Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1)(=O)=O.[N:17]1(C2C=CC(C=O)=CC=2)[CH:21]=[N:20][CH:19]=[N:18]1>>[N:17]1([C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=2)[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: O=Cc1ccc(-n2cncn2)cc1
Reactant: CS(=O)(=O)Oc1ccc(/C=C/C(=O)O)cc1
Product: O=C(O)/C=C/c1ccc(-n2cncn2)cc1

Procedure:
1.9 g of (E)-3-(4-(1,2,4-triazol-1-yl)phenyl)acrylic acid were prepared as described for (E)-3-(4-(methanesulfonyloxy)phenyl)acrylic acid, using 4-(1,2,4-triazol-1-yl)benzaldehyde instead of methanesulfonic acid 4-formylphenyl ester.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[C:10]([CH3:18])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]1C=C(C(O)=O)N2C=CC=CC=12>>[CH3:18][C:10]1[C:11]2[C:12]([NH2:17])=[CH:13][CH:14]=[CH:15][C:16]=2[N:8]([CH2:1][C:2]2[CH:7]=[N:19][C:5]([CH3:6])=[CH:4][CH:3]=2)[N:9]=1
Reactant: O=C(O)c1cnc2ccccn12
Reactant: Cc1nn(Cc2ccccc2)c2cccc(N)c12
Product: Cc1ccc(Cn2nc(C)c3c(N)cccc32)cn1
Yield: 11 %

Procedure:
Prepared according to the method of Example 80, replacing 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid and 1-benzyl-3-methyl-1H-indazol-4-amine with imidazo[1,2-a]pyridine-3-carboxylic acid and 3-methyl-1-((6-methylpyridin-3-yl)methyl)-1H-indazol-4-amine (8 mg, 11% yield). MS (APCI) m/z=397 (M+H).
Reaction SMILES: B(F)(F)F.CCOCC.[OH:10][C:11]1[C:20]([O:21][CH3:22])=[C:19]2[C:14]([CH:15]=[C:16]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17](=[O:23])[O:18]2)=[CH:13][CH:12]=1.ClC(Cl)(Cl)C(=N)O[C@H:39]1[C@@H:44]2[O:45][C:46](=[O:48])[O:47][C@@H:43]2[C@@H:42]([O:49][CH3:50])[C:41]([CH3:52])([CH3:51])[O:40]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:22][O:21][C:20]1[C:11]([O:10][C@H:39]2[C@@H:44]3[O:45][C:46](=[O:48])[O:47][C@@H:43]3[C@@H:42]([O:49][CH3:50])[C:41]([CH3:52])([CH3:51])[O:40]2)=[CH:12][CH:13]=[C:14]2[C:19]=1[O:18][C:17](=[O:23])[C:16]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[CH:15]2
Reactant: COc1c(O)ccc2cc(NC(=O)OCc3ccccc3)c(=O)oc12
Reactant: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](OC(=N)C(Cl)(Cl)Cl)OC1(C)C
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1c(O[C@@H]2OC(C)(C)[C@H](OC)[C@H]3OC(=O)O[C@@H]23)ccc2cc(NC(=O)OCc3ccccc3)c(=O)oc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.1 %

