Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC(CC)=CN=1)C.[CH2:22]([C@@H:24]1[C@H:32]([NH2:33])[C:28]2[CH:29]=[CH:30][S:31][C:27]=2[CH2:26][CH2:25]1)[CH3:23].Br[C:35]1[C:40]([CH2:41][CH3:42])=[N:39][C:38]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=2[Cl:50])=[C:37]([CH2:51][CH3:52])[N:36]=1>>[Cl:50][C:44]1[CH:45]=[C:46]([Cl:49])[CH:47]=[CH:48][C:43]=1[C:38]1[N:39]=[C:40]([CH2:41][CH3:42])[C:35]([NH:33][C@@H:32]2[C:28]3[CH:29]=[CH:30][S:31][C:27]=3[CH2:26][CH2:25][C@@H:24]2[CH2:22][CH3:23])=[N:36][C:37]=1[CH2:51][CH3:52]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1Br
Reactant: CC[C@H]1CCc2sccc2[C@H]1N
Agent: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccsc2CC[C@@H]1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting cis-5-ethyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine and 2-bromo-5-(2,4-dichlorophenyl)-3,6-diethylpyrazine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ; 7.50, 7.32, 7.08, 6.98, 5.77, 4.42, 2.99, 2.95, 2.62, 2.50, 1.98, 1.73, 1.39–1.18, 1.00; HRMS (FAB) calcd for C24H27Cl2N3S+H 460.1381, found 460.1376.
Reaction SMILES: [CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]([CH2:32][C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=3)[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CI)cc1
Reactant: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(C#N)cc2)CC1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
Sodium iodide (99 mg, 0.660 mmol) and 4-(chloromethyl)benzonitrile (100 mg, 0.660 mmol) were dissolved in Acetone (Volume: 2.199 mL) and allowed to stir at room temperature for 4 hours. The resulting solid was filtered and the filtrate concentrated to obtain 4-(iodomethyl)benzonitrile (130 mg, 0.535 mmol, 81% yield) as an orange oil. It was taken directly to the next step without characterization and purification. N-benzyl-1-(1H-indole-2-carbonyl)-N-methylpiperidine-4-carboxamide (100 mg, 0.266 mmol) was dissolved in 1.0 mL of DMF and added to a suspension of sodium hydride (12.78 mg, 0.320 mmol) in 2.0 of DMF. The reaction was stirred at 80° C. for 10 minutes before adding 4-(iodomethyl)benzonitrile (129 mg, 0.533 mmol) dissolved in 2.0 mL of DMF. The reaction was allowed to stir overnight. After 18 hours, the reaction was cooled to room temperature before diluting with water and ethyl acetate. The organic phase was washed with water followed by saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude material was purified via column chromatography using 50% ethyl acetate/hexanes to 100% ethyl acetate. The purification provided product as a white solid. (Yield: 50 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 7.78-7.67, 7.66-7.57, 7.49, 7.43-7.01, 6.80-6.68, 5.65-5.51, 4.62, 4.54-3.83, 3.16-2.83, 2.75, 2.35-2.26, 1.80-1.24
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[N:10]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:19]([CH2:22][C:23](=[O:25])[CH3:24])(=[O:21])[CH3:20]>C(O)(=O)C.Cl.O>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][N:10]=[C:22]([C:23](=[O:25])[CH3:24])[C:19](=[O:21])[CH3:20])=[C:4]([F:9])[CH:3]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1ccc(Cl)cc1F
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C(=NNc1ccc(Cl)cc1F)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
To a solution of 4-chloro-2-fluoroaniline (1 g, 6.87 mmol) in 9.8 mL of acetic acid and 1.6 mL of concentrated hydrochloride solution, sodium nitrite (568 mg, 8.24 mmol) in 2.6 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture were added sodium acetate (1.69 g, 20.6 mmol) and acetylacetone (893 mg, 8.93 mmol). The mixture was stirred at room temperature for 2 h, filtered, washed with water, EtOH/H2O (1/1) and hexane, and dried to give the title compound (1 g, 57% yield): 1H NMR (400 MHz, CDCl3): δ ppm 2.49 (s, 3H), 2.60 (s, 3H), 7.15-7.25 (m, 2H), 7.69 (t, J=8.4 Hz, 1H), 14.64 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]([Cl:16])([CH3:15])[CH:13]=O.[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:17]1([CH:13]([NH:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[C:12]([Cl:16])([Cl:11])[CH3:15])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(Cl)(Cl)C=O
