Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[CH:20]1([C:23](=[O:32])[CH2:24][C:25](=[O:31])[C:26](OCC)=[O:27])C[CH2:21]1>C(O)(=O)C>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[C:24]([C:23](=[O:32])[CH2:20][CH3:21])=[C:25]([OH:31])[C:26](=[O:27])[N:1]2[C:2]2[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)=[CH:14][CH:13]=1
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Solvent: CC(=O)O
Product: CCC(=O)C1=C(O)C(=O)N(c2cc(C)c(=O)n(C)c2)C1c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
A mixture of 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2) (1.77 g, 12.78 mmol), 4-chlorobenzaldehyde (1.63 g, 11.62 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (2 g, 11.62 mmol) in acetic acid (10 mL) was stirred for 2 h at 100° C. The reaction mixture was concentrated, diluted with CH2Cl2/1 N NaOH, and extracted with CH2Cl2. The combined organic extracts were discarded. The aqueous layer was acidified to pH 3 with 6 N HCl and extracted twice with CH2Cl2. The combined organic extracts were dried (Na2SO4) and concentrated to afford 3.06 g of the title compound as a beige foam. tR. 0.83 min (LC-MS 2); ESI-MS: 387.0 [M+H]+ (LC-MS 2).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1C=C(C(OCC)=O)C=CN=1)C.CC(C)(C)C#C/C=C/CN(C[C:35]1[O:39][N:38]=[C:37]([C:40]([O:42]CC)=O)[CH:36]=1)CC.CC1ON=C(C(OCC)=O)C=1.BrN1C(=O)CCC1=O.C(NC/C=C/C#CC(C)(C)C)C>>[CH3:1][C:2]([CH3:22])([CH3:23])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([C:35]1[O:39][N:38]=[C:37]([CH:40]=[O:42])[CH:36]=1)[CH2:10][CH3:11]
Reactant: CCOC(=O)c1ccnc(CN(C)C/C=C/C#CC(C)(C)C)c1
Reactant: CCOC(=O)c1cc(CN(CC)C/C=C/C#CC(C)(C)C)on1
Agent: CCNC/C=C/C#CC(C)(C)C
Agent: CCOC(=O)c1cc(C)on1
Agent: O=C1CCC(=O)N1Br
Product: CCN(C/C=C/C#CC(C)(C)C)c1cc(C=O)no1

Procedure:
The same reaction as in Referential Example 49 is carried out except that instead of the starting (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-4-ethoxycarbonyl-2-pyridylmethylamine, (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-ethoxycarbonyl-5-isoxazolylmethylamine [synthesized by brominating ethyl 5-methylisoxazole-3-carboxylate with N-bromosuccinimide and condensing the brominated product with (E)-N-ethyl-6,6-dimethyl-2-hepten-4-ynylamine] is used, (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-formyl-5-isoxazolylamine is obtained.
Reaction SMILES: [O:1]=C1NCNC1=O.[N+:8]([C:11]1[CH:12]=[C:13]([CH:27]=[CH:28][CH:29]=1)[CH2:14][N:15]1[C:19](=[O:20])[C:18](=[O:21])[N:17]([CH2:22][C:23]([OH:25])=[O:24])[C:16]1=C)([O-:10])=[O:9].C(=O)(O)[O-].[K+].BrCC(O[C:40]([CH3:43])([CH3:42])[CH3:41])=O>CC(C)=O>[OH:20][CH:19]1[N:15]([CH2:14][C:13]2[CH:27]=[CH:28][CH:29]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=2)[C:16](=[O:1])[N:17]([CH2:22][C:23]([O:25][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:24])[C:18]1=[O:21]
Reactant: C=C1N(CC(=O)O)C(=O)C(=O)N1Cc1cccc([N+](=O)[O-])c1
Reactant: O=C1NCNC1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)CN1C(=O)C(O)N(Cc2cccc([N+](=O)[O-])c2)C1=O