Procedure:
Boron trifluoride etherate (17.3 μL, 0.14 mmol) was added to 23g (157 mg, 0.46 mmol) and (3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate (665 mg, 1.83 mmol) in anhydrous CH2Cl2 (11.5 mL). After stirring at room temperature for 24 hours, triethylamine (150 μL) was added and the solvent was concentrated. The residue was purified via column chromatography (SiO2, 40:1→10:1 CH2Cl2:Acetone) to give 25g as a colorless foam (237 mg, 95%): 1H NMR (CDCl3, 500 MHz) 8.20 (s, 1H), 7.48 (s, 1H), 7.33-7.29 (m, 5H), 7.09 (dd, J=14.2, 8.8 Hz, 2H), 5.72 (d, J=1.8 Hz, 1H), 5.16 (s, 2H), 5.02 (dd, J=7.8, 1.8 Hz, 1H), 4.89 (t, J=7.8 Hz, 1H), 3.88 (s, 3H), 3.52 (s, 3H), 3.21 (d, J=7.8 Hz, 1H), 1.27 (s, 3H) 1.17 (s, 3H); 13C NMR (CDCl3, 125 MHz) 158.0, 153.3, 153.2, 153.1, 149.8, 143.8, 137.1, 135.5, 128.7 (2C), 128.6, 128.3 (2C), 122.7, 122.2, 121.4, 116.1, 113.7, 95.3, 74.7, 72.9, 67.6, 61.9, 60.7, 60.6, 29.7, 29.4; IR (film) νmax 3400, 3319, 2984, 2935, 2359, 1815, 1715, 1609, 1526, 1464, 1383, 1364, 1285, 1213, 1175, 1111, 1063, 968, 764, 737, 700 cm−1; HRMS (ESI+) m/z: [M+Na]+ calcd for C27H27NO11, 564.1482; found, 564.1455.
Reaction SMILES: [Br:1][C:2]1[S:6][N:5]=[C:4]([CH2:7]Br)[CH:3]=1.C(N(CC)CC)C.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)Cl>[Br:1][C:2]1[S:6][N:5]=[C:4]([CH2:7][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]=1
Reactant: BrCc1cc(Br)sn1
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Brc1cc(CN2CCCCC2)ns1
Yield: 76.1 %

Procedure:
5-Bromo-3-bromomethylisothiazole (1.92 g, 7.5 mmol), triethylamine (1.57 mL, 11.2 mmol) and piperidine (1.5 mL, 15.0 mmol) in DCM (10 mL) were stirred for 16 h at ambient temperature. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (75 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as a colourless oil (1.49 g, 97%) that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): 7.25 (s, 1H), 3.59 (s, 2H), 2.46-2.33 (m, 4H), 1.62-1.53 (m, 4H), 1.48-1.38 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([CH3:21])([CH3:20])[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[C:23]1[Na].O>C(O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:9])([C:11]([CH3:21])([CH3:20])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:10][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)=[CH:4][CH:3]=1
Reactant: [Na]c1ncc[nH]1
Reactant: CC(C)(Cc1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Solvent: O
Solvent: CCCO
Product: CC(C)(Cc1ccc(Cl)cc1)C(O)(Cn1ccnc1)c1ccc(Cl)cc1
Yield: 34.9 %

Procedure:
30 g (0.0935 mol) of 2-(4-chlorophenyl)-2-(4-chlorophenyl-tert.-butyl)-oxirane in 40 ml of n-propanol are added dropwise to a solution of 7.7 g (0.108 mol) of imidazolyl-sodium in 60 ml of n-propanol at the reflux temperature. The reaction mixture is stirred under reflux for a further 48 hours and cooled, water is added, and the mixture is extracted with methylene chloride. The organic phase is dried over sodium sulphate and concentrated in vacuo. The oily residue is stirred in diisopropyl ether. The crystalline precipitate formed is filtered off under suction and dried. 12.7 g (35% of theory) of 2,4-bis(4-chlorophenyl)-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-ol of melting point 174° C. are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1>C1(C)C(C)=CC=CC=1>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1)([O-:14])=[O:13]
Reactant: c1ccc2c(c1)CCN2
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCc2ccccc21

