Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.Cl.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([NH2:24])[CH2:20][CH2:19]1.CN(C)CCN(C)C>O1CCOCC1>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19]1
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CN1CCN(N)CC1
Agent: CN(C)CCN(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCN(Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
A 50 mL round-bottomed flask was charged with 4-chloro-3-nitrobenzenesulfonamide (1 g, 4.23 mmol), 4-methylpiperazin-1-amine dihydrochloride (1 g, 5.32 mmol), and N1,N1,N2,N2-tetramethylethane-1,2-diamine (3 mL, 20.01 mmol) in dioxane (10 mL). The reaction mixture was refluxed for 12 hours. After this time, the reaction mixture was cooled to room temperature, the salt filtered off via a Buchner funnel, and the solvent removed in vacuo. The crude product was added to a silica gel column (Analogix, SF65-200g) and purified by eluting with 0-5% methanol in dichloromethane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1[CH:8]=O.[O-:11][CH2:12][CH3:13].[Na+].C([O-])(O)=O.[Na+].[CH3:20][CH2:21][OH:22]>>[CH2:12]([O:11][C:21](=[O:22])[CH:20]=[CH:8][C:7]1[C:2]([Br:1])=[CH:3][N:4]=[CH:5][C:6]=1[Br:10])[CH3:13]
Reactant: CCO
Reactant: CC[O-]
Reactant: O=Cc1c(Br)cncc1Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C=Cc1c(Br)cncc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3,5-Dibromo-pyridine-4-carbaldehyde (Sigma-Aldrich, St. Louis, USA) (1 eq, 15.1 mmol, 4.0 g) is suspended in EtOH (50 ml). Then triethyl phosphonoacetate (Sigma-Aldrich, St. Louis, USA) (1.1 eq, 16.6 mmol, 3.32 ml) and sodium ethoxide (21% in EtOH, 1.1 eq, 16.6 mmol, 6.12 ml) are added. The resulting mixture is stirred for 15 min at r.t., before adding sat. aqueous NaHCO3 solution. The mixture is extracted with DCM, and the organic layer is dried with MgSO4 and concentrated in vacuo. Purification by column chromatography (hexane/EtOAc) yields the title compound; [M+H]+=336.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][S:8][C@H:9]2[CH2:13][N:12]([S:14]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)(=[O:16])=[O:15])[C@H:11]([CH2:27][CH2:28][C:29]([OH:31])=O)[CH2:10]2)=[CH:5][CH:4]=1.[CH2:34]1[CH2:38]O[CH2:36][CH2:35]1.CCN=C=N[CH2:44][CH2:45][CH2:46][N:47]([CH3:49])C.C1C=CC2N(O)N=NC=2C=1>CCOC(C)=O>[CH2:46]([N:47]([CH3:49])[C:29](=[O:31])[CH2:28][CH2:27][C@@H:11]1[CH2:10][C@@H:9]([S:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:33][CH:32]=2)[CH2:13][N:12]1[S:14]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)(=[O:15])=[O:16])[C:45]1[CH:44]=[CH:36][CH:35]=[CH:34][CH:38]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: C1CCOC1
Reactant: COc1ccc(CS[C@@H]2C[C@@H](CCC(=O)O)N(S(=O)(=O)c3ccc4ccccc4c3)C2)cc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Product: COc1ccc(CS[C@@H]2C[C@@H](CCC(=O)N(C)Cc3ccccc3)N(S(=O)(=O)c3ccc4ccccc4c3)C2)cc1
Temperature: 0 °C
Yield: 144.5 %