Procedure:
The above-prepared dioxoimidazolidine product of paragraph (1) (12.5 g) and 10 g of potassium bicarbonate were suspended in 150 mL of acetone, 9 mL of tert-butyl bromoacetate was added thereto and the mixture was heated to reflux for eight hours with stirring. Insoluble matters were filtered off, the filtrate was concentrated in vacuo, the residue was dissolved in ethyl acetate and the solution was washed with water and a saturated saline solution. Then the solution was dried over sodium sulfate, ethyl acetate was evaporated therefrom and the resulting residue was purified by a silica gel column to give 12.4 g of tert-butyl 5-hydroxy-1-(3-nitrobenzyl)-2,4-dioxoimidazolidine-3-acetate.
Reaction SMILES: [NH2:1][C:2]1[C:19]([NH2:20])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH:3]=1.[C:28](C1NC=CN=1)(C1NC=CN=1)=[S:29]>CN(C=O)C>[NH:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([NH:8][C:6]([C:5]3[C:4]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:3][C:2]4[NH:1][C:28]([SH:29])=[N:20][C:19]=4[CH:18]=3)=[O:7])[CH:17]=2)[CH:13]=[N:14]1
Reactant: CN1CCN(c2cc(N)c(N)cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Product: CN1CCN(c2cc3[nH]c(S)nc3cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4,5-diamino-2-(4-methylpiperazin-1-yl)-N-(1H-indazol-6-yl)-benzamide (0.5 mmol; see Example 181) in DMF (1 mL) was added thiocarbonyl diimidazole (0.55 mmol). Following the addition, the mixture was warned at 45° C. for 1 h. The reaction mixture was cooled to RT, and the contents were poured onto ice cold water with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 2-mercapto-6-(4-methylpiperazin-1-yl)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide as a yellow solid.
Reaction SMILES: C[C:2]([CH3:16])([CH2:6][C:7]1[NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=1)[C:3](O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:24])C=CC=CC=1.C([N:36]([CH2:39]C)CC)C>C(O)(C)(C)C>[CH3:16][C:2]1([CH3:3])[CH2:6][C:7]2=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]2[C:39](=[O:24])[NH:36]1
Reactant: CC(C)(Cc1nc2ccccc2[nH]1)C(=O)O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: CC(C)(C)O
Product: CC1(C)Cc2nc3ccccc3n2C(=O)N1

Procedure:
A solution containing 11.2 g of this benzimidazolepropanoic acid (0.05 mole), diphenylphosphorylazide (14.0 g, 0.05 mole) and triethylamine (5.0 g, 0.0 mole) in 100 mL of t-butanol was heated at reflux for 10 hr. The volatile material was evaporated at 100° and 30 torr and the residue was diluted with ethanol-methylene chloride. Filtration of the chilled mixture provided a total of 6.5 g of 3,4-dihydro-3,3-dimethylpyrimido{1,6-a}benzimidazol-1(2H)-one as a white solid, m.p. 205°-210°. This material can be purified by reprecipitation from acid solution using 20% NaOH to afford white flakes, m.p. 211°-215°.
Reaction SMILES: C1([C@@H:4](C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)[N:5]2[CH2:10][CH2:9][C@:8]([CH2:17][C:18]([OH:21])(C)C)(C3C=CC=CC=3)OC2=O)CC1.Br[C:39]1[CH:44]=[CH:43][C:42]([C@H:45]([CH:64]2[CH2:66][CH2:65]2)[N:46]2[CH2:51][CH2:50][C@:49]([CH2:58][C:59]([OH:62])([CH3:61])[CH3:60])([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:48][C:47]2=[O:63])=[CH:41][CH:40]=1.BrC1C=CN(C)C(=O)C=1>>[CH:64]1([C@@H:45]([C:42]2[CH:43]=[CH:44][C:39]([C:8]3[CH:9]=[CH:10][N:5]([CH3:4])[C:18](=[O:21])[CH:17]=3)=[CH:40][CH:41]=2)[N:46]2[CH2:51][CH2:50][C@:49]([CH2:58][C:59]([OH:62])([CH3:61])[CH3:60])([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:48][C:47]2=[O:63])[CH2:66][CH2:65]1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H](c2ccc(Br)cc2)C2CC2)C(=O)O1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C2CC2)C(=O)O1
Agent: Cn1ccc(Br)cc1=O
Product: Cn1ccc(-c2ccc([C@H](C3CC3)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc1=O