Procedure:
An initial solution of 22.6 g of 4-chloro-3-nitrobenzotrifluoride and 29.8 g of indoline in 500 ml of xylene is stirred and refluxed under N2 for 18 hours. The indoline HCl salt which separates is filtered off, and the xylene filtrate is washed with water, with 3 N HCl, with 3 N--NaOH, and finally again with water, dried over MgSO4, and concentrated to an oil on a rotovac at 60° C., first at aspirator pressure, then in vacuo. This oil is taken up in 100 ml hexane and allowed to crystallize 18 hours to yield 1-(2-nitro-4-trifluoromethylphenyl)indoline, m.p. 89°-92° C.
Reaction SMILES: [O:1]=[C:2]1[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]([S:17]NC2C=CC=CC=2)[N:3]1[CH:25]([C:30]([CH3:32])=[CH2:31])[C:26]([O:28][CH3:29])=[O:27].[ClH:33]>C(Cl)Cl>[Cl:33][C:30]1([CH3:32])[CH:25]([C:26]([O:28][CH3:29])=[O:27])[N:3]2[C:2](=[O:1])[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C@H:4]2[S:17][CH2:31]1
Reactant: Cl
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SNc1ccccc1
Solvent: ClCCl
Product: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SCC1(C)Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Methyl 2-oxo-3-(2-phenoxyacetamido)-4-anilinothio-α-isopropenylazetidine-1-acetate (0.12 g) was dissolved in dry methylene chloride (5 ml). To this solution was added 5% methanolic hydrochloric acid (0.8 ml) and the mixture was stirred for 10 hours at room temperature. After the reaction, the reaction mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was distilled off and the residue was subjected to column chromatography on silica gel using chloroform as developing solvent to give oily methyl 3-chloro-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (0.07g).
Reaction SMILES: [C@@H:1]1([N:9]2[CH2:14][N:13]([CH3:15])[C:12](=[O:16])[NH:11][C:10]2=[O:17])[O:6][C@H:5]([CH2:7][OH:8])[C@@H:3]([OH:4])[CH2:2]1.CN(C)C=O.N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>O.C(Cl)(Cl)Cl>[Si:28]([CH:7]([OH:8])[C@H:5]1[O:6][C@@H:1]([N:9]2[CH2:14][N:13]([CH3:15])[C:12](=[O:16])[NH:11][C:10]2=[O:17])[CH2:2][C@@H:3]1[OH:4])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CN1CN([C@H]2C[C@H](O)[C@@H](CO)O2)C(=O)NC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CN1CN([C@H]2C[C@H](O)[C@@H](C(O)[Si](C)(C)C(C)(C)C)O2)C(=O)NC1=O
Reaction time: 18 h
Yield: 82.5 %

Procedure:
A reaction mixture consisting of 12.25 gm. (0.050 mole) of 1-(2-deoxy-β-D-ribofuranosyl)-5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione, 50 ml. dimethylformamide, and 8.5 gm. (0.125 mole) of imidazole was warmed to 35° C. and stirred until the imidazole had dissolved. There was then added with continued stirring 7.55 gm. (0.050 mole) tert-butyldimethylsilyl chloride. Stirring was continued for 18 hours at 35° C. The solvent medium was then removed by evaporation under reduced pressure, and the residue thus obtained was dispersed in a solvent mixture consisting of 200 ml. chloroform and 50 ml. water. The two phases were allowed to stabilize and the aqueous phase was recovered. It was washed two times with 50 ml. portions of chloroform. The three chloroform layers (original and two washings) were combined and washed with three-25 ml. portions of water. The washed chloroform solution was dried over anhydrous magnesium sulfate and filtered. The chloroform was then removed by evaporation under reduced pressure to give 14.8 gm. (82.5% yield) of 1-(5-tert-butyldimethylsilyl-2-deoxy-β-D-ribofuranosyl)5,6-dihydro-5-methyl-s-triazine-2,4-(1H,3H)-dione.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[NH:3]1.Cl[CH2:9][C:10]1[N:14]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[N:13]=[N:12][N:11]=1>C(#N)C>[CH3:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([CH3:7])[N:3]1[CH2:9][C:10]1[N:14]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[N:13]=[N:12][N:11]=1
Reactant: CC1CCC(C)N1
Reactant: N#Cc1ccc(-n2nnnc2CCl)cc1
Solvent: CC#N
Product: C[C@@H]1CC[C@H](C)N1Cc1nnnn1-c1ccc(C#N)cc1
Yield: 48.6 %