Reactant: NC(=O)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(Cl)(Cl)C(NC(=O)c1ccc(Br)cc1)n1nnc2ccccc21

Procedure:
A suspension of 4-bromobenzamide, 2,2-dichloropropionaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 53A to provide the desired product.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:19]=[C:9]2[N:10]=[C:11](S(C)(=O)=O)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[NH2:20][CH2:21][C@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>CC#N>[C:30]([O:29][C:27]([N:23]1[CH2:24][CH2:25][CH2:26][CH:22]1[CH2:21][NH:20][C:11]1[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:19]=[C:9]2[N:10]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CN
Reactant: CS(=O)(=O)c1nc(N)n2nc(-c3ccco3)nc2n1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCC1CNc1nc(N)n2nc(-c3ccco3)nc2n1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
2-Furan-2-yl-5-methanesulfonyl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (2.5 mmol; see Example 1(a)) was suspended in 20 mL of CH3CN along with 5 mmol of (R)-2-aminomethyl-1-Boc-pyrrolidine (Astatech, Monmouth Junction, N.J.). The reaction mixture was stirred under reflux for 2 hours. It was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with CH2Cl2 and washed with dilute 1% citric acid, brine, dried with Na2SO4 and concentrated under reduced pressure. Purification by chromatography (98% CH2Cl2, 2% MeOH) afforded 880 mg of 2-[(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH2:18])[N:17]=3)[CH:14]=2)=[CH:5][CH:4]=1.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1>CN(C)C(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:24]([CH:21]4[CH2:23][CH2:22]4)=[O:25])[N:17]=3)[CH:14]=2)=[CH:19][CH:20]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(COc2ccc3nc(N)cn3c2)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(COc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
To a solution of 6-[(4-methoxybenzyl)oxy]imidazo[1,2-a]pyridin-2-amine (8.5 g, 31.6 mmol) in N,N-dimethylacetamide (80 mL) was added a solution of cyclopropanecarbonyl chloride (3.43 mL, 37.9 mmol) in N,N-dimethylacetamide (20 mL) at 0° C., and the mixture was stirred at 0° C. for 3 hr. The reaction mixture was diluted with water, and the precipitate was collected by filtration and washed with water and ethyl acetate to give the title compound (8.9 g, 83%) as a gray solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:8]([C:27]2[CH:32]=[CH:31][C:30](N)=[CH:29][CH:28]=2)[N:9]2[C:14]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:10]2)=[O:5])[CH3:2].C=O.[BH3-][C:42]#[N:43].[Na+].[CH3:45]C(O)=O>CC#N.CCOCC.CCCCCC.CCOCC>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:8]([C:27]2[CH:32]=[CH:31][C:30]([N:43]([CH3:42])[CH3:45])=[CH:29][CH:28]=2)[N:9]2[C:14]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn2c1-c1ccc(N)cc1
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(=O)c1c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn2c1-c1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 55 (78 mg, 0.152 mmol) in CH3CN (10 mL) was added 37% aqueous CH2O (123 μL, 1.52 mmol), NaBH3CN (29 mg, 0.450 mmol), and AcOH (31 μL, 0.531 mmol). The reaction mixture was stirred at ambient temperature for 2 h. Et2O was added and the solution was washed with saturated aqueous NaHCO3, brine, dried (MgSO4), filtered, and concentrated in vacuo to provide a yellow oil. Purification by flash chromatography (silica gel, 40% EtOAc/hexane) provided an off-white solid. The solid was suspended in (1:1) Et2O/hexane, collected by vacuum filtration and washed with hexane to provide the title compound as an off-white solid. 1H NMR (DMSO-d6) δ 0.85 (t, J=7.1 Hz, 3H), 1.10 (t, J=7.1 Hz, 3H), 2.96 (s, 6H), 3.40 (m, 4H), 3.51 (q, J=7.2 Hz, 2H), 3.67 (m, 4H), 4.07 (q, J=7.1 Hz, 2H), 6.77 (d, J=9.0 Hz, 2H), 6.82 (s, 1H), 7.44-7.48 (m, 7H). Mass Spectrum (ESI+) m/e=543.2 (M+H).