Procedure:
The title compound was prepared from 3-{(S)-cyclopropyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]methyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one {prepared in analogy to the intermediate in Example 3 from 3-[(S)-(4-bromo-phenyl)-cyclopropyl-methyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one} and 4-bromo-1-methyl-1H-pyridin-2-one following a procedure analogous to that described in Example 3. LC-MS (Method 1): tR=3.34 min; Mass spectrum (ESI+): m/z=487 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][NH:7][C:8]([N:10]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=1)=[O:9])(=[O:3])C>C(O)C>[OH2:3].[OH2:3].[OH:4][CH2:5][CH2:6][NH:7][C:8]([N:10]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=1)=[O:9]
Reactant: CC(=O)OCCNC(=O)N(CCN(C)C)c1cc(C)cc(C)n1
Solvent: CCO
Product: Cc1cc(C)nc(N(CCN(C)C)C(=O)NCCO)c1
Product: O

Procedure:
A solution of N-(2-acetoxyethyl)-N'-(2-dimethylamino ethyl)-N'-(4,6-dimethyl-2-pyridyl)urea (11.5 g, 0.034 mole) in 1:1 ethanol-aqueous ammonia (300 ml.) is allowed to overnight at room temperature. The solvent is then removed under vacuum and the residue is crystallized from acetonitrile. The yield of crude product is 7.30 g, m.p. 173-176. Recrystallization from acetonitrile gives pure product melitng at 177°-179° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@H:2]1[CH2:11][C:12]([OH:14])=O.Cl.[NH:16]1[CH2:27][S:26][CH2:25][C@@H:17]1[C:18]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19].C1C2C(=CC=CC=2)CC1CCC(O)=O.Cl.N1CSC[C@H]1C(N1CCCC1)=O>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@H:2]1[CH2:11][C:12]([CH:25]1[S:26][CH2:27][NH:16][C@H:17]1[C:18]([N:20]1[CH2:21][CH2:22][CH2:23][CH2:24]1)=[O:19])=[O:14]
Reactant: O=C([C@H]1CSCN1)N1CCCC1
Reactant: O=C(O)C[C@@H]1CCc2ccccc2C1
Agent: Cl
Agent: O=C(O)CCC1Cc2ccccc2C1
Agent: O=C([C@@H]1CSCN1)N1CCCC1
Product: O=C(C[C@@H]1CCc2ccccc2C1)C1SCN[C@H]1C(=O)N1CCCC1
Yield: 59 %

Procedure:
Colorless crystals of 1-{3-[(R)-(+)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl]-D-thioprolyl}pyrrolidine were prepared in the same manner as in Example 25, except that (R)-(+)-1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and 1-D-thioprolylpyrrolidine hydrochloride were used instead of 3-(indan-2-yl)propionic acid and 1-L-thioprolylpyrrolidine hydrochloride, respectively (yield: 59%).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2[F:35])=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C1(N)CCCCC1>C(O)(=O)C>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=4[F:35])[C:10]=3[N:9]=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Solvent: CCOC(OCC)OCC
Solvent: NC1CCCCC1
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3F)c2ncn1C1CCCCC1
Yield: 57.9 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (1.0 ml), cyclohexylamine (0.128 ml, 0.92 mmol), and acetic acid (0.1 ml) were used to give 76 mg (0.23 mmol, 57.9% yield) of the title compound.
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[S-:21][C:22]#[N:23].[Na+]>C(O)C>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH:2]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:23]=[C:22]=[S:21])=[CH:6][CH:7]=1
Reactant: N#C[S-]
Reactant: COc1ccc(C(=O)C(Br)c2ccc(OC)cc2)cc1
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(=O)C(N=C=S)c2ccc(OC)cc2)cc1

Procedure:
100 g of 2-bromo-1,2-bis-(p-methoxyphenyl)-ethanone are mixed with 700 ml of 96% strength ethanol and 25.4 g of sodium thiocyanate and the mixture is heated at 45° for 2 hours. The mixture is then concentrated to dryness by evaporation under reduced pressure, 500 ml of ice-water are added, the mixture is filtered with suction and the residue is then washed twice with ice-water. The crude product is taken up in 1500 ml of methylene chloride, the remaining water is removed and the product is dried over magnesium sulphate. The product is then concentrated to approximately 200 ml, allowed to cool, filtered with suction again, then washed with a little methylene chloride and dried under reduced pressure. 1,2-bis-(p-methoxyphenyl)-2-isothiocyano-ethanone having a melting point of 155° is obtained.
Reaction SMILES: [C:1]([C:6]1([C:9]([OH:11])=O)[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].C(N(CC)CC)C.ClC(OCC)=O.[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([CH2:33][CH3:34])[CH:27]=1>C(#N)C>[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:9]([C:6]2([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:7][CH2:8]2)=[O:11])=[C:28]([CH2:33][CH3:34])[CH:27]=1
Reactant: CCc1cc(Cl)ccc1N
Reactant: CCOC(=O)C1(C(=O)O)CC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C1(C(=O)Nc2ccc(Cl)cc2CC)CC1
Temperature: 25 °C
Yield: 40 %

