Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.N#N.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1>C1COCC1>[OH:26][CH:25]([C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=1)[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CC(C)[Mg]Cl
Agent: N#N
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 4-iodobenzoate 63a (8 mmol, 2.1 g) in 10 mL of dry THF was added i-propyl magnesium chloride (2M in THF, 8.4 mmol, 4.2 mL) dropwise under N2 at −20° C. The solution was stirred for 30 min. The formed Grignard reagent in THF was then added slowly to a solution of 4-trifluoromethylbenzaldehyde (8 mmol, 1.1 mL) in THF (20 mL) at −40° C. After 20 min, the reaction mixture was allowed to warm up slowly to room temperature. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give the 63c as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:24][O:25][C:26]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32])=[O:27].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:31]([C:30]5[CH:29]=[C:28]([CH:36]=[CH:35][CH:34]=5)[C:26]([O:25][CH3:24])=[O:27])=[O:32])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)c1
Yield: 70.7 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (250 mg, 0.81 mmol), 3-(methoxycarbonyl)benzoic acid (150 mg, 0.83 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (160 mg, 0.84 mmol), 1-hydroxybenzotriazole (110 mg, 0.81 mmol) and N,N-dimethylformamide (8.0 mL) as starting materials and in the same manner as in Example 318, the title compound (270 mg, 72%) was obtained as a white powder.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[CH:11]1[C:23]2[CH:22]([CH2:24][O:25][C:26](Cl)=[O:27])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>>[NH:1]([C:26]([O:25][CH2:24][CH:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]2[C:23]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:27])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C

Procedure:
5.48 g (37.5 mmoles) of finely ground glutamine (Chemical Dynamics Corp.) was placed in a 250 mL round bottom flask (oven dried) which was fitted with a heating mantle and condenser (oven dried). A nitrogen gas line was attached at the top of the condenser. The solid was suspended in 87.5 mL of dry N,N-dimethyl-acetamide and stirred vigorously. 19.04 mL (150 mmoles) of Tms-Cl was injected in one portion. The mixture was warmed slightly for 1 hour and cooled in an ice bath. 9-Fluorenylmethyloxycarbonyl chloride (6.47 g, 25 mmoles) and 19.78 mL (175 mmoles) of diisopropylethylamine were added. The solution was stirred in ice for 20 minutes and warmed to room temperature for 1-1.5 hrs. The mixture was concentrated on a rotary evaporator and then distributed between 200 mL diethyl ether and 250 mL 2.5% sodium bicarbonate. The phases were separated and the aqueous layer was extracted with 2×50 mL diethyl ether. The ether layers were backwashed with 2×25 mL H2O. The combined aqueous layers were acidified to pH 2 with 1.0N HCl. The white precipitate was filtered, washed with cold H2O and dried under high vacuum. Appropriate solvents were used to recrystallize the product. The product was found to be homogeneous (Table II).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15](C3C=CN=CC=3)[CH:16]=2)[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:36]3[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=3)[CH:16]=2)[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc2cc(-c3ccncc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: OB(O)c1ccncc1
Product: Cc1cc2cc(-c3cccnc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyridin-3-yl)naphthalen-2-yl)acetic acid (54) was prepared in a similar fashion to compound 53 of Example 51 with the substitution of pyridin-3-ylboronic acid for pyridin-4-ylboronic acid in step 5. The title compound (0.024 g) was isolated as an amorphous white powder. LCMS-ESI− (m/z): [2M−H]− calcd for C56H51Cl2N2O6: 917.31; found: 917.39. 1H-NMR: 400 MHz, (CD3CN) δ: 9.08 (s, 1H); 8.74 (d, J=5.2 Hz, 1H); 8.61 (d, J=8 Hz, 1H); 8.19 (s, 1H); 7.93-7.88 (m, 1H); 7.84 (s, 1H); 7.66-7.53 (m, 4H); 7.44-7.35 (m, 2H); 5.24 (s, 1H); 2.59 (s, 3H); 0.99 (s, 9H).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([O:14]C2CCCCO2)[CH:11]=[CH:12][CH:13]=1.[Br:21]CCBr>Cl>[Br:21][C:9]1[C:8]([O:7][CH3:6])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:14]
Reactant: COc1cccc(OC2CCCCO2)c1
Reactant: BrCCBr
Agent: Cl
Agent: [Li]CCCC
Product: COc1cccc(O)c1Br
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 30 %

