Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH2:26])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].N[C:29]1[C:45](Cl)=[CH:44][C:32]2NC(N3C=C(C(O)=O)C=N3)=N[C:31]=2[CH:30]=1.BrC1C=CC=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH:26][C:29]4[CH:45]=[CH:44][CH:32]=[CH:31][CH:30]=4)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(N)c(Cl)cc3n2COCCOC)c1
Reactant: Nc1cc2nc(-n3cc(C(=O)O)cn3)[nH]c2cc1Cl
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: Brc1ccccc1
Product: CCOC(=O)c1cnn(-c2nc3cc(Nc4ccccc4)c(Cl)cc3n2COCCOC)c1
Temperature: 50 °C
Yield: 6 %

Procedure:
An oven-dried flask was charged with 1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 41, product from Step A) (0.100 g, 0.254 mmol), bromobenzene (43.8 mg, 0.279 mmol), Pd(dba)2 (1.50 mg, 2.50 μmol), Q-Phos (3.60 mg, 5.10 μmol), and sodium tert-butoxide (36.6 mg, 0.381 mmol). The flask was purged with N2. Dry toluene (0.5 mL) was added and the slurry was briefly sonicated. The reaction mixture was heated at 50° C. for 18 h. The reaction mixture was then diluted with dichloromethane and filtered through a pad of Celite®. The filter cake was rinsed with EtOAc and the filtrate was concentrated under reduced pressure. The residue was purified (FCC) (10-45% EtOAc/hexanes) to yield the titled compound (7.1 mg, 6% yield), which was used in the next step without further purification. MS (ESI/CI): mass calcd. for C23H24ClN5O4, 469.2; m/z found, 470.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].Cl[CH:11]([CH3:15])[C:12]([OH:14])=[O:13]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C@H:11]([C:12]([OH:14])=[O:13])[CH3:15])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: CC(Cl)C(=O)O
Reactant: Nc1cc(F)cc(F)c1
Product: C[C@H](Nc1cc(F)cc(F)c1)C(=O)O

Procedure:
Using the procedure set forth in U.S. Pat. No. 3,598,859 and Example Q above, N-(3,5-difluorophenyl)alanine was prepared using 3,5-difluoroaniline (Aldrich) and 2-chloropropionic acid (Aldrich).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]2[CH:7]=[C:8]([C:20](=[O:23])[CH2:21][CH3:22])[CH:9]=[C:10](B3OC(C)(C)C(C)(C)O3)[C:5]=2[O:4][CH2:3]1.Br[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=[O:30].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C(OCC)(=O)C.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>[CH3:24][C:2]1([CH3:1])[C:6]2[CH:7]=[C:8]([C:20](=[O:23])[CH2:21][CH3:22])[CH:9]=[C:10]([C:32]3[CH:31]=[C:28]([CH:27]=[CH:26][C:33]=3[O:34][C:35]([F:36])([F:37])[F:38])[CH:29]=[O:30])[C:5]=2[O:4][CH2:3]1
Reactant: CCC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c2c(c1)C(C)(C)CO2
Reactant: O=Cc1ccc(OC(F)(F)F)c(Br)c1
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: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC(=O)c1cc(-c2cc(C=O)ccc2OC(F)(F)F)c2c(c1)C(C)(C)CO2
Temperature: 25 °C
Yield: 73.6 %