Procedure:
To a stirred solution of 1.54 grams (0.01 mole) of 1-carboethoxycyclopropanecarboxylic acid (the monocarboxylic acid intermediate described in Example XVIII) and 0.99 gram (0.01 mole) of triethylamine in 75 milliliters of acetonitrile was added a solution of 1.06 grams (0.01 mole) of ethyl chloroformate in 25 milliliters of acetonitrile dropwise with cooling to 0° C.-5° C. After stirring at ice temperature for 30 minutes a solution of 1.52 grams (0.01 mole) of 4-chloro-2-ethylaniline in 20 milliliters of acetonitrile was fed dropwise with stirring and continued cooling. The reaction mixture was allowed to warm to room temperature, then stirred for approximately sixteen hours following which it was filtered and the filtrate freed of solvent by evaporation. The residue was dissolved in dichloromethane and extracted, successively, with water (2×50 milliliters), 2N HCl (2×50 milliliters) and water (1×50 milliliters). After drying (MgSO4), solvent was removed by evaporation and the solid recrystallized from hexane to give 1.15 grams (0.004 mole) of ethyl 1-(4-chloro-2-ethylphenylaminocarbonyl)cyclopropanecarboxylate as cream colored prisms having a melting point of 77° C.-80° C. Elemental analysis of the product indicated the following:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CS([O:11][CH2:12][C:13]([CH3:18])([N+:15]([O-:17])=[O:16])[CH3:14])(=O)=O.O[C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][C:21]=1[C:30]1[N:31]([CH3:35])[N:32]=[CH:33][CH:34]=1>CC(N(C)C)=O>[CH3:35][N:31]1[C:30]([C:21]2[CH:22]=[C:23]([NH:26][C:27](=[O:29])[CH3:28])[CH:24]=[CH:25][C:20]=2[O:11][CH2:12][C:13]([CH3:18])([N+:15]([O-:17])=[O:16])[CH3:14])=[CH:34][CH:33]=[N:32]1
Reactant: CC(=O)Nc1ccc(O)c(-c2ccnn2C)c1
Reactant: CC(C)(COS(C)(=O)=O)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1ccc(OCC(C)(C)[N+](=O)[O-])c(-c2ccnn2C)c1
Temperature: 160 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
Cesium carbonate (7.04 g, 21.6 mmol) was added to a solution of 2-methyl-2-nitropropyl methanesulfonate (2.39 g, 12.1 mmol) and N-(4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)phenyl)acetamide (2.00 g, 8.65 mmol) in dimethylacetamide (15 mL) and the mixture was stirred at 160° C. After 2 h, the solvent was evaporated, and the residue was triturated with water. The precipitate was isolated by filtration, washed with water and dried in vacuo to afford the product (2.38 g, 83%) as a tan solid. LCMS m/z (%)=333.4 (M+H 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (s, 6 H), 2.02 (s, 3 H), 3.53 (s, 3 H), 4.32 (s, 2 H), 6.15 (d, J=2.02 Hz, 1 H), 7.14 (d, J=8.84 Hz, 1 H), 7.44 (d, J=1.77 Hz, 1 H), 7.49 (d, J=2.78 Hz, 1 H), 7.62 (dd, J=8.97, 2.65 Hz, 1 H), 9.94 (s, 1 H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[N:8]=[C:9]([CH2:23][CH2:24][CH3:25])[N:10]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#N)=[CH:13][C:12]=3[C:19]([F:22])([F:21])[F:20])[C:6]=2[CH:5]=[CH:4][NH:3]1.[OH-:26].[Na+].ClCCl.C[OH:32]>C(O)C>[O:1]=[C:2]1[C:7]2[N:8]=[C:9]([CH2:23][CH2:24][CH3:25])[N:10]([C:11]3[CH:18]=[CH:17][C:14]([C:15]([OH:32])=[O:26])=[CH:13][C:12]=3[C:19]([F:20])([F:21])[F:22])[C:6]=2[CH:5]=[CH:4][NH:3]1
Reactant: CCCc1nc2c(=O)[nH]ccc2n1-c1ccc(C#N)cc1C(F)(F)F
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCCc1nc2c(=O)[nH]ccc2n1-c1ccc(C(=O)O)cc1C(F)(F)F
Yield: 98 %