Procedure:
33 mL (52.8 mmol) n-butyllithium (1.6 M in hexane) were added dropwise to a solution 10 gm (48.1 mMol) tetrahydropyran-2-yl 3-methoxyphenyl ether in 100 mL tetrahydrofura over 15 minutes. After stirring for 2.5 hours at room temperature, the reaction mixture was cooled to 0° C. and then 4.6 mL (53.2 mMol) 1,2-dibromoethane were added dropwise. The reaction mixture was then allowed to stir at room temperature for about 14 hours. The reaction mixture was then diluted with 50 mL 1 N hydrochloric acid and was stirred for 1 hour. The aqueous phase was extracted with three 100 mL portions of diethyl ether. The organic phases were combined and extracted well with 5 N sodium hydroxide. These basic aqueous extracts were combined and cooled in an ice/water bath. The pH of this aqueous solution was adjusted to about 1 with 5 N hydrochloric acid and then extracted with three 100 mL portions of diethyl ether. These ether extracts were combined and washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0 to 10% ethyl acetate. Fractions containing the desired compound were combined and concentrated under reduced pressure to provide 2.91 gm (30%) of a residue which crystallized upon standing.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)NCC2
Temperature: 15 °C
Reaction time: 0.67 h

Procedure:
A solution of indole-6-carboxylic acid methyl ester (534 mg, 3.05 mmol) in acetic acid (7.5 ml) was cooled to 0° C. Sodium cyanoborohydride (580 mg, 9.2 mmol, 3 equiv.) was added and the mixture stirred at 15° C. for 40 min. A further aliquot of sodium cyanoborohydride (193 mg, 3.05 mmol, 1 equiv.) was added, and the reaction mixture was stirred for 30 min. at room temperature. The solvent was then evaporated, and the residue dissolved in dichloromethane and washed with 1N NaOH. The organic phase was dried with Na2SO4 and evaporated, yielding 2,3-dihydro-1H-indole-6-carboxylic acid methyl ester as a light yellow solid, 494 mg (77%). This was used as such in the following reaction.
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]1)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:16]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17]1>>[CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:20]([CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:21])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C1CCC1
Reactant: C(=C/c1ccccc1)\CC1CCCCN1
Product: O=C(C1CCC1)N1CCCCC1C/C=C/c1ccccc1