Procedure:
A solution of 2,5-dimethylpyrrolidine (0.334 mL, 2.73 mmol) and 4-[5-(chloromethyl)-1H-tetrazol-1-yl]benzonitrile (200 mg, 0.911 mmol, Intermediate 10) in acetonitrile (1.5 mL) was heated to 150° C. for 45 minutes in a microwave reactor. The reaction mixture was purified by high PH MDAP (2 injections). Relevant fractions were combined and the solvent removed. The resulting solid was partitioned between DCM (10 mL) and water (5 mL). The organic layer was collected via a hydrophobic frit and the solvent removed under vacuum to yield the title compound as a white solid (125 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[H-].[Na+].[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][Cl:22])([O-:18])=[O:17].Cl>CO.CCOCC>[ClH:22].[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N+:16]([O-:18])=[O:17])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: Oc1ccc(Cc2ncc[nH]2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: O=[N+]([O-])c1ccccc1COc1ccc(Cc2ncc[nH]2)cc1

Procedure:
Analogously to Example 1, a crude ether is obtained from 1.74 g. of 4-(1-imidazolylmethyl)-phenol, 300 mg. of sodium hydride suspension, and 1.72 g. of 2-nitrobenzyl chloride. This crude ether is dissolved in methanol and combined with an excess of methanol which contains hydrogen chloride until the mixture shows an acidic reaction. After the solvent has been removed by evaporation under vacuum, the residue is dissolved in methylene chloride and mixed with ether until the onset of crystallization, thus obtaining 925 mg. of [4-(1-imidazolylmethyl)-phenyl]-(2-nitrobenzyl)-ether, hydrochloride, which melts at 156°-158° after another recrystallization from isopropanol.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[N:9]1([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[N:10]1.[CH3:22][C:23]1([CH3:31])[O:28][C:27](=[O:29])[CH2:26][C:25](=[O:30])[O:24]1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>C(O)C.C(O)(C)C>[N:9]1([C:14]2[CH:21]=[CH:20][C:17]([CH2:18][CH:26]3[C:27](=[O:29])[O:28][C:23]([CH3:31])([CH3:22])[O:24][C:25]3=[O:30])=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[N:10]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Solvent: CC(C)O
Product: CC1(C)OC(=O)C(Cc2ccc(-n3cccn3)cc2)C(=O)O1
Reaction time: 0.67 h

Procedure:
L-Proline (4.07 g, 35.0 mmol) was added to a semi-heterogeneous mixture of 4-(1H-pyrazol-1-yl)benzaldehyde (30.0 g, 174 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (25.6 g, 174 mmol) in ethanol (996 mL) at room temperature. After 40 minutes, diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (44.1 g, 174 mmol) was added in one portion followed by ethanol (125 mL). After overnight stirring, the mixture was concentrated under reduced pressure to afford a yellow solid. Isopropanol (300 mL) was added and the heterogeneous mixture was sonicated for 30 minutes. The mixture was filtered and the filter cake was washed with isopropanol. The solids were collected and dried under vacuum to provide the title compound as a white solid.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:21]3[C:22](=[O:26])[C:23](Br)(Br)[C@H:20]3[S:19](=[O:27])[C:18]2([CH3:29])[CH3:28])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+].[Bi](Cl)(Cl)Cl.[Al]>ClCCl.O.CO>[C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:21]3[C:22](=[O:26])[CH2:23][C@H:20]3[S:19](=[O:27])[C:18]2([CH3:29])[CH3:28])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(Br)(Br)[C@H]2S1=O
Agent: Cl[Bi](Cl)Cl
Agent: [Al]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC1(C)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C[C@H]2S1=O
Temperature: 25 °C
Yield: 89 %

