Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)=[O:4].C(Cl)Cl.[I:20]Cl.S(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[F:16][C:2]([F:1])([F:15])[C:3]([N:5]1[C:10]2[CH:11]=[C:12]([I:20])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: ClI
Reactant: O=C(N1CCOc2ccccc21)C(F)(F)F
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: O=C(N1CCOc2ccc(I)cc21)C(F)(F)F
Reaction time: 0.75 h

Procedure:
A mixture of 0.5 g (2.16 mmol) of this 4-(trifluoroacetyl)-3,4-dihydro-2H-1,4-benzoxazine, 20 ml of glacial acetic acid and 5 ml of methylene chloride was cooled to 10° in an ice bath. A solution of 1 ml of iodine monochloride in 1 ml of acetic acid was added slowly over a period of 5 minutes. Following the addition, the mixture was stirred for 45 minutes and was then diluted with water and a aqueous solution of sodium bisulfite. The product was extracted with ether. The extracts were washed with water, dried and evaporated. Crystallization of the residue from hexane yielded colorless crystals with m.p. 78°-80°.
Reaction SMILES: C([O:8][C@H:9]1[C@@H:17]([C@@H:18]([OH:20])[CH3:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:21](C)[C:22](=O)OC(C)(C)C)[S:14]2)[C@H:10]1[F:30])C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[F:30][C@@H:10]1[C@H:11]2[N:12]=[C:13]([NH:21][CH3:22])[S:14][C@H:15]2[O:16][C@H:17]([C@@H:18]([OH:20])[CH3:19])[C@@H:9]1[OH:8]
Reactant: C[C@H](O)[C@H]1O[C@@H]2SC(N(C)C(=O)OC(C)(C)C)=N[C@@H]2[C@@H](F)[C@H]1OCc1ccccc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CNC1=N[C@@H]2[C@@H](F)[C@@H](O)[C@@H]([C@H](C)O)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
To a solution of tert-butyl ((3aR,5R,6S,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((S)-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.180 g, 0.409 mmol) and PMB (0.20 g, 1.3 mmol) in anhydrous DCM (6 mL) at −78° C. under N2, was added BCl3 (1.0 M in DCM, 2.0 mL, 2.0 mmol). The mixture was stirred for ˜3 h while the temperature of the cooling bath slowly warmed to room temperature. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH/DCM, 1:10), affording (3aR,5R,6S,7R,7aR)-7-fluoro-5-((S)-1-hydroxyethyl)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.092 g, 90%). 1H NMR (400 MHz, CDCl3) δ 6.45 (dd, J=1.1, 6.4 Hz, 1H), 4.59 (ddd, J=3.2, 8.1, 48.0 Hz, 1H), 4.30-4.22 (m, 1H), 4.18-4.14 (m, 1H), 4.08-4.02 (m, 1H), 3.66 (d, J=7.4 Hz, 1H), 2.83 (s, 3H), 1.22 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ 164.73, 95.14 (d, J=183.0 Hz), 92.31 (d, J=8.7 Hz), 79.15 (d, J=6.2 Hz), 69.62 (d, J=20.7 Hz), 67.98 (d, J=2.9 Hz), 67.56 (d, J=16.7 Hz), 30.28, 18.92; MS, (ES, m/z) [M+H]+ 251.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH2:11][C:12]1[C:13]([I:26])=[C:14]([C:23]([Cl:25])=[O:24])[C:15]([I:22])=[C:16]([C:20]=1[I:21])[C:17]([Cl:19])=[O:18]>CN(C=O)C>[CH3:1][O:2][CH2:3][C:4]([NH:11][C:12]1[C:20]([I:21])=[C:16]([C:17]([Cl:19])=[O:18])[C:15]([I:22])=[C:14]([C:13]=1[I:26])[C:23]([Cl:25])=[O:24])=[O:6]
Reactant: COCC(=O)O
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COCC(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Temperature: 10 °C
Reaction time: 1 h