Procedure:
To 75 mg (0.154 mmol, 1 eq) (2R,4R)-3-[4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-propionic acid in 0.86 ml THF 24 μl (0.185 mmol, 1.2 eq) benzyl methylamine were added, the solution was cooled to 0° C. and 71 mg (0.371 mmol, 2.4 eq) EDCI and 21 mg (0.151 mmol, 1.2 eq) HOBT were added. The mixture was stirred at RT over night, diluted with EtOAc and washed with 10% KHSO4, sat NaHCO3 solution and brine, dried over Na2SO4 and evaporated, yielding 131 mg (50%) (2R,4R)-N-Benzyl-3-[4-(4-methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-N-methyl-propionamide as brown gum, which was subjected to deprotection without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](O)(=O)[CH2:10][OH:11].O>C1(C)C=C(C)C=C(C)C=1>[OH:11][CH2:10][C:9]1[NH:8][C:7]2[CH:6]=[CH:5][CH:4]=[N:3][C:2]=2[N:1]=1
Reactant: Nc1cccnc1N
Reactant: O=C(O)CO
Solvent: O
Solvent: Cc1cc(C)cc(C)c1
Product: OCc1nc2ncccc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
using a Dan-Stark separator, 2,3-diaminopyridine (54.6 g; 0.5 mol) and glycolic acid (38 g; 0.5 mol) in 700 ml of mesitylene were boiled under reflux until the calculated amount of water had separated off. The mixture was then cooled to room temperature, and the resulting precipitate was filtered off with suction and, with addition of activated carbon, boiled in 800 ml of water for 15 min. The hot suspension was filtered and once more cooled to room temperature, and the colourless crystals that precipitated out were filtered off with suction and dried. Yield: 56.4 g (75%).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:11])[OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-].[K+].[CH2:14](O)[CH3:15]>O>[NH:8]1[C:14]2[C:15](=[CH:4][C:5]([O:11][C:9](=[O:10])[NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:6][CH:7]=2)[CH2:3][CH2:2][CH2:1]1
Reactant: CCO
Reactant: CCCCCCCNC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCNC(=O)Oc1ccc2c(c1)CCCN2
Temperature: 50 °C

Procedure:
Ni—Al alloy (0.098 g.) was added portionwise during 1 min. to stirring mixture of heptyl-carbamic acid quinolia-6-yl ester (0.145 g.), 10% potassium hydroxide in water (3.54 ml) and ethanol (10 ml) at 0-4° C. The reaction mixture was continued to stir for additional 2.5 hours while the temperature of the reaction mixture was maintained at 50° C. The reaction mixture was filtered, Ni—Al alloy was discarded through filtration, and the filtrate was concentrated under vaccum. The residue so obtained was crystallized with methanol (or acetone) to give 2b; yield: 0.10 g. (67.7%).
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[C:9]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=S)=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[NH3:27]>>[CH3:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[C:9]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[NH:27])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: N
Reactant: Cc1ccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)cc1
Product: Cc1ccc(COc2cccnc2NC(=N)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of yellow mercuric oxide (0.68 g, 0.0031 mol), N-[3-(4-methylbenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (1.01 g, 0.0026 mol) and methanolic ammonia solution (40 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent and recrystallisation from acetonitrile gave the desired product. Yield 0.5 g (52%), m.p. 174°-175 ° C.
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4](OC)=[O:5])#[N:2].[NH3:14]>C1C=CC=CC=1>[C:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([NH2:14])=[O:5])#[N:2]
Reactant: N
Reactant: COC(=O)C(C#N)c1ccccc1
Solvent: c1ccccc1
Product: N#CC(C(N)=O)c1ccccc1
Reaction time: 2 h
Yield: 75 %

Procedure:
A 10% solution of methyl 2-cyano-2-phenylacetate in benzene is saturated with ammonia under ice cooling. The reaction mixture is allowed to stand at room temperature for 2 hours, and then the product is filtered off. 2-Cyano-2-phenylacetic acid amide is obtained with a yield of 75%; m.p.: 148.5°-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C(O)=O.C(N(CC)CC)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH:8]([OH:13])[C:9]([CH3:11])([CH3:12])[CH3:10])=[CH:19][CH:20]=1
Reactant: CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1ccnc1
Solvent: O=CO
Solvent: CCN(CC)CC
Product: CC(C)(C)C(O)C(Oc1ccc(Cl)cc1)n1ccnc1
Yield: 55.8 %

Procedure:
14 g (0.048 mol) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-one and 61.8 g (0.143 mol) of formic acid/triethylamine (5:2 addition compound) were heated at 145° C. for 4 hours. The reaction mixture was allowed to cool and was concentrated in vacuo. The residue was taken up in dilute sodium hydroxide solution and the mixture was extracted with methylene chloride. The organic phase was washed with water, dried over sodium sulphate and concentrated in vacuo. The residue was suspended in hot cyclohexane, the suspension was filtered hot and the solid was dried. 7.9 g (56% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-ol of melting point 145°-147° C. were obtained.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[OH:21])=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.Cl[CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[N:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26]([CH2:25][O:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]2[O:14][C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=3)=[N:11][N:12]=2)=[CH:27][CH:28]=1
Reactant: Oc1ccccc1-c1nnc(Nc2cccc(C(F)(F)F)c2)o1
Reactant: ClCc1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccc(Nc2nnc(-c3ccccc3OCc3ccnc4ccccc34)o2)c1
Temperature: 60 °C
Yield: 27.2 %