Reaction SMILES: [OH:1]O.[CH:3]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1>C(O)(C)(C)C>[O:1]1[CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:3]12
Reactant: OO
Reactant: C1=CCCCCCCCCCC1
Solvent: CC(C)(C)O
Product: C1CCCCCC2OC2CCCC1
Reaction time: 1 h
Yield: 99 %

Procedure:
20 mg of solid tetramethyltetraoxodirhenium (VI) (CH3)4Re2O4 were added to a 5 ml portion of the "oxidation solution" initially prepared according to B) from tertbutanol and H2O2. This immediately produced a yellow coloration. 0.15 ml of cyclododecene was then added. This caused slight heating of the solution. After 1 hour, the mixture was worked up as in Examples 1-34 and analyzed (GC/IR/MS). 99% pure epoxycyclododecane was obtained by this procedure.
Reaction SMILES: P(Br)(Br)([Br:3])=O.O[C:7]1[CH:12]=[C:11]([CH3:13])[NH:10][C:9](=[O:14])[CH:8]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Br:3][C:7]1[CH:12]=[C:11]([CH3:13])[NH:10][C:9](=[O:14])[CH:8]=1
Reactant: Cc1cc(O)cc(=O)[nH]1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(=O)[nH]1
Temperature: 110 °C

Procedure:
16 mmol of phosphorus oxybromide are added under an argon atmosphere to a solution of 21 mmol of 4-hydroxy-6-methyl-1H-pyridin-2-one [3749-51-7] in 9 ml of N,N-dimethylformamide. The reaction mixture is heated to 110° C. for 30 minutes and subsequently cooled to room temperature, and 10 ml of water are added. The solution is brought to pH 7 by adding sodium carbonate and cooled to 0° C. The precipitate is filtered off and washed with water and diethyl ether. The title compound is identified on the basis of the Rf value.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:12]2=[C:13]([N:21]3[CH2:24][CH2:23][CH2:22]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[C:17](I)[CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)#[CH:28].C(N(CC)CC)C>[Cu]I.O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:12]2=[C:13]([N:21]3[CH2:24][CH2:23][CH2:22]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[C:17]([C:28]#[C:27][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2nc3c(I)cnn3c(N3CCC3)c2CC1
Reactant: C#Cc1ccccn1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2nc3c(C#Cc4ccccn4)cnn3c(N3CCC3)c2CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.1 g (0.21 mmol) 10-azetidin-1-yl-3-iodo-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in a sealed tube under nitrogen was added 3 mL of dioxane and the mixture was degassed with nitrogen for 3 minutes. 14.7 mg (0.02 mmol) 1,1′-bis-(diphenylphosphino)-ferrocenedichloro palladium (II) was added and the reaction mixture was stirred at room temperature for 30 minutes. 86 μL (0.85 mmol) 2-ethynyl pyridine was added followed by 0.53 mL (3.8 mmol) triethylamine and 4 mg (0.02 mmol) CuI, and the reaction was stirred at 60° C. for 16 hours under nitrogen. The mixture was cooled to room temperature and partitioned between 20 mL EtOAc and 20 mL saturated ammonium chloride. The mixture was extracted with EtOAc (3×10 mL), the organic layers combined, washed with 20 mL brine, and dried with MgSO4. After filtration and evaporation of the solvent the desired product was purified by column chromatography (silica, heptane/EtOAc 9:1 to 3:7).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5][NH2:6])[CH3:2].Cl.CCN(CC)CC.[CH2:16]([N:20]=[C:21]=[O:22])[CH2:17][CH2:18][CH3:19]>C(Cl)Cl>[CH2:16]([NH:20][C:21]([NH:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:7])=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN=C=O