Procedure:
Stage a) The method is the same as that of Example 1.1, Stage a), the initial reactants being (E)-2-(cinnamyl)piperidine and cyclobutanecarboxylic acid chloride, which furnish (E)-2-cinnamyl-1-(cyclobutanecarbonyl)piperidine (formula II; Ar=C6H5, m=1, n=2, R=cyclobutyl). Yield: 99%.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([C:14]2[N:18]([CH2:19][CH2:20][CH3:21])[C:17]([CH:22]=O)=[N:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][NH:25][CH3:26].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[NH:1]([C:8]1[N:13]=[C:12]([C:14]2[N:18]([CH2:19][CH2:20][CH3:21])[C:17]([CH2:22][N:25]([CH3:26])[CH3:24])=[N:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CCCn1c(-c2ccnc(Nc3ccccc3)n2)cnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCn1c(-c2ccnc(Nc3ccccc3)n2)cnc1CN(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
A mixture of 2-anilino 4-(2-formyl-1-propylimidazol-5-yl)pyrimidine (Method 118; 200 mg, 0.65 mmol) and dimethylamine (391 μl of 2M solution in THF, 0.78 mmol) in MeOH (6 ml) stirred for 3 hours at ambient temperature. Acetic acid (41 mg, 0.716 mmol) and sodium cyanoborohydride (45 mg, 0.716 mmol) were added and the mixture stirred for a further 18 hours. The volatiles were removed by evaporation and residue dissolved in EtOAc (7 ml). This solution was washed with saturated aqueous sodium hydrogen carbonate solution, water, and brine, then dried and the solvent removed by evaporation to give the title compound (210 mg, 96%) as a yellow foam. NMR: 0.62 (t, 6H), 1.50 (m, 2H), 2.23 (s, 6H), 3.60 (s, 2H), 4.56 (m, 2H), 6.98 (t, 1H), 7.10 (d, 1H), 7.28 (t, 2H), 7.62 (m, 3H), 8.39 (d, 1H), 9.39 (s, 1H); m/z 337.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35].CCOCC>C(Cl)(Cl)Cl>[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[NH:33][C:34]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[C:17]([CH3:24])[C:18]=1[CH3:23])=[O:35]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(C)c3C)c2cc1OC
Yield: 70 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethyl-aniline (710 mg) was dissolved in chloroform (7 ml), and 2,4-difluorophenyl isocyanate (310 μl) was then added to the solution. The mixture was heated under reflux for one hr, and a large amount of ether was added to the reaction solution. The resultant precipitate was collected by suction filtration to give 735 mg (yield 70%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH2:23][CH3:24])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:25]([N:1]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH2:23][CH3:24])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:3]=1)[C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCc1nc(C2CCCC2)n2nc(-c3cccc(N)c3)[nH]c(=O)c12
Product: CCc1nc(C2CCCC2)n2nc(-c3cccc(N(C(=O)c4ccccc4)C(=O)c4ccccc4)c3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 31, 50 mg (0.15 mmol) 2-(3-aminophenyl)-7-cyclopentyl-5-ethylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (Example 29), 43 mg (0.31 mmol) benzoyl chloride and proportionate amounts of the other reagents are used.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4cc(Cl)ccc4Cl)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(Cl)cc(-c3cc(Cl)ccc3Cl)c2O1

Procedure:
The title compound was prepared (0.027 g, 23%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.152 g, 0.31 mmol) and methylamine (0.086 g, 3.1 mmol). mp 185-187° C.
Reaction SMILES: [CH3:1][C:2]1[C:14]([N+:15]([O-])=O)=[C:13]([C:18]([O:20][CH3:21])=[O:19])[C:12]([CH3:22])=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[H][H]>O1CCCC1.[Pd]>[NH2:15][C:14]1[C:2]([CH3:1])=[C:3]([CH:11]=[C:12]([CH3:22])[C:13]=1[C:18]([O:20][CH3:21])=[O:19])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: COC(=O)c1c(C)cc(C(=O)OC(C)(C)C)c(C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1c(C)cc(C(=O)OC(C)(C)C)c(C)c1N
Yield: 98.1 %

