Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]2)[C:10]2[CH:21]=[CH:22][C:23]([S:25]([N:28]3[CH2:33][CH2:32][CH2:31][C@H:30]([C:34]([O:36]CC)=[O:35])[CH2:29]3)(=[O:27])=[O:26])=[CH:24][C:9]=2[N:8]=1)([CH3:6])([CH3:5])[CH3:4]>CO.O.O>[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:14][CH2:15][C:16]([F:19])([F:20])[CH2:17][CH2:18]2)[C:10]2[CH:21]=[CH:22][C:23]([S:25]([N:28]3[CH2:33][CH2:32][CH2:31][C@H:30]([C:34]([OH:36])=[O:35])[CH2:29]3)(=[O:27])=[O:26])=[CH:24][C:9]=2[N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)[C@H]1CCCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCC[C@H](C(=O)O)C3)ccc2n1CC1CCC(F)(F)CC1
Reaction time: 8 h

Procedure:
NaOH (2 mL, 2 M, 4.0 mmol) was added to a solution of ethyl (3S)-1-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)piperidine-3-carboxylate (1.4 g, 2.7 mmol) in 80 mL of MeOH—H2O (1:1) at ambient temperature. The reaction mixture was stirred overnight and diluted with water (80 mL). The solvent was concentrated to 80 mL. The resulting solution was neutralized with 2 N HCl. The product was extracted with EtOAc and dried over anhydrous Na2SO4. The solvent was concentrated to provide the title compound as white solid. Yield: 1.3 g (95%); 1H NMR (400 MHz, CDCl3) δ 1.24-1.27 (m, 1 H), 1527-1.39 (m, 1 H), 1.45-1.59 (m, 2 H), 1.62 (s, 9 H), 1.68 (s, 3 H), 1.70-1.86 (m, 4 H), 1.93-2.06 (m, 1 H), 2.08-2.25 (m, 2 H), 2.33 (t, J=12.11 Hz, 1 H), 2.46 (t, J=10.94 Hz, 1 H), 2.53-2.66 (m, 1 H), 3.69 (d, J=11.72 Hz, 1 H), 3.89 (d, J=9.96 Hz, 1 H), 4.31 (d, J=7.23 Hz, 2 H), 7.48 (d, J=8.79 Hz, 1 H), 7.67 (d, J=8.20 Hz, 1 H), 8.26 (s, 1 H); MS (ESI) (M+H)+=498.1.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH:4]([CH3:9])[C:5]([O:7]C)=O.[Cl:20][C:21]1[N:22]=[C:23]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[S:24][CH:25]=1>>[Cl:20][C:21]1[N:22]=[C:23]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH2:29][N:1]2[CH:2]([C:10]3[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=3[O:16][CH3:17])[CH2:3][CH:4]([CH3:9])[C:5]2=[O:7])[S:24][CH:25]=1
Reactant: O=Cc1cccc(-c2nc(Cl)cs2)c1
Reactant: COC(=O)C(C)CC(N)c1c(OC)ccnc1OC
Product: COc1ccnc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2nc(Cl)cs2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,4-dimethoxypyridin-3-yl)-2-methylbutanoate with synthesized 3-(4-chlorothiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.81 min.; [M+H]+: 443.85 g/mol.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].[CH:17]1(Br)[CH2:19][CH2:18]1>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH:17]2[CH2:19][CH2:18]2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: BrC1CC1
Reactant: N#Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(OC2CC2)ccc1Br
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 2.50 g (13 mmol) 2-bromo-5-hydroxy-benzonitrile in 100 mL DMF are added 5.23 g (38 mmol) K2CO3 and 3.05 g (25 mmol) cyclopropylbromide. The reaction mixture is stirred for 16 h at 120° C. Afterwards the reaction is quenched by the addition of ice water and extracted with EtOAc. The org. layers are combined, washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE/EtOAc).
Reaction SMILES: [C:1]([O-:12])(=[O:11])[C:2]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH2:13]([N+](CC)(CC)CC)[CH3:14].NC1C=CC=CC=1.C(OC(=O)C(OCC)=O)C>[Pt]>[CH2:13]([O:11][C:1](=[O:12])[C:2]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3])[CH3:14]
Reactant: O=C([O-])C(=O)Nc1ccccc1
Reactant: CC[N+](CC)(CC)CC
Agent: [Pt]
Solvent: Nc1ccccc1
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)Nc1ccccc1
Yield: 90 %