Procedure:
A mixture of 1-[3,3-dimethyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-5-yl]-propan-1-one (1.33 g, 4.05 mmol), 3-bromo-4-trifluoromethoxybenzaldehyde (example 1h) (1.09 g, 4.05 mmol) and potassium carbonate (1.12 g, 8.10 mmol) in toluene (12 mL), ethanol (2.4 mL) and water (1.5 mL) was degassed with argon for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (234 mg, 0.20 mmol) was added and the mixture heated at reflux under argon for 19 hrs. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (10% ethyl acetate in hexane) to give 1.17 g of 3-(3,3-dimethyl-5-propionyl-2,3-dihydro-benzofuran-7-yl)-4-trifluoromethoxy-benzaldehyde (50%). 1H NMR (300 MHz; CDCl3): 1.23 (t, J=7.2 Hz, 3H), 1.42 (s, 6H), 2.99 (q, J=7.2 Hz, 2H), 4.34 (s, 2H), 7.52 (dd, J1=7.2 Hz, J2=1.8 Hz, 1H), 7.84 (d, J=2.1 Hz, 1H), 7.85 (d, J=2.13 Hz, 1H), 7.96 (dd, J1=8.4 Hz, J2=2.1 Hz, 1H), 8.03 (d, J=2.1 Hz, 1H), 10.05 (s, 1H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.Br[C:11]1[O:15][C:14]([CH:16]=[O:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I.CNCCNC>[N:1]1([C:11]2[O:15][C:14]([CH2:16][OH:17])=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=Cc1ccc(Br)o1
Reactant: c1ccc2[nH]cnc2c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Product: OCc1ccc(-n2cnc3ccccc32)o1

Procedure:
Benzimidazole is mixed with 5-bromo-furan-2-yl formaldehyde in the presence of CuI/N,N′-dimethylethylenediamine and cesium carbonate. The resulting [5-(benzimidazol-1-yl)-furan-2-yl]-formaldehyde is purified, then reduced to the title compound with sodium borohydride.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C.C1(C#C)C=CC=CC=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#N>C(#N)C1C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:21]([C:22]#[C:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:20]=1
Reactant: COc1cccc(C#N)c1
Reactant: C#CCCCCCC
Solvent: N#Cc1ccccc1
Solvent: C#Cc1ccccc1
Product: CCCCCCC#Cc1cccc(OC)c1
Reaction time: 23 h
Yield: 80 %

Procedure:
The procedure was identical to Example 1, with the exception that 1-octyne (0.590 ml; 0.441 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 3-methoxybenzonitrile (0.245 ml; 0.266 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 23 h at 65° C. showed the presence of 1.60 mmol (80% yield) of 1-methoxy-3-(1-octynyl)benzene and no remaining 3-methoxybenzonitrile in the reaction mixture.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[C:4](Cl)[N:3]=1.[OH-].[Na+]>CO.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nc(Cl)cc(-c2cccc3ccccc23)n1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nccc(-c2cccc3ccccc23)n1
Yield: 54.4 %

Procedure:
2-Amino-6-chloro-4-(naphth-1-yl)-pyrimidine (170 mg) was dissolved in 10 mL of methyl alcohol at 0° C. 10% Palladium on activated carbon (70 mg) and approximately 1 mL of 20% sodium hydroxide were added to the solution, and the mixture was hydrogenated (1 atmosphere) for 1 hour to give solid 2-amino-4-(naphth-1-yl)-pyrimidine (80 mg). Treatment of the solid with hydrochloric acid/ethyl alcohol yielded 2-amino-4-(naphth-1-yl)-pyrimidine hydrochloride (25 mg), m.p. 181-184° C.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[CH3:16][C:17]1[C:18]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:19][C:20]([CH:23]=O)=[N:21][CH:22]=1>CO>[CH3:16][C:17]1[C:18]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:19][C:20]([CH:23]=[CH:4][C:3]([C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8][CH:7]=2)=[O:5])=[N:21][CH:22]=1
Reactant: CC(=O)c1cccc2ccccc12
Reactant: Cc1cnc(C=O)cc1N1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cnc(C=CC(=O)c2cccc3ccccc23)cc1N1CCCCC1
Reaction time: 8 h