Procedure:
To a solution of 2-(5-(3-trifluoromethylphenylamino)-1,3,4-oxadiazol-2-yl) phenol (100 mg, 0.31 mmol; Reference Compound 9-(1)) and 4-chloromethylquinoline (55 mg, 0.31 mmol) in N,N-dimethylformamide (1.0 mL) was added potassium carbonate (86 mg, 0.62 mmol) at room temperature and then the mixture was stirred at 60° C. over night. The reaction solution was cooled to a room temperature and diluted with ethyl acetate (100 mL). The ethyl acetate solution was washed with a saturated brine solution (30 mL), dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The residue was purified with a silica gel column chromatography (hexane/ethyl acetate) to give 39 mg (27%) of the titled compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>CCOCC>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:34](=[O:35])[C:33]1[CH:37]=[CH:38][C:30]([O:29][CH3:28])=[CH:31][CH:32]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)CCCCCCCNc1ccc(OC)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCCN(C(=O)c1ccc(OC)cc1)c1ccc(OC)cc1
Reaction time: 5 h

Procedure:
12 g (43 mmol) of 8-(4-methoxyphenylamino)-caprylic acid methyl ester are dissolved in 400 cc. of ether. 5.1 g (50 mmol) of triethylamine are added thereto. 7.3 g (43 mmol) of 4-methoxybenzoic acid chloride are added dropwise to the mixture with stirring and cooling with ice. After the addition, stirring is continued at 25° C. for 5 hours. The separated triethylamine-hydrochloride is filtered off with suction and the ethereal phase is washed in sequence with water, 5% bicarbonate solution, water, 2 n hydrochloric acid and water is dried over Na2SO4, and the solvent is distilled off. The crude product is used in the next step without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=1[C:24](=O)[CH3:25].O.[NH2:28][NH2:29].C(N(CC)CC)C>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=1[C:24](=[N:28][NH2:29])[CH3:25]
Reactant: NN
Reactant: COc1cc2nccc(Oc3cc(C)c(C)cc3C(C)=O)c2cc1OC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: COc1cc2nccc(Oc3cc(C)c(C)cc3C(C)=NN)c2cc1OC
Yield: 69.2 %

Procedure:
1-[2-(6,7-Dimethoxy-quinolin-4-yloxy)-4,5-dimethylphenyl]-1-ethanone (compound 38) (50 mg) was dissolved in ethanol (1.5 ml) to prepare a solution. Hydrazine monohydrate (20 mg) and triethylamine (45 mg) were added to the solution, and the mixture was stirred under reflux for 3 hr. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using hexane-acetone to give the title compound (36 mg, yield 67%).
Reaction SMILES: [SH:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH3:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[CH2:22][CH2:23][C:24]1[N:25]=[C:26]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[S:27][C:28]=1[CH:29](O)[CH3:30].[CH2:42](P(CCCC)CCCC)[CH2:43]CC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH2:42]([O:9][C:8](=[O:10])[CH2:7][O:6][C:5]1[CH:11]=[CH:12][C:2]([S:1][CH:29]([C:28]2[S:27][C:26]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)=[N:25][C:24]=2[CH2:23][CH2:22][C:16]2[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=2[Cl:14])[CH3:30])=[CH:3][C:4]=1[CH3:13])[CH3:43]
Reactant: CCCCP(CCCC)CCCC
Reactant: CC(O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CCc1c(F)cccc1Cl
Reactant: Cc1cc(S)ccc1OCC(=O)O
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1ccc(SC(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2CCc2c(F)cccc2Cl)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
A solution of (4-Mercapto-2-methyl-phenoxy)-acetic acid (158 mg, 0.7 mmol) and 1-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol (200 mg, 0.465 mmol) in toluene (3.0 mL) is degassed and filled with nitrogen for 3 times. Tributylphosphine (0.174 mL, 0.7 mmol) is added to the reaction mixture under nitrogen at 0° C., followed by addition of of 1,1′-(azodicarbonyl)-dipiperidine (177 mg, 0.7 mmol). The reaction mixture is allowed to warm to room temperature and stirred overnight, the mixture is loaded on silica gel column. Chromatography gave the title compound (160 mg).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1.N1C=CC=C[CH:25]=1.Cl.S(Cl)(Cl)=O>CO>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:25])=[O:12])=[CH:5][C:4]=1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1
Reactant: COc1ccc(CCC(=O)O)cc1-c1ccc2ccccc2c1
Reactant: c1ccncc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)CCc1ccc(O)c(-c2ccc3ccccc3c2)c1