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCNC(=O)NCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Glycine ethyl ester·HCl (5.58 g, 40 mmol) was suspended in distilled CH2Cl2 (20 ml). After cooling in an ice bath, distilled Et3N (6.13 ml, 44 mmol) was added. Distilled n-butyl isocyanate (4.95 ml, 44 mmol) was added. The cooling bath was removed and the mixture was left stirring overnight at room temperature. Additional Et3N (3.05 ml) was added and the mixture was stirred 3 more hours. After diluting with more CH2Cl2, the solution was washed with water (50 ml), lN HCl (50 ml), saturated NaHCO3 solution (50 ml) and water (50 ml). After drying (MgSO4), the solvent was removed in vacuo leaving the title compound (7.641 g, 94%) which slowly crystallized. This was used without further purification.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:34]=[CH:33][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]3[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH:61]2[CH2:63][O:62]2)=[CH:55][CH:54]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[OH:62][C@H:61]([CH2:60][O:59][C:56]1[CH:57]=[CH:58][C:53]([OH:52])=[CH:54][CH:55]=1)[CH2:63][NH:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:31][CH:32]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)COc1ccc(NC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: O=CO
Solvent: CO
Product: O=C(O)COc1ccc(NC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 31 %

Procedure:
Methyl 2-{4-[({4-[4-(2-aminoethyl)anilino]-1-piperidinyl}carbonyl)amino] phenoxy}acetate formate (0.48 g, 1.0 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.25 g, 0.62 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.16 g, 0.192 mmol).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1.Cl>O.CN(C)C=O>[SH:7][C:4]1[S:3][C:2]([S:1][CH2:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[N:6][N:5]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: Sc1nnc(S)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(CSc2nnc(S)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
To a mixture of 1.5 g of 2,5-dimercapto-1,3,4-thiadiazole, 2.76 g of anhydrous potassium carbonate and 10 ml of N,N-dimethylformamide was added 1 g of p-(bromomethyl)benzoic acid followed by stirring at room temperature for 3 hours. The reaction mixture was diluted with 30 ml of water, made acidic with diluted hydrochloric acid and, extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was applied to silica gel column chromatography. Elution with a mixture of toluene-ethyl acetate (1:1) gave 400 mg of p-[(5-mercapto-1,3,4-thiadiazol-2-yl)thiomethyl]benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[Cl:11].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:29])[CH2:27]Br)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][N:23]([C:26](=[O:29])[CH2:27][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:12])=[C:5]([Cl:11])[CH:6]=2)[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CBr)CC1
Reactant: COC(=O)c1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1Cl
Yield: 100 %

Procedure:
2-Chloro-4-hydroxy-benzoic acid methyl ester from example E41b (2.0 g, 10.9 mmol) and 4-(2-Bromo-acetyl)-piperazine-1-carboxylic acid tert-butyl ester from Example E41a (3.68 g, 12.0 mmol) in acetonitrile (30 ml) were treated with potassium carbonate (1.6 g, 11.5 mmol), and the mixture heated at reflux 18 h. before the solvents were removed in vacuo. The residue was adsorbed onto silica gel and purified by flash chromatography on silica gel (eluant; 20% EtOAc:80% cyclohexane to 50% EtOAc:50% cyclohexane to 70% EtOAc:30% cyclohexane) to yield the title compound (4.5 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.[OH-].[K+].[C:25](Cl)(=[O:28])[CH2:26][CH3:27].[Cl-]>ClCCl.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][CH2:14][NH:15][C:25](=[O:28])[CH2:26][CH3:27]
Reactant: CCC(=O)Cl
Reactant: COc1ccc2ccccc2c1CCN
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=O)NCCc1c(OC)ccc2ccccc12
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