Procedure:
Prepared analogously to Example 1f from 4-(4-oxo-2-propyl-4,5-dihydroimidazo[4,5-c]-pyridin-1-yl)-3-trifluoromethylbenzonitrile and sodium hydroxide solution in ethanol. Yield: 98%; Rf value: 0.42 (silica gel: dichloromethane/methanol/glacial acetic acid=4:1:0.1).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH:5]=[C:4]([CH3:9])[O:3]1.[Cl:11][CH2:12][C:13](Cl)=[O:14].[Li+].CC([N-]C(C)C)C.Cl>C(OCC)(=O)C.CCOCC>[CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH:5]=[C:4]([CH2:9][C:13](=[O:14])[CH2:12][Cl:11])[O:3]1
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: O=C(Cl)CCl
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)C=C(CC(=O)CCl)O1
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
In an argon gas stream, 20.6 ml of n-butyl lithium (1.6M solution in hexane) were added to 60 ml of an ether solution containing 3.53 g (0.033 mol) of diisopropylamine at -20° C. to form LDA. After stirring for 30 minutes, a mixture of 4.26 g (0.03 mol) of 2,2-dimethyl-6-methyl-1,3-dioxin-4-one and 60 ml of ether as well as 60 ml of an ether solution containing 1.69 g (0.015 mol) of chloroacetyl chloride were added to LDA. After the temperature was gradually returned to room temperature, 10% hydrochloric acid was added thereto to neutralize the solution, and extraction was then carried out with ether. The resultant organic layer was dried over anhydrous magnesium sulfate. Next, the solvent was distilled off, and the residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate =4:1), thereby obtaining 2.26 g (yield 69%) of 2,2-dimethyl-6-(3-chloro-2-oxopropyl)-1, 3-dioxin-4 -one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:17])[C:12](=[N+:15]=[N-:16])[CH:13]=O)[CH3:9].O>CCO>[CH2:8]([O:10][C:11]([C:12]1[N:15]=[N:16][N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=1)=[O:17])[CH3:9]
Reactant: CCOC(=O)C(C=O)=[N+]=[N-]
Reactant: Nc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccccc2)nn1
Reaction time: 8 h
Yield: 86.8 %

Procedure:
Aniline (143 mg, 1.5 mmol) was added to a solution of 2-diazo-3-oxo-propionic acid ethyl ester (200 mg, 1.4 mmol) and HAc (0.2 mL) in EtOH (0.5 mL) and stirring was at room temperature overnight. Reaction mixture was concentrated to get the residue. Cold water was then added, filtered the solid precipitated to afford 264 mg (87.41% Yield) of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester. 1H NMR (CDCl3): δ 8.5 (s, 1H), 7.8 (d, 2H), 7.6-7.48 (m, 3H), 4.5 (q, 2H), 1.4 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)[CH:6]=[CH:5]2.[NH2:20][CH2:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2.[OH:31][CH2:32][CH2:33][N:34]1[C:42]2[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=2)[CH:36]=[CH:35]1>>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[C:22]1[CH2:21][NH:20][C:15]([C:14]1[CH:18]=[CH:19][C:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][C:43]([C:39]4[CH:38]=[C:37]5[C:42](=[CH:41][CH:40]=4)[N:34]([CH2:33][CH2:32][OH:31])[CH:35]=[CH:36]5)=[O:44])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:12][CH:13]=1)=[O:17]
Reactant: NCc1cc2ccccc2[nH]1
Reactant: Nc1ccc2c(ccn2-c2ccc(C(=O)O)cc2)c1
Reactant: O=C(O)c1ccc2c(ccn2CCO)c1
Product: O=C(NCc1cc2ccccc2[nH]1)c1ccc(-n2ccc3cc(NC(=O)c4ccc5c(ccn5CCO)c4)ccc32)cc1