Procedure:
The electrochemical oxidation of tetraethylammonium oxanilate was carried out in an one-compartment cell (graphite anode, platinum cathode). The starting material was prepared by firstly reacting aniline and diethyloxalate to give ethyloxanilate which compound was then saponified with tetraethylammonium hydroxide; the yield was more than 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.O.[C:14]1([CH3:24])[CH:19]=CC(S(O)(=O)=O)=C[CH:15]=1.[CH3:25]CCCCC.C1(C)C=CC=CC=1>C(=O)C(C)(C)C.C(OCC)(=O)C>[C:14]([C@H:24]1[O:10][C:9](=[O:11])[C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[O:12]1)([CH3:25])([CH3:19])[CH3:15]
Reactant: O=C(O)[C@H](O)c1ccc(Cl)cc1
Reactant: CCCCCC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(C)(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@H]1OC(=O)[C@@H](c2ccc(Cl)cc2)O1
Reaction time: 12 h

Procedure:
To a solution of 16 g of (2R)-2-(4-chlorophenyl)-2-hydroxyacetic acid (cf. JP-Hei 6 (1994)-165695A) in 440 ml of hexane/toluene (10:1), 23 ml of pivalaldehyde and 326 mg of p-toluenesulfonic acid monohydrate were added by the order stated, followed by 12 hours' heating under reflux while removing the generated water with Dean-Stark trap. The reaction liquid was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, 14 g of the title compound was obtained.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13].[C:14](O)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:14]2[NH:6][C:7]3[CH:12]=[C:11]([S:1]([OH:3])(=[O:5])=[O:2])[CH:10]=[CH:9][C:8]=3[N:13]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1N
Reactant: O=S(=O)(O)O
Reactant: O=C(O)c1ccccc1
Product: O=S(=O)(O)c1ccc2nc(-c3ccccc3)[nH]c2c1
Temperature: 200 °C
Yield: 49 %

Procedure:
Without intermediate isolation which (apart from starting materials and secondary products) can, as in this case, still comprise large amounts of sulphuric acid, it is not always possible to further process crude reaction solutions. This often leads to the formation of contaminated products and/or to poor yields in the subsequent stage. This is described in the example in EP-A 4 203 072, wherein a mixture of 1,2-diaminobenzene, benzoic acid and 96% strength sulphuric acid is mixed and heated to 200° C. In the subject process, 2-phenylbenzimidazole-5-sulphonic acid is obtained as the secondary product in a yield of 49% of theory. The product is isolated in a yield of 60%, with the process carried out in 86% strength sulphuric acid at 178°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: COc1ccccc1-c1nc(Nc2cc[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-methoxy-phenylboronic acid to give [1-(2-Methoxy-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 317(MH+).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]([C:17]([F:20])([F:19])[F:18])=[C:10]([CH2:12][CH2:13][CH2:14][C:15]#N)[N:11]=2)=[CH:3][CH:2]=1.[OH2:22].[CH3:23][OH:24]>>[C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]([C:17]([F:20])([F:19])[F:18])=[C:10]([CH2:12][CH2:13][CH2:14][C:15]([O:24][CH3:23])=[O:22])[N:11]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(-c2nc(CCCC#N)c(C(F)(F)F)o2)cc1
Reactant: O
Reactant: CO
Product: COC(=O)CCCc1nc(-c2ccc(C)cc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-[2-(p-Tolyl)-5-trifluoromethyloxazol-4-yl]butanenitrile (5.28 g) was dissolved in 40 ml of methanol, and stirred for 10 minutes under ice-cooling under bubbling hydrogen chloride gas. After the bubbling was stopped, the mixture was warmed to room temperature and stirred for 30 minutes. To the reaction solution was added 5 ml of water, and the mixture was stirred for 30 minutes, allowed to stand at room temperature overnight. After addition of water, the reaction solution was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=4:1) to provide 5.63 g of the objective compound as colorless crystals. M.p. 44.5–45° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]1([C:26]([OH:28])=O)[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][CH:18]=1>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:26](=[O:28])[C:17]1[CH:18]=[CH:19][C:20]([C:23]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:25])=[CH:21][CH:22]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)c1ccc(C(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)cc1
Yield: 71.8 %