Procedure:
121.2 g. (1.6 mole) of methoxyacetic acid is dissolved in 400 ml. of dry DMF, cooled to 0° C., and within 60 minutes 116 ml. (1.6 mol) of thionyl chloride is added dropwise thereto. The mixture is stirred for 30 minutes at 10° C. and 138.3 g. (0.4 mol) of 5-amino-2,4,6-triiodoisophthalic acid dichloride is introduced into the reaction mixture and the latter is stirred for 20 hours at room temperature. The reaction solution is stirred into 10 l. of water, the precipitate is vacuum-filtered, washed with water, again stirred with water, vacuum-filtered, and dried at 50° C. under vacuum. Yield: 198 g. (0.296 mol)=74% of theory.
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=1)[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([CH2:21][CH3:22])=[N:19][N:20]=[C:14]2[CH2:13]1)=[O:11])=O)C.[ClH:33]>CO>[ClH:33].[ClH:33].[NH2:7][C@H:8]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=1)[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([CH2:21][CH3:22])=[N:19][N:20]=[C:14]2[CH2:13]1)=[O:11]
Reactant: CCc1nnc2n1CCN(C(=O)C[C@@H](Cc1ccc(F)c(F)c1)NC(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CO
Product: CCc1nnc2n1CCN(C(=O)C[C@H](N)Cc1ccc(F)c(F)c1)C2

Procedure:
The title compound was prepared from 7-[(3R)-3-[(1,1-dimethylethoxycarbonyl)-amino]-4-(3,4-difluorophenyl)butanoyl]-3-ethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-α]pyrazine (30 mg, 0.067 mmol from Step C), in 1.5 mL of methanol saturated with hydrogen chloride, using a procedure analogous to that described in Example 1, Step D. Evaporation of solvent afforded 28 mg of the title compound as a viscous oil. 1H NMR (500 MHz, CD3OD) δ 1.45 (t, 3H), 2.93-3.07 (m, 6H), 3.90-4.31 (m, 5H), 5.08 (m, 2H), 7.16 (s, 1H), 7.31 (m, 2H). ESI-MS 350 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[C:5]([O:20][CH3:21])=[CH:6][C:7]([O:16][CH2:17][CH2:18][CH3:19])=[CH:8][C:9]=1[C:10]2=[O:15].Cl.Cl[CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28].C[O-].[Na+]>CO.ClC1C=CC=CC=1>[CH2:25]([N:26]([CH2:29][CH3:30])[CH2:27][CH2:28][O:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[C:5]([O:20][CH3:21])=[CH:6][C:7]([O:16][CH2:17][CH2:18][CH3:19])=[CH:8][C:9]=1[C:10]2=[O:15])[CH3:24]
Reactant: CCN(CC)CCCl
Reactant: CCCOc1cc(OC)c2c(c1)C(=O)c1cccc(O)c1-2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: CO
Product: CCCOc1cc(OC)c2c(c1)C(=O)c1cccc(OCCN(CC)CC)c1-2
Yield: 47.1 %

Procedure:
In a manner analagous to Example 9B, react 5-hydroxy-2-propoxy-4-methoxy-fluoren-9-one (1.75 g, 6.1) in 5 mL methanol and 100 mL chlorobenzene with 2-chloroethyldiethyl amine hydrochloride (4.4 g, 25 mmole) and sodium methoxide (0.51 g, 9.5 mmole) and reflux for 2 hours then continue as in Example 9B to give 1.1 g. of the title compound (2.9 mmole, 47%).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(NC(=O)c2ccccc2)cc1
Solvent: CCO
Product: O=C(O)CCc1ccc(NC(=O)c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
(Method H6) To a solution of 3-(4-benzoylamino-phenyl)-acrylic acid (5b) (1.350 g, 5.05 mmol) in 90% ethanol 10% Pd/C (0.03 g) was added and the mixture was stirred under hydrogen