Procedure:
A 82.6 g quantity of Compound 1 was dissolved in 300 mL of dichloromethane. To the solution was added 115 mL of 20% aqueous solution of ammonium chloride and 36 mL of methanol with stirring. After adding 1.6 g of bismuth chloride, 10 g of aluminum powder was gradually added to the mixture while maintaining at 20 to 30° C. The mixture was reacted for 5 hours while maintaining at 20 to 30° C. After adding 120 mL of water, insoluble metalresidue was filtered and an orgaic layer was separated. The organic layer was washed with 120 mL of 5% aqueous solution of sodium chloride. The organic layer was concentrated to give Compound 2.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]([C:20]3[NH:24][CH:23]=[N:22][N:21]=3)=[C:14]([O:16][CH2:17][CH:18]=[CH2:19])[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.O1CCCC1>C(O)C.[Pd]>[CH3:1][C:2]1[C:10]([C:11]2[S:12][C:13]([C:20]3[NH:24][CH:23]=[N:22][N:21]=3)=[C:14]([O:16][CH2:17][CH2:18][CH3:19])[N:15]=2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: C=CCOc1nc(-c2c(C)nn3ccccc23)sc1-c1nnc[nH]1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCOc1nc(-c2c(C)nn3ccccc23)sc1-c1nnc[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23 %

Procedure:
To a solution of 2-methyl-3-[4-(prop-2-en-1-yloxy)-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyrazolo[1,5-a]pyridine (70 mg, 0.55 mmol) produced in Example 27 in ethanol (15 mL)-tetrahydrofuran (15 mL) was added 10% palladium/carbon (73 mg), and the mixture was stirred at room temperature for 5 hr under a hydrogen atmosphere (1 atm). Palladium/carbon was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound (43 mg, 61%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)#[N:2].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)(N)[C@@H:44]([NH2:50])[CH2:45][O:46]COC)=[CH:39][CH:38]=1>C1(C)C=CC=CC=1>[C:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]2[NH:50][C@@H:44]([CH2:45][OH:46])[C:43]([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)([C:52]3[CH:53]=[CH:54][C:55]([F:58])=[CH:56][CH:57]=3)[N:2]=2)[CH:8]=1)#[N:10]
Reactant: COCOC[C@H](N)C(N)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: N#Cc1ccnc(C#N)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: Cc1ccccc1
Product: N#Cc1ccnc(C2=NC(c3ccc(F)cc3)(c3ccc(F)cc3)[C@H](CO)N2)c1
Reaction time: 48 h
Yield: 21.2 %

Procedure:
2,4-Dicyanopyridine (601 mg) and ytterbium trifluoromethanesulfonate (289 mg) were added to a solution of (2R)-1,1-bis(4-fluorophenyl)-3-(methoxymethoxy)-1,2-propanediamine (1.50 g) in toluene (30 mL), and the mixture was refluxed under stirring for 2 days. The reaction mixture was concentrated in vacuo, and then the residue was dissolved in tetrahydrofuran (20 mL). 6N Hydrochloric acid (10 mL) was added to the solution, and then the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated in vacuo, and then the residue was purified by silica gel column chromatography (C-300; hexane: ethyl acetate=2:1) to give the objective compound (385 mg).
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=O)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.COC1C=CC(P2SP(C3C=CC(OC)=CC=3)S2)=CC=1>C(COC)OC>[N:1]1([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[S:32])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCN1S(=O)(=O)c1ccc(N2CCCCCC2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: COc1ccc(P2SP(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Product: O=S(=O)(c1ccc(N2CCCCCC2)cc1)N1CCCC1=S
Yield: 57.3 %