Procedure:
Compound 963 was prepared according to the procedure described in Scheme IV from 4-(5-amino-1H-indol-1-yl)benzoic acid, 2-aminomethylindole, and 1-(2-hydroxyethyl)-1H-indole-5-carboxylic acid. 1H NMR (500 MHz, DMSO-d6) δ 10.14 (s, 1H), 9.42 (s, 1H), 8.31 (dd, J=1.0, 5.5 Hz, 2H), 8.14 (d, J=8.5 Hz, 2H), 8.06 (t, J=5.5 Hz, 1H), 7.87 (dd, J=1.5, 9 Hz, 1H), 7.74 (d, J=8 Hz, 1H), 7.66 (d, J=9 Hz, 2H), 7.62 (d, J=2 Hz, 1H), 7.61 (s, 1H), 7.57 (d, J=3 Hz, 1H), 7.55 (d, J=9 Hz, 1H), 7.37 (d, J=2.5 Hz, 1H), 7.11 (ddd, J=1, 7, 9 Hz, 1H) 7.03 (ddd, J=1, 7, 8.5 Hz, 1H), 6.70 (d, J=3.5 Hz, 1H), 6.56 (d, J=3.5 Hz, 1H), 4.82 (d, J=5.5 Hz, 2H), 4.35 (t, J=5.5 Hz, 2H), 3.92 (q, J=5 Hz, 2H), 3.31 (d, J=5 Hz, 1H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:21])([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[CH:18][NH:17][C:16]2=[O:20])=[CH:11][CH:10]=1)[CH:5]([F:7])[F:6].[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C@@:30]1([CH2:34][N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[C@H:32]([CH3:33])[O:31]1>>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C@@:30]([OH:31])([CH2:34][N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)[C@H:32]([N:17]1[CH:18]=[CH:19][N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:4]([F:3])([F:21])[CH:5]([F:6])[F:7])=[CH:10][CH:11]=2)[C:16]1=[O:20])[CH3:33]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=c1[nH]ccn1-c1ccc(OC(F)(F)C(F)F)cc1
Agent: [H-]
Agent: [Na+]
Product: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
60% Sodium hydride in oil (2.4 g) was added portion-wise to a stirred solution of 1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (16.6 g) and the resulting mixture was stirred for 30 minutes at room temperature. (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (10 g) was added and the mixture was stirred at 80° C. for 20 hours. After cooling, the mixture was concentrated into a volume of about 50 ml under reduced pressure and diluted ice-water (400 ml) and ethyl acetate (500 ml). The ethyl acetate layer was separated, washed with a 10% aqueous phosphoric acid solution (400 ml) and an aqueous solution of sodium chloride (400 ml×2) successively and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1 to 2/1) to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone (7.56 g) as an oily substance, which was identical with the compound obtained in the Reference Example 47.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11](Cl)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([OH:20])[CH2:17][CH2:18][OH:19].[OH-].[K+].CN(C)C=O>O>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([O:19][CH2:18][CH2:17][CH2:16][OH:20])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCO
Reactant: O=c1cc(Cl)cnn1Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(OCCCO)cnn1Cc1ccccc1
Yield: 79.7 %

Procedure:
The mixture of 10 g of 2-benzyl-5-chloro-3(2H)-pyridazinone, 50 g of 1,3-propanediol, 3.0 g of 85 % potassium hydroxide and 50 ml of N,N-dimethylformamide was reacted for 24 hours at room temperature, then to the reaction solution was added water and extracted with ethyl acetate, dried and freed of solvent to obtain 9.4 g of the intended compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CCN)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
Compound 114 (308 mg, 1.25 mmol) was dissolved in DCM (4 mL) and the solution was cooled in an ice-water bath. TFA (3.5 mL) was then added and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (50 mL). The solution washed with K2CO3 (sat., 3×), brine, dried and concentrated to yield 115 (175 mg, 95%) as a pale yellow oil. MS (APCI): m/z 147 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[C:20]([NH:25][C:26](=[O:28])[CH3:27])[CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]=4[NH:25][C:26](=[O:28])[CH3:27])[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC(=O)Nc1cccc2c1CCNC2C
Product: CC(=O)Nc1cccc2c1CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with N-(1-Methyl-1,2,3,4-tetrahydro-isoquinolin-5-yl)-acetamide to provide the title compound in moderate yield.