Procedure:
According to the procedure described in the synthesis method of Intermediate 20 in Reference Example 6 (Step f), Intermediate 35 (551 mg), pyridine and concentrated hydrochloric acid (5 ml each) were reacted and treated. According to the procedure described in the synthesis method of Intermediate 1 in Reference Example 1 (Step c), the obtained residue was reacted with thionyl chloride (0.33 ml) in methanol to obtain the title compound (Intermediate 36, 531 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[C:7](=[O:12])[C:6]=2[CH:13]=1.[Br:15]N1C(=O)CCC1=O.C(Cl)(=O)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:14][C:4]1[C:5]2[O:9][C:8]([CH3:10])([CH3:11])[C:7](=[O:12])[C:6]=2[CH:13]=[C:2]([F:1])[CH:3]=1
Reactant: Cc1cc(F)cc2c1OC(C)(C)C2=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=C(Cl)c1ccccc1
Product: CC1(C)Oc2c(CBr)cc(F)cc2C1=O

Procedure:
A solution of provide 5-fluoro-2,2,7-trimethylbenzofuran-3(2H)-one (659) (100 mg, 0.515 mmol), N-Bromosuccinimide (100.8 mg, 0.567 mmol), benzoyl chloride (1.2 mg, 0.005 mmol) and carbon tetrachloride (2 mL) was heated at reflux overnight. Saturated sodium bicarbonate was added and extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (5%) to give 7-(bromomethyl)-5-fluoro-2,2-dimethylbenzofuran-3(2H)-one (660).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl[CH2:11][CH2:12][CH2:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl.CCN(C(C)C)C(C)C>[O:15]=[S:14]1(=[O:16])[CH2:13][CH2:12][CH2:11][N:1]1[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cccc(N)c1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1cccc(N2CCCS2(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 g of 3-Aminobenzonitril were dissolved in 10 ml DCM and 2.2 ml of DIPEA. 1.3 ml of 3-Chloro-propane-1-sulfonyl chloride were added and the reaction mixture stirred at rt overnight. The organic layer was evaporated, the crude taken up in DMF and 1.5 ml DBU added. The reaction mixture was stirred at rt overnight. DCM was added and the organic phase washed with water. The organic layer was separated, dried over Na2SO4 and evaporated. MS(ISO): 232.2 (MH+)
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[C:6]([CH2:21][CH2:22][CH3:23])[C:5]=1[OH:24])(=[O:3])[CH3:2].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])[CH:26]=1>>[C:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:35][CH2:34][CH2:33][CH2:32][CH2:31][C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)=[O:18])=[C:6]([CH2:21][CH2:22][CH3:23])[C:5]=1[OH:24])(=[O:3])[CH3:2]
Reactant: NCCCCc1cccnc1
Reactant: CCCc1c(OCCCCCCCC(=O)O)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCCCCCC(=O)NCCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
8-(4-Acetyl-3-hydroxy-2-propylphenoxy)octanoic acid was allowed to react with 3-pyridine butanamine according to procedure A and the product was purified by high performance liquid chromatography (HPLC) to give 8-(4-acetyl-3-hydroxy-2-propylphenoxy)-N-[4-(3-pyridinyl)butyl]octanamide, the title compound, mp 48°-51° (from ether-hexane) in 83% yield.
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[C:4]([C:23]([OH:25])=O)[CH:3]=1.S(Cl)([Cl:28])=O>C(Cl)(Cl)Cl.C(N(CC)CC)C>[OH:1][C:2]1[C:7]2[O:8][C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[C:4]([C:23]([Cl:28])=[O:25])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(O)c2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1cc(O)c2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 70 °C
Reaction time: 6 h