Procedure:
1-tert-Butyl 4-methyl 2,5-dimethyl-3-nitroterephthalate (0.5 g, 1.62 mmol) was dissolved in tetrahydrofuran (4 mL). 10 wt % Palladium on carbon (Degussa type, 50 mg) was added to the solution and the mixture was treated with hydrogen at ambient temperature for 3 h. 10 wt % Palladium on carbon (Degussa type, 50 mg) was added to the solution, and the mixture was treated with hydrogen at ambient temperature for a further 2 h. 10 wt % Palladium on carbon (Degussa type, 100 mg) was added to the solution, and the mixture was treated with hydrogen at ambient temperature for a further 5 h. The mixture was filtered and the filtrate was concentrated to afford 1-tert-butyl 4-methyl 3-amino-2,5-dimethylterephthalate (0.444 g, 1.59 mmol, 98% yield) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 6.78 (s, 1H), 5.20 (br s, 2H), 3.90 (s, 3H), 2.40 (s, 3H), 2.24 (s, 3H), 1.59 (s, 9H); MS (EI) for C15H21NO4: 280 (MH+).
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:12][NH:13][C:14]([C:16]2[N:17]=[C:18]([C:34]#[N:35])[C:19]3[C:24]([C:25]=2[OH:26])=[CH:23][CH:22]=[C:21]([S:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:20]=3)=[O:15])[CH2:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:34]([C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[C:21]([S:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:20]=2)[C:25]([OH:26])=[C:16]([C:14]([NH:13][CH2:12][C:8]2([C:6]([OH:7])=[O:5])[CH2:9][CH2:10][CH2:11]2)=[O:15])[N:17]=1)#[N:35]
Reactant: CC(C)(C)OC(=O)C1(CNC(=O)c2nc(C#N)c3cc(Sc4ccccc4)ccc3c2O)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1nc(C(=O)NCC2(C(=O)O)CCC2)c(O)c2ccc(Sc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A mixture of 1-{[(1-cyano-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carbonyl)-amino]-methyl}-cyclobutanecarboxylic acid tert-butyl ester (58 mg), TFA (2 mL) and DCM (6 mL) was stirred at rt for 1 h; then concentrated, the residue was dissolved in water and added 2 M HCl solution, solids were collected via filtration, washed with water and air dried to give the desired product (50 mg). LC MS ESI+: 434 (M+1)+.
Reaction SMILES: O[CH2:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4]1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[OH-].[Na+]>C(O)C>[O:21]1[CH2:22][CH2:23][N:18]([CH2:2][N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:4]2)[CH2:19][CH2:20]1
Reactant: OCn1nc(-c2ccccc2)c2ccccc21
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc(-c2nn(CN3CCOCC3)c3ccccc23)cc1

Procedure:
1-Hydroxymethyl-3-phenylindazole (2 g), morpholine (0.84 g) and 5% aqueous sodium hydroxide solution (1 ml) were dissolved in ethanol (30 ml), and the mixture was heated under reflux for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The resulting oily residue was treated with ether-hydrochloric acid to obtain 1-morpholinomethyl-3-phenylindazole having a melting point between 166°-167° C (decomposition) after recrystallization from ethanol-ether.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH:16][C:17]4[CH:25]=[C:24]5[C:20]([C:21]([CH3:28])([CH3:27])[C:22](=[O:26])[NH:23]5)=[CH:19][CH:18]=4)[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH2:3]1.O[C@H]1CCNC1>>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH:16][C:17]4[CH:25]=[C:24]5[C:20]([C:21]([CH3:28])([CH3:27])[C:22](=[O:26])[NH:23]5)=[CH:19][CH:18]=4)[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH2:3]1
Reactant: CC1(C)C(=O)Nc2cc(Nc3nc4c(N5CC[C@@H](O)C5)nccn4n3)ccc21
Agent: O[C@H]1CCNC1
Product: CC1(C)C(=O)Nc2cc(Nc3nc4c(N5CC[C@H](O)C5)nccn4n3)ccc21

