brought to 2 using 6N hydrochloric acid, and the mixture was extracted using dichloromethane. The combined organic phases were dried over sodium sulphate, the solvent was removed in vacuo, and the residue was distilled. This gave 32 g (43% of theory) of 3,5-dimethyl-2-(2-propen-1-yl)phenyl 2,2,2-trifluoroethyl ether of a boiling point of 100° C. at 1 mbar.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([Si](C)(C)C)([F:32])[F:31].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=1)[CH:10]([OH:11])[C:30]([F:32])([F:31])[F:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=CC(c1cccc(C(F)(F)F)c1)N(Cc1ccccc1)Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(C(c1cccc(C(F)(F)F)c1)N(Cc1ccccc1)Cc1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Of the compound from Example 97A, 300 mg (0.78 mmol) were dissolved in 5 ml of THF, cooled to 0° C., and admixed with 183 μl (1.17 mmol) of (trifluoromethyl)trimethylsilane and then with 39 μl (39 μmol) of a 1M solution of tetra-n-butylammonium fluoride in THF. The cooling bath was removed and the mixture was stirred at RT overnight. Following addition of 2 ml of 1N hydrochloric acid, it was stirred for a further 30 min. The THF was removed on a rotary evaporator and the product was purified by preparative chromatography (Method 10). This gave 168 mg (47% of theory) of the title compound as a diastereomer mixture (ratio about 3:2)
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=1.[OH-].[K+]>CC(C)=O.O.[OH-].[Na+]>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:16])=[O:2])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)Cc1cccc(-c2ccco2)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)Cc1cccc(-c2ccco2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of 3-(2-furyl)phenylacetic acid methyl ester (0.047 g, 0.217 mmol, 1.0 eq) in acetone (3.0 ml) was added potassium hydroxide (0.5 ml of a 30% solution in H2O). The mixture was stirred at room temperature for 16 hours before diluting with 1 N NaOH (10 ml), and washing with CH2Cl2 (15 ml). The aqueous phase was acidified with 1 N HCl (15 ml) and the organics extracted with CH2Cl2 (3×20 ml). The extract was dried (Na2SO4) and concentrated under reduced pressure to yield 3-(2-furyl)phenylacetic acid (0.043 g, 100%) as a white solid; 1H-NMR (CDCl3, 400 MHz): δ 7.60 (1H, br s), 7.46 (1H, t, J=1.0 Hz), 7.34 (1H, t, J=7.5 Hz), 7.19 (2H, m), 6.65 (1H, d, J=3.2 Hz), 6.46 (1H, m), 3.67 (2H, s).