Procedure:
A 10% aqueous solution of sodium hydroxide (1.6 ml) and then 174 mg of 1-acetylnaphthalene at about 4° C. were added to a solution of 204 mg (1.0 mmole) of 5-methyl-4-piperidino-2-pyridinecarbaldehyde in 3 ml of methanol, and the mixture was allowd to stand overnight at the above temperature. The reaction mixture was concentrated under reduced pressure. The residue was mixed with water, and then extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with dichloromethane) to give 5-methyl-2-[3-(1-naphthyl)-3-oxo-1-propenyl]-4-piperidinopyridine. The product was treated with an ethanol solution of hydrogen chloride to form its hydrochloride. Recrystallization from methanol/ether gave 350 mg (yield 75%) of the captioned compound as crystals.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(C2NC=CN=2)=CN=C(CCN)N=1.Cl[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=1.[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[C:40]1[C:45]([C:46]2[NH:47][CH:48]=[CH:49][N:50]=2)=[CH:44][N:43]=[C:42]([NH:51][CH2:52][CH2:53][NH:54]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:41]=1>>[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[C:40]1[C:45]([C:46]2[NH:50][CH:49]=[CH:48][N:47]=2)=[CH:44][N:43]=[C:42]([NH:51][CH2:52][CH2:53][NH:54][C:24]2[N:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=2)[N:41]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: N#Cc1ccc(Cl)nc1
Agent: NCCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Product: N#Cc1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)amino]-pyridine-3-carbonitrile was prepared from [4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-ylethylamine and 2-chloro-5-cyanopyridine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:14][C:15]([CH3:17])=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:15]([CH3:17])[CH3:14])[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(NC(C)C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (1 equiv.) in methanol (5 mL), acetone (5 equiv.) and acetic acid (2 equiv.) were added and reaction mixture stirred at room temperature for 2 h. Then NaBH3CN (3 equiv.) was added at 0° C. The resulting reaction mixture was stirred further for 16 h at room temperature. On completion, solvent was evaporated and water added to the residue and the extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford crude product which was used in next step without further purification (yield 80-90%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21]>>[F:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1ncnc2ccc(-n3ccnc3)cc12
Reactant: Nc1ccc(F)c(F)c1
Product: Fc1ccc(Nc2ncnc3ccc(-n4ccnc4)cc23)cc1F
Yield: 35 %

Procedure:
Using an analogous procedure to that described in Example 4, 4-chloro-6-(1-imidazolyl)quinazoline was reacted with 3,4-difluoroaniline to give 4-(3,4-difluoroanilino)-6-(1-imidazolyl)quinazoline in 35% yield, NMR Spectrum: (CD3SOCD3) 7.2 (s, 1H), 7.4-7.7 (m, 3H), 7.95 (d, 1H), 8.1 (m, 1H), 8.2 (m, 1H), 8.4 (s, 1H), 8.65 (s, 1H), 8.7 (d, 1H), 9.7 (broad s, 1H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C:20]2=[CH2:28])[CH2:12][C@@H:11]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C12BC(CCC1)CCC2.[OH-:46].[Na+].OO>CO>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][OH:46])[CH2:12][C@@H:11]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C1CC[C@H]2[C@@H]3CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H](CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 1α,3β-bis(tert-butyldimethylsilyloxy)-17-methyleneandrost-5-ene (30.3 g), was added 9-borabicyclo[3,3,1]nonane (0.5M solution in tetrahydrofuran, 228 ml) and reacted by stirring at room temperature for 4 hours. Under cooling with ice, a 3M sodium hydroxide solution (150 ml) and then a 30% hydrogen peroxide solution (150 ml) were added to the reaction mixture, followed by stirring at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the solvent, giving crude crystals (37.3 g). The crude crystals were mixed with methanol, stirred while under suspension, filtered and the thus obtained crystals were dried to give the titled compound (24.3 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([C:28]([O:30][CH2:31][CH3:32])=[O:29])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:17]1([CH2:16][C:15]([C:28]([O:30][CH2:31][CH3:32])=[O:29])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(Cc1ccccc1)(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(Cc1ccccc1)(CC1CCNCC1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 153.1 %