Procedure:
A mixture comprising 5 g of 1-[4-(1-hexahydroazepinyl)benzenesulphonyl]-2-pyrrolidinone, prepared as in Example 18 of the European Patent Application published under No. 0,033,578, and 3.13 g of Lawesson reagent (or 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane in 100 cm3 of dimethoxyethane is heated to reflux for 3 hours. The mixture is allowed to return to room temperature and is evaporated to dryness, and the residue is chromatographed on silica (eluant: benzene). 2 g of product are recovered. M.p. 168°-170° C. After crystallization in methanol, 1.5 g of expected product are obtained. M.p. 172°-173° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]O)[C:3]=1[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.CCN(CC)CC.CS(Cl)(=O)=O.[F:30][C:31]([F:40])([F:39])[C:32]1[C:33]([OH:38])=[N:34][CH:35]=[CH:36][CH:37]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:39])([F:40])[F:30])[C:33]2=[O:38])[C:3]=1[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: Oc1ncccc1C(F)(F)F
Reactant: Cc1ccnc(CO)c1COC1CCCCO1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccnc(Cn2cccc(C(F)(F)F)c2=O)c1COC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
[4-Methyl-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-yl]-methanol (138 mg. 0.58 mmol) was dissolved in DCM (5 mL) and cooled to 0° C. NEt3 (324 μL. 2.33 mmol) and methanesulfonyl chloride (90 μL. 1.16 mmol) were added and the reaction mixture was stirred for 1 h at 0° C. After removal of the solvents in vacuo the residue was dissolved in DMF (10 mL) and CsCO3 (570 mg. 1.75 mmol) and 3-trifluoromethyl-pyridin-2-ol (142 mg. 0.87 mmol) were added. After stirring for 2 h at RT the solvent was removed in vacuo and the residue was partioned between water (20 mL) and DCM (20 mL) extracted with DCM (3×20 mL) and the combined organic fractions were dried over Na2SO4 filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexane/EtOAc 2:1→1:1) to give the title compound. MS (m/z): 382.9 [M+H+].
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.B(O)(O)[C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1>>[F:20][C:15]1[CH:14]=[C:13]([C:4]2[CH:3]=[C:2]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2cc(-c3ccc(O)c(F)c3)nc3ccc(O)cc23)cc1
Yield: 85 %

Procedure:
This compound was prepared from 6b using p-tolylboronic acid according to method P. Orange powder; Yield: 85%; mp 184–188° C.; 1H-NMR (300 MHz, DMSO-d6) δ 2.44 (s, 3H), 7.07 (dd, J=8.8, 8.8 Hz, 1H), 7.12 (d, J=2.6 Hz, 1H), 7.31 (dd, J=9.1, 2.6 Hz, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.82 (s, 1H), 7.94 (dd, J=8.4, 2.1 Hz, 1H), 7.96 (d, J=9.0 Hz, 1H), 8.07 (dd, J=13.0, 2.0 Hz, 1H), 9.91 (s, 1H), 10.21 (s, 1H); MS (ESI) m/z 344 ([M−H]−), 346 ([M+H]+); Anal. Calcd for C22H16FNO2: C: 76.51, H: 4.67, N: 4.06. Found: C: 75.55, H: 4.50, N: 3.74.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=O)[O:8][CH:7]2[CH3:12].COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:22]2)=CC=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[S:22])[O:8][CH:7]2[CH3:12]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1OC(=O)c2c(O)cccc21
Solvent: Cc1ccccc1C
Product: CC1OC(=S)c2c(O)cccc21

Procedure:
1.67 g of 7-hydroxy-3-methyl-phthalide (see Example 101) and 2.17 g of 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetan (Lawesson reagent) are heated in 8 ml of xylene at 138° C. for 3 hours. When it has cooled, the reaction material is filtered directly over a column of silica gel [eluant: ethyl acetate/n-hexane (1:4)] in order to isolate the 7-hydroxy-3-methyl-isobenzofuran-1(3H)-thione; m.p. 38°-40° C.; IR spectrum: 1624, 1604, 1368, 1330, 1304, 1165 cm-1 ; mass spectrum: 180 (M+ =100), 165 (58), 137 (24).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][CH2:5][CH:6]([C:9]1[S:10][CH:11]=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=1)[CH2:7][CH3:8].Cl>C1COCC1.O>[CH3:4][CH2:5][CH:6]([C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1)[CH2:7][CH3:8]
Reactant: CCOC(=O)c1csc(C(CC)CC)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)c1nc(C(=O)O)cs1
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (2.07 g) was added to a solution of ethyl 2-(pentan-3-yl)thiazole-4-carboxylate (example 71, step c) (2.8 g) in a mixture of THF (80 mL) and water (20 mL). The resulting mixture was stirred overnight. The reaction was acidified with concentrated hydrochloric acid (6 mL) and the volatiles evaporated. The resulting aqueous mixture was saturated with sodium chloride and extracted with ethyl acetate (3×100 mL). The combined organic solutions were dried over sodium sulphate, filtered and evaporated to give the subtitled compound as a white solid. Yield 2.3 g