1.40 g (6.96 mmol) of 2-(2-methoxynaphthyl)ethylamine, which is solubilized in 20 cm3 of anhydrous dichloromethane, are introduced into a 100-cm3 two-necked flask under an inert atmosphere. The mixture is cooled with an ice bath and stirred, and 1.5 cm3 (10.4 mmol) of triethylamine dried over potassium hydroxide and 0.7 cm3 (8.056 mmol) of propanoyl chloride are introduced. After the introduction of the reactants, the ice bath is removed and reaction is allowed to proceed at room temperature for 30 min. Hydrolysis of the excess chloride is carried out by pouring the reaction mixture into water. After extraction three times with dichloromethane, the organic phase is dried over magnesium sulfate. After evaporation of the solvent and recrystallization of the solid obtained, in the heated state, in a pentane/ethyl acetate mixture, 0.70 g (2.72 mmol) of N-[2-(2-methoxy-1-naphthyl)ethyl]propionamide (white solid) is obtained, equivalent to a yield after purification of 39%. ##STR19##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:28]=[C:29]([CH2:33][C:34](O)=[O:35])[CH:30]=[CH:31][CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C(=O)C.N1C=CC=CC=1.C(OCC)(=O)C>[F:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[CH:3][C:2]=1[NH:1][C:34](=[O:35])[CH2:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:37])([F:25])[F:38])[CH:28]=1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Cc1cccc(C(F)(F)F)c1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 90 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
N-[5-(3-Amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.44 mmol) produced in Example 16(vi) was dissolved in N,N-dimethylacetamide (3.0 mL)/pyridine (9.0 mL), [3-(trifluoromethyl)phenyl]acetic acid (110 mg, 0.52 mmol) and 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (330 mg, 0.65 mmol) were added, and the mixture was stirred at 90° C. for 2 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (27 mL), and washed successively with water (27 mL) and saturated brine (27 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/heptane to give the title compound (78 mg, 34%) as a colorless powder.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:26]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].O>C1COCC1>[C:29]([O:28][C:26]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH:34]1[S:14]([C:13]1[C:7]2[O:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:9][C:8]=2[CH:10]=[CH:11][C:12]=1[Cl:18])(=[O:16])=[O:15])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCNCC1S(=O)(=O)c1c(Cl)ccc2nc(C(C)(C)C)oc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.6 %

Procedure:
The solution of 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (10.75 g, 34.9 mmol) in 100 mL of THF was cooled to 0° C., Et3N (3.47 mL, 24.9 mmol) and then Boc-piperazine (5.0 g, 26.8 mmol) were added. The resulting mixture was stirred for 20 h, warming to room temperature. The mixture was poured into water, extracted with EtOAc and washed with another portion of water; organic layers were dried and concentrated. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (30/70, v/v), yielded 11.12 g (91%) desired product 1c. LC-MS (m/z) 458.2 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[O-:8][C:9]#[N:10].[Na+].NN.[CH3:14][C:15]1[CH:16]=[C:17]([N:22]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[NH2:23])[CH:18]=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[NH2:10][C:9]([NH:23][N:22]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:17]1[CH:16]=[C:15]([CH3:14])[CH:20]=[C:19]([CH3:21])[CH:18]=1)=[O:8]
Reactant: N#C[O-]
Reactant: COC(=O)CN(N)c1cc(C)cc(C)c1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)CN(NC(N)=O)c1cc(C)cc(C)c1
Reaction time: 2 h
Yield: 76 %

Procedure:
Trifluoroacetic acid (1.06 ml, 13.9 mmol) was added under nitrogen to a stirred suspension of sodium cyanate (1.00 g, 15.2 mmol) in a solution of the hydrazine (Intermediate 36; 1.00 g, 4.8 mmol) in dry toluene (30 ml). The mixture was stirred for ca. 2 h, causing formation of a viscous insoluble gum. Saturated aqueous sodium hydrogen carbonate (25 ml) was added (causing effervescence and dissolution of the gum) and the mixture was extracted with ethyl acetate (3×75 ml). The combined extracts were washed with saturated brine (50 ml) dried and evaporated to afford a light yellow solid which was triturated with hexane/ethyl acetate (1:1) to give the title compound as a white powder (0.92 g, 76%), m.p. 139°-141°.