Procedure:
A solution of 520 mg (1.16 mmol) of 1-(t-butoxycarbonyl)-4-(3-phenyl-2,2-bis(carboethoxy)propyl)piperidine (from EXAMPLE 32, Step C) in 5 mL of CH2Cl2 at 0° C. was treated with 5 mL of TFA. The resulting mixture was warmed to rt and stirred for 1.5 h. The reaction was concentrated and triturated with ether. The solid that formed was filtered and dried to afford 617 mg of 4-(3-phenyl-2,2-bis(carboethoxy) propyl)piperidine.TFA.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH:17]=[C:18]([CH3:20])[CH3:19])=[C:15]([C:21]([OH:23])=O)[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:27]2N(O)N=[N:30][C:28]=2[CH:29]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:28]1([NH:30][C:21]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:8]=[CH:7][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=3)[C:16]=2[CH:17]=[C:18]([CH3:20])[CH3:19])=[O:23])[CH2:29][CH2:27]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2C=C(C)C)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2C=C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 191.3 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-(2-methylprop-1-en-1-yl)-1H-1,2,3-triazole-4-carboxylic acid (490 mg, 1.56 mmol) obtained in Example 95b), HOBt (106 mg, 0.779 mmol, 0.5 eq.) and cyclopropylamine (0.145 ml, 2.03 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 8.0 ml), WSC (366 mg, 1.87 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate-hexane (5:1, 48 ml) and washed with 2% aqueous sodium carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane-THF (4:1:1, 48 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated, and ethyl acetate was added to the residue. The precipitate was collected by filtration, washed with ethyl acetate and diethyl ether and dried to give the title compound as a white powder (526 mg, 1.49 mmol, 95.4%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:25][C:24]=1[NH2:35]>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)=[CH:25][C:24]=1[NH:35][C:6]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[O:8]
Reactant: COc1ccc(N2CCOCC2)cc1N
Reactant: O=C(O)c1ncc[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1ccc(N2CCOCC2)cc1NC(=O)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
According to scheme 1, to a suspension of a imidazole-2-carboxylic acid (X) was added CDI (1,1′-carbonyl-diimidazole) and stirred at ambient temperature for about 1 h. Then the mixture was refluxed and cooled to ambient temperature. 2-Methoxy-5-morpholin-4-yl-phenylamine (for R1=morpholinyl, IX) was added and the reaction mixture was heated to reflux for about 16 h. After workup 1H-imidazole-2-carboxylic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (XI) was obtained, which was then treated with the Lawesson reagent. The reaction mixture was then heated to reflux for about 22 h. The obtained 1H-imidazole-2-carbothioic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (II) was taken up in water and treated with KOH and potassium hexacyano ferrate to give 2-(1H-imidazol-2-yl)-4-methoxy-7-morpholin-4-yl-benzothiazole (Ia for R1=morpholinyl).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[CH:2]1.Cl[CH2:12][O:13][CH3:14]>>[CH2:9]([O:8][C:6]([C:4]1[N:3]=[CH:2][N:1]([CH2:12][O:13][CH3:14])[CH:5]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1c[nH]cn1
Reactant: COCCl
Product: CCOC(=O)c1cn(COC)cn1

Procedure:
In analogy to Step (1) of Example 1, but using ethyl imidazole-4-carboxylate (26.3 g) and chloromethylmethylether (21.2 mL), the title compound (17.2 g) was afforded.
Reaction SMILES: Br[CH:2]1[C:6]([CH3:8])([CH3:7])[O:5][C:4]([CH3:10])([CH3:9])[C:3]1=O.[NH2:12][C:13]([NH2:15])=[S:14].C(N(CC)CC)C>C(O)C>[CH3:7][C:6]1([CH3:8])[C:2]2[N:12]=[C:13]([NH2:15])[S:14][C:3]=2[C:4]([CH3:10])([CH3:9])[O:5]1
Reactant: CC1(C)OC(C)(C)C(Br)C1=O
Reactant: NC(N)=S
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(C)OC(C)(C)c2sc(N)nc21

Procedure:
To a solution of Example 248A (10.0 g, 0.045 mol) in ethanol (100 mL) were added thiourea (3.8 g, 0.05 mol) and triethylamine (6.3 mL, 0.045 mol). The reaction mixture was heated at reflux overnight, then cooled, and concentrated under reduced pressure. The residue was diluted with water (25 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (SiO2, 0-5% methanol in CH2Cl2) to afford the title compound MS (ESI+) m/z 199 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C(=O)C)=[CH:13][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C[O-].[Na+]>CO>[CH2:1]([O:5][C:6]([NH:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)NC=Cc1ccc(OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCOC(=O)NC=Cc1ccc(O)cc1
Temperature: 50 °C