Procedure:
7-Hydroxy-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid (334 mg, 1 mmol) was dissolved in chloroform (5 ml). One drop of triethyl amine was added. At 45 to 50° C. thionylchloride (0.33 ml, 4.5 mmol) was added within 30 minutes. The solution was than stirred for 6 hours at 70° C. The exccess thionyl chloride was removed by evaporation. The crude 7-hydroxy-2,2-diphenyl-benzo[1,3]dioxole-5-carbonyl chloride was used without further purification in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@@H:13]([OH:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](N(CC)CC)C.[C:23]1(C)[C:24]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=1.C(OCC)(=O)C.CCCCCC>C(Cl)Cl>[S:29]([O:15][C@@H:13]([CH3:14])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])([C:24]1[CH:23]=[CH:28][C:27]([CH3:16])=[CH:26][CH:25]=1)(=[O:30])=[O:31]
Reactant: CCN(CC)CC
Reactant: C[C@H](O)CNC(=O)OCc1ccccc1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)O[C@@H](C)CNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of the product of Example-3A, (S)-1-[(benzyloxycarbonyl)amino]-2-propanol, (9.74 g, 46.7 mmol) and triethylamine 7.27 g, 72 mmol) in methylene chloride (60 mL) at 0° C. was added toluene sulfonyl chloride (9.15 g, 48 mmol) in methylene chloride (18 mL) slowly, in portions, over a period of 20 min while vigorously stirring under nitrogen. The mixture allowed to warm to room temperature and stirred for a further 36 hours under nitrogen. The organic layer was washed with 1N HCl, water, 5% NaHCO3 solution, water and brine before it was dried over anhydrous MgSO4. Evaporation of all solvent gave a white solid which was passed though a silica plug with ethyl acetate/hexane (1:4) to remove excess toluene sulfonyl chloride and then with ethyl acetate/hexane (1:3) to give the title product as white crystals. This material was recrystallized from ethyl acetate/hexane to give white needles (10.8 g). 1H NMR (CDCl3) δ1.22 (d, 3H,) 2.39 (s, 3H), 3.20 (m, 1H), 3.43 (dd, 1H)), 4.66 (m, 1H), 5.02 (m, 1H), 5.04 (ABq, 2H), 7.34 (m, 7H), 7.77 (d, 2H). MS m/z (electrospray) 386 [M+23]+ (100%), 320 (66). The product was examined on a Regis Technologies Inc. Perkle Covalent (R,R) β-GEM1 HPLC column using mobile phase of isopropanol/hexane and a gradient of 10% isopropanol for 5 min, then 10 to 40% isopropanol over a period of 25 min, and using both UV and Laser Polarimetry detectors. Retention time major peak: 22.2 min, >98% ee.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH2:2][C:3]2[O:4][C:5](=[O:9])[O:6][C:7]=2[CH3:8])=[CH:13][CH:12]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Cc1oc(=O)oc1CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1oc(=O)oc1CSc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
In 40 ml of dichloromethane was dissolved 2.0 g of 4-chloromethyl-5-methyl-1,3-dioxol-2-one, and 2.0 g of 4-chlorobenzenethiol was added. Then, 1.4 g of triethylamine was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, the solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The insoluble materials were separated by filtration, and the solvent was evaporated under reduced pressure. The residue was subjected to medium-pressure silica gel column chromatography as in Example 1. The eluate was evaporated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 2.9 g of the captioned compound as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][OH:13])[N:6]2[N:5]=[CH:4][N:3]=1.CC(O)C.C(=O)=O.[Br:21]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([Br:21])[CH:9]=[C:10]([CH2:11][CH2:12][OH:13])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Nc1ncnn2c(CCO)ccc12
Agent: O=C=O
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: Nc1ncnn2c(CCO)cc(Br)c12
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 184.1 %

Procedure:
To a solution of 2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)ethanol (777 mg, 4.3 mmol) in DMF (22 mL) at −20° C. (IPA and dry ice) was added 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (359 mg, 1.72 mmol) ) was added in 4 portions within 20 min. The reaction was stirred at −20° C. for 30 min. Analytical HPLC indicated 22% starting material remanded, additional B (90 mg, 0.30 mmol) was added and stirred for 20 min. The reaction was quenched with satd. Na2SO3 and warmed up to rt. The crude was extracted w/EtOAc 5×. The organic was washed with 5% aq K2CO3 and brine. Dried over Na2SO4 and concentrated. The crude was purified by MPLC with 0-7% MeOH/CH2Cl2 to give 814 mg of desired product (yield, 72.6%). MS [M+H]+=257.3; LCMS RT=1.14 min.