Procedure:
The compound is synthesized using the procedure described for 6-[8-((R)-3-hydroxy-pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamino]-3,3-dimethyl-1,3-dihydro-indol-2-one with (S)-3-hydroxy-pyrrolidin as nuceophile.
Reaction SMILES: [Mg].II.[CH2:4](Cl)[CH:5]=[CH2:6].[CH2:8](Cl)/[CH:9]=[C:10](/[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])\[CH3:11]>C(O)(=O)C.CCOCC>[CH3:11][C:10]([CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:9][CH2:8][CH2:6][CH:5]=[CH2:4]
Reactant: C=CCCl
Reactant: CC(C)=CCC/C(C)=C/CCl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: CC(=O)O
Product: C=CCCC=C(C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Magnesium turnings (51 g., 2.1 mole) were suspended in 1700 ml. of ether and activated with a crystal of iodine. Allyl chloride (153 g., 2.0 mole) in 200 ml. of ether was added dropwise so as to maintain the mixture at reflux temperature throughout the addition. The mixture was refluxed for an additional 2 hours, then a solution of technical 82% pure geranyl chloride (210 g., 1.05 mole) in 200 ml. of ether was added dropwise at reflux temperature. The mixture was stirred for 2 hours at room temperature, then it was cooled down to 10° and slightly acidified with 20% aqueous acetic acid. The mixture was extracted with ether. The extracts were neutralised with 10% NaOH, washed with water, dried as usual and concentrated. The residue gave 217 g. of crude triene as a light yellow liquid the purity of which was 80% according to vapour phase chromatography; it was used without further purification.
Reaction SMILES: [CH:1]1[CH:8]=[CH:7][C:5](=[O:6])[C:4]([OH:9])=[CH:3][CH:2]=1.[C:10](=O)([O-])[O-].[K+].[K+].C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3.CI>C(#N)C>[CH3:10][O:6][C:5]1[C:4](=[O:9])[CH:3]=[CH:2][CH:1]=[CH:8][CH:7]=1
Reactant: O=c1cccccc1O
Reactant: O=C([O-])[O-]
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1cccccc1=O
Yield: 91.8 %

Procedure:
To the mixture of 20 g (0.16 mol) of tropolone (2-hydroxy-2,4,6-cycloheptatrienone), 68 g (0.48 mol) of anhydrous potassium carbonate, 6.1 g (0.016 mol) of dicyclohexyl-18-crown-6 and 750 ml of acetonitrile were added 117 g (0.8 mol) of methyl iodide with stirring. After stirred under reflux for 10 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. After washing with 13.8% aqueous solution of potassium carbonate and water. After drying with magnesium sulfate anhydrous, dichloromethane was evaporated under reduced pressure, and the residue was subjected to purification by means of silica gel column chromatography. Elution was carried out by using ethyl acetate and the solvent was evaporated under reduced pressure to give 20 g of 2-methoxytropone (2-methoxy-2,4,6-cycloheptatrienone) (yield: 92%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]2)[C:4]1=[O:18].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23]Cl.Cl>CN(C)C=O.O.O1CCCC1>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]2)[C:4]1=[O:18]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: O=C1NC(=O)C2(N1)C(=O)Nc1ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (1.5 g., 50% w/w dispersion in mineral oil) was added continuously to a solution of spiro[imidazoline-4,3'-indoline]-2,2',5-trione (2.17 g.) in N,N-dimethylformamide (40 ml.) and water (20 ml.). The resultant mixture was stirred for 30 minutes and then a solution of 3,4-dichlorobenzyl chloride (1.95 g.) in tetrahydrofuran (5 ml.) was added dropwise during 10 minutes. The solution obtained was stirred at room temperature for two hours and then poured into water (150 ml.). The mixture was acidified with concentrated hydrochloric acid and then extracted with ether (2×100 ml.). The combined extracts were washed with water (3×100 ml.), then with saturated sodium chloride solution (100 ml.), dried (MgSO4) and evaporated. The residual solid was dissolved in chloroform and purified by chromatography on silica (25 g.) using an increasing concentration of ethyl acetate in cyclohexane as eluant. Evaporation of the ethyl acetate rich fractions gave 1'-(3,4-dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5 -trione identical with that obtained in Example 1.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[F:25][C:26]([F:39])([F:38])[C:27]1[S:31][C:30]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:29][N:28]=1>>[CH:1]([S:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:35]1[CH2:34][CH2:33][N:32]([C:30]2[S:31][C:27]([C:26]([F:38])([F:25])[F:39])=[N:28][N:29]=2)[CH2:37][CH2:36]1)=[O:9])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Reactant: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Sc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nnc(C(F)(F)F)s2)CC1
Yield: 34 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropylsulfanyl-5-methanesulfonyl-benzoic acid (Example A22) and 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine trifluoroacetate (Example 62(b)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a white solid (yield 34%). MS (m/e): 495.0 (M+H+, 100%).