Procedure:
12.5 g (0.045 mol) of p-(2-n-butoxycarbonylaminovinyl)-acetoxybenzene, after dissolving in 75 ml of absolute methanol, addition of a solution of 2.43 g (0.045 mol) of sodium methoxide in 50 ml of methanol, heating to 50° C. for 15 minutes and subsequent evaporation to dryness in vacuo, yield the crude sodium salt of p-(2-n-butoxycarbonylaminovinyl)-phenol. This is heated to the boil with 45 ml of epichlorohydrin for 24 hours under a reflux condenser, whilst stirring. Thereafter, the excess epichlorohydrin is removed by vacuum distillation. The residue is partitioned between water and methylene chloride and the organic phase is separated off, dried over sodium sulphate and evaporated. 1-[p-(2-n-Butoxycarbonylaminovinyl)-phenoxy]-2,3-epoxy-propane of melting point 120° C. (from ether) is obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[O:28][CH2:29][O:30][CH3:31])[OH:20].C(N(CC)CC)C>ClCCl>[CH3:31][O:30][CH2:29][O:28][C:22]1[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH3:11])=[O:20]
Reactant: COCOc1c(C)cccc1C(O)c1ccccc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOc1c(C)cccc1C(=O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 8.72 ml of oxalyl chloride in 300 ml of dichloromethane was cooled with a dry ice-acetone bath and a solution of 13.9 ml of dimethyl sulfoxide in 50 ml of dichloromethane was added dropwise with stirring. After 30 min, (2-methoxyphenyl) (3-methyl-2-methoxymethoxyphenyl)methanol (26.4 g) dissolved in 100 m of dichloromethane was added slowly with stirring and the mixture allowed to react for 1 hour. Triethylamine (64 ml) was then added and the resulting mixture was stirred another 30 min cold and then allowed to warm to room temperature. The product mixture was extracted sequentially with water, 5 percent hydrochloric acid, water, and 5 percent sodium carbonate. It was then dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain an oil. This was purified by preparative liquid chromatography to obtain the title compound as an oil. The assigned structure was consistent with the proton NMR spectrum.
Reaction SMILES: [CH3:1]N(C)C(CC)CN(C)C.N#N.CCO.[Li]C(CC)C.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1>C1COCC1>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([CH3:1])[CH:23]=1
Reactant: CCC(CN(C)C)N(C)C
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: N#N
Agent: [Li]C(C)CC
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1C(=O)O
Temperature: -50 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
In a dry round-bottomed flask (3 L) equipped with a mechanical stirrer under N2, anhydrous N,N,N′,N′-tetramethylethylethylenediamine (TMEDA, 99.7 mL, 660 mmol, 2.2 eq.) and anhydrous THF (600 mL) were added and the mixture was cooled to −90° C. in a bath of liquid N2/EtOH. Freshly titrated sec-BuLi (550 mL, 1.2M in cyclohexane, 660 mmol., 2.2 eq.) was added slowly via cannula as to maintain the temperature at −50° C. The solution was cooled to −90° C. and 4-chlorobenzoic acid (47.0 g in 400 mL anhydrous THF, 300 mmol) was added slowly via cannula, while stirring carefully to maintain the temperature at −90° C. The reaction mixture was stirred at −90° C. for 1 h before allowed to warm-up to −80° C. and CH3l (80 mL, 1.28 moles) was added very slowly. The reaction mixture was stirred for 10 min at 0° C., then quenched slowly with H2O (600 mL) and allowed to warm-up to room temperature. The aqueous layer was separated, washed with Et2O (2×500 mL) and then acidified with HCl (2.5 N, 600 mL) while cooling in an ice bath; cooling was continued for 16 h at 4° C. to allow crystallization of the desired product. The crude product was dried under vacuum and over anhydrous P2O5 and then re-crystallized from hot toluene (700 mL) to obtain pure 4-chloro-2-methylbenzoic acid (40 g).