Procedure:
Using General Procedure A with 5.8 g (24.0 mmol) D-Proline benzyl ester hydrochloride and 2.0 g (12.0 mmol) benzene-1,4-dioic acid afforded, after flash chromatography (EtOAc), 4.66 g (72%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)(=[O:3])[CH3:2].[CH3:10][N:11]([CH2:15][C:16]#[CH:17])[C:12](=[O:14])[CH3:13].C=O.[C:20](=O)(O)[O-].[Na+]>ClCCl.O1CCOCC1.C(O)(=O)C>[C:1]([O:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:20][C:17]#[C:16][CH2:15][N:11]([CH3:10])[C:12](=[O:14])[CH3:13])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCNC1
Reactant: O=C([O-])O
Reactant: C#CCN(C)C(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(=O)OC1CCN(CC#CCN(C)C(C)=O)C1

Procedure:
A mixture of 1.17 g of 3-acetoxy pyrrolidine, 1.2 g of N-methyl-N-propargyl acetamide, 465 mg of paraformaldehyde, 200 mg of cuprous chloride, 1.5 ml of acetic acid and 50 ml of dioxane was stirred at reflux under argon for 75 minutes. A 100 ml portion of dichloromethane was added followed by the addition of 50 ml of 10% aqueous sodium bicarbonate. The phases were separated, sodium chloride was added to the aqueous phase and the aqueous phase was reextracted with dichloromethane. The organic solutions were combined, dried, filtered and concentrated. The residue was purified by chromatography (alumina), giving 1.43 g of the desired product as a yellow oil.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:24])[C:6]1[CH:11]=[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[N:14]([CH3:20])[C:13]2=[O:21])[C:9]([F:22])=[CH:8][C:7]=1Cl)([CH3:3])[CH3:2].[Cu][C:26]#[N:27].C(OCC)(=O)C.Cl>CN1CCCN(C)C1=O.O>[CH:1]([O:4][C:5](=[O:24])[C:6]1[CH:11]=[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([CH3:19])[N:14]([CH3:20])[C:13]2=[O:21])[C:9]([F:22])=[CH:8][C:7]=1[C:26]#[N:27])([CH3:3])[CH3:2]
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Reactant: N#C[Cu]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(C#N)cc2F)c(=O)n1C
Temperature: 195 °C
Reaction time: 0.75 h

Procedure:
A mixture of 50.0 g of 2-chloro-5-[3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-4-fluorobenzoic acid isopropyl ester and 25.4 g of copper(I) cyanide in 225 ml of dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone is heated for 2.5 hours at 195° C. under nitrogen. The mixture is then cooled to room temperature and 2 l of ethyl acetate are added. The mixture is then poured onto 1.31 of water and 300 ml of 32% hydrochloric acid, and the whole is stirred for 45 minutes at room temperature until two distinct layers have formed. The organic phase is removed, washed twice with 200 ml of water each time and dried over anhydrous sodium sulfate. Concentration by evaporation of the organic solution yields crystalline 2-cyano-5-[3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-4-fluorobenzoic acid isopropyl ester, m.p. 188°-200° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7](Br)[S:8][CH:9]=1)(=[O:3])[CH3:2].[Na].[CH2:12]([OH:14])[CH3:13]>>[C:1]([NH:4][C:5]1[N:6]=[C:7]([O:14][CH2:12][CH3:13])[S:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1csc(Br)n1
Reactant: CCO
Agent: [Na]
Product: CCOc1nc(NC(C)=O)cs1

Procedure:
Following the procedure of Example 1 4-acetamido-2-bromothiazole is treated with sodium in absolute ethanol to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20]>CC(O)C.CCCCCC>[Cl:17][CH2:18][C:19]([N:9]([C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:20]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(Nc2c(F)cccc2Cl)cc1
Solvent: CCCCCC
Solvent: CC(C)O
Product: Cc1ccc(N(C(=O)CCl)c2c(F)cccc2Cl)cc1
Temperature: 37.5 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
20.4 g of crude (2′-chloro-6′-fluorophenyl)-(4-methylphenyl)-amine are heated to about 80° C. and treated with 10.75 g of chloroacetylchlonde. The mixture is stirred for 2 hours and diluted with 10 ml of 2-propanol. The solution is cooled to 35-40° C. and seeded. The precipitated suspension is diluted with 30 ml of hexane, cooled to 0-5° C. and stirred for about 1 hour. The crystals are isolated by filtration, washed with a cold solution of 2-propanol/hexane ⅓. After drying, 22.7 g of 2-chloro-N-(2′-chloro-6′-fluorophenyl)-N-(4-methylphenyl)acetamide are obtained. HPLC purity: 99%. Melting point: 79-80° C. 1H-NMR(DMF-d7, 400 MHz, 393K) δ 2.44(s, 3H, CH3); 4.32 (s, 2H, CH2), 7.35[d, J=8.0 Hz, 2H, HC(3) and HC(5)], 7.43[ddd, J=8.0, 2.0 Hz, JH-F=8.0, 1H, HC(5′)], 7.48[d, J=8.0 Hz, 2H, HC(2) and HC(6)], 7.55[d, J=8.0 Hz, 1H, HC(3′)], 7.60[ddd, J=8.0 Hz, JH-F=5.5, 1H, HC(4′)].
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7](O)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.[C:21]1([CH:27]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@@H:28]([NH2:51])[CH:29]=[CH:30][S:31]([CH:34]=[CH:35][C@H:36]([NH2:50])[CH:37]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:33])=[O:32])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:52]1([CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:28]([NH:51][C:7](=[O:8])[C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[NH:1][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:29]=[CH:30][S:31]([CH:34]=[CH:35][C@H:36]([NH:50][C:7](=[O:8])[C@H:2]([CH2:3][CH:4]([CH3:5])[CH3:6])[NH:1][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)(=[O:33])=[O:32])[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: N[C@@H](C=CS(=O)(=O)C=C[C@H](N)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C=CS(=O)(=O)C=C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Yield: 81 %

Procedure:
Cbz-Leu-D-Phe-VS-Ph was prepared from Cbz-Leu-OH and D-Phe-VS-Ph.HCl using standard mixed anhydride coupling method, yield 81%. 1H-NMR (CDCl3) δ 0.8-0.9 (2d, 6H, 2×Leu-CH3), 1.4-1.6 (m, 2H, Leu-CH2), 2.06 (m, 1H, Leu-CH), 2.9-3.0 (m, 2H, CH2-Phe), 3.9-4.0 (m, 1H, α-H), 4.8-4.9 (b, 1H, α-H), 4.9-5.0 (m, 1H, NH), 5.1 (m, 2H, Cbz), 6.3-6.4 (d & b, 2H, NH and CH═), 6.9-7.0 (dd, 1H, CH═), 7.1-7.4 (m, 10H, 2×Ph), 7.5-7.7 (m, 5H, SO2-Ph). MS (ESI) m/z 535.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Cl-].[OH:14][NH3+:15].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[N:15][OH:14]
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C(c1ccccc1)C(F)(F)F
Yield: 89.6 %

Procedure:
25 g (0.144 mol) of 2,2,2-Trifluoro-1-phenyl-ethanone are dissolved in 40 ml of ethanol at 80° C. To the solution are added dropwise 10.5 g (0.151 mol) of hydroxylammonium chloride and 20.1 g (0.245 mol) of sodium acetate dissolved in 20 ml of water. The reaction mixture is refluxed overnight, and the solvent is distilled off by a rotary evaporator. The residue is poured into water, the white precipitate is rinsed with water and dried under vacuum, yielding 24.4 g of 2,2,2-trifluoro-1-phenyl-ethanone oxime. The crude product is used in the next step without further purification.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2.[CH3:17][C:18]1[C:19](=O)[CH2:20][CH2:21][C:22]=1[CH3:23].Cl.N>C1COCC1>[N:15]1[C:16]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[C:19]2[CH2:20][CH:21]=[C:22]([CH3:23])[C:18]=2[CH3:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CC1=C(C)C(=O)CC1
Reactant: Brc1cccc2cccnc12
Agent: Cl
Agent: N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=CCC(c2cccc3cccnc23)=C1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.4 %

Procedure:
5 ml of n-BuLi (2.5 M in hexane, 12.5 mmol) were added dropwise at −95° C. to a solution of 2.5 g of 8-bromoquinoline (12 mmol) in 120 ml of THF, the mixture was stirred for 15 minutes, and 1.3 g of 2,3-dimethylcyclopent-2-enone (12 mmol) dissolved in 10 ml of THF were subsequently added. After warming to room temperature, the solution was refluxed for one hour. The cooled reaction mixture was hydrolyzed using ice, acidified using hydrochloric acid and then neutralized using ammonia solution. The aqueous phase was extracted with diethyl ether, and the combined organic phases were dried. Distillation at 150° C./0.05 mbar gave 1.1 g of 1-(8-quinolyl)-2,3-dimethylcyclopentadiene (40%) as a yellow, viscous oil.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[NH:28][C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)[N:3]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cn2)nc(Cl)c1Cl
Reactant: COc1cccc(N)c1
Product: COc1cccc(Nc2nc(-c3ccc(C(F)(F)F)cn3)nc(C)c2Cl)c1

Procedure:
The title compound was prepared from 4,5-dichloro-6-methyl-2-[5-(trifluoromethyl)-2-pyridinyl]pyrimidine (100 mg, 0.325 mmol) and m-anisidine (37 μl, 0.325 mmol) similar to Example 11 as a pale white solid (26 mg, 20%). 1H NMR (CDCl3): 9.05 (dd, J=0.8, 1.4 Hz, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.06 (dd, J=2.3, 8.3 Hz, 1H), 7.57 (t, J=2.3 Hz, 1H), 7.36 (s, 1H), 7.31 (t, J=8.1 Hz, 1H), 7.18-7.14 (m, 1H), 6.75-6.72 (m, 1H), 3.88 (s, 3H), 2.71 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)[C:11]2=[O:21])=[CH:6][CH:5]=1.[CH3:24][CH:25]([CH3:31])[CH2:26][S:27](Cl)(=[O:29])=[O:28]>>[CH3:24][CH:25]([CH3:31])[CH2:26][S:27]([N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:21])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:15][C:16]1=[O:20])(=[O:29])=[O:28]
Reactant: O=C1CC2(CCN1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Reactant: CC(C)CS(=O)(=O)Cl
Product: CC(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1=O

Procedure:
This material was prepared as a white solid in analogy to example 3 from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-1,7-dione, product of example 1 step D), and 2-methyl-propane-1-sulfonyl chloride. MS (ESI): 466.1 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[O-]CC.[Na+].[Na]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]#[N:10])[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)C(C#N)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
A mixture of 45.3 g. (0.31 mol.) of p-chlorophenyl-acetonitrile and 107 g. (0.72 mol., 99 ml.) of diethyl oxalate in an alcoholic sodium ethoxide solution [prepared by dissolving 7.13 g. (0.31 g.-atom) of sodium in 120 ml. of absolute ethanol] was refluxed with stirring for two hours. The cooled reaction mixture was diluted with 700 ml. of water, acidified with acetic acid and cooled to ice bath temperature. The resulting solid was collected and recrystallized from aqueous methanol to give ethyl 3 -(p-chlorophenyl)-3-cyanopyruvate, m.p. 134°-135°.
Reaction SMILES: [S:1]1[C:5]([NH2:6])=[N:4][CH:3]=[N:2]1.C(N(CC)CC)C.[Cl:14][CH2:15][C:16](Cl)=[O:17]>ClCCl>[Cl:14][CH2:15][C:16]([NH:6][C:5]1[S:1][N:2]=[CH:3][N:4]=1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: Nc1ncns1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ncns1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of [1,2,4]-thiadiazol-5-ylamine (3.0 g) in dry dichloromethane (30 mL) under nitrogen at 0° C. was treated with triethylamine (4.6 mL) followed by slow addition of chloroacetyl chloride (2.6 mL). The reaction mixture was allowed to warm up to room temperature. After 2 h, the mixture was partitioned between dichloromethane and water. The phases were separated and the aqueous layer was extracted with dichloromethane (×2). The combined organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated to give the crude product which was purified by silica gel chromatography eluting with 50-75% EtOAc/cyclohexane to give the title compound (1.00 g) as a yellow solid.
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25](OC)=O>C(O)C>[CH:2]1([N:7]2[C:11]3=[N:12][C:25]([CH2:24][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: COC(=O)Cc1ccccn1
Agent: [Na]
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccccn3)nc(=O)c1-2

Procedure:
Sodium metal (310 mg) was dissolved in ethanol (75 ml) and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.1 g, 5 mmol) and methyl 2-pyridinylacetate (1.52 g, 10 mmol) were added. The reaction mixture was heated at reflux for 28 hours, the solvent was removed in vacuo and the residue was dissolved in water (50 ml) and acidified with acetic acid. The mixture was extracted with CHCl3 (100 ml), the solvent was removed and the oily residue was crystallized from cyclohexane to afford 0.85 g of crude product. The product was purified by column chromatography on silica gel eluting with ether, followed by recrystallization from cyclohexane, to afford 1-cyclopentyl-3-ethyl-6-(2-pyridinylmethyl) pyrazolo[3,4-d]pyrimidin-4-one, as yellow crystals, m.p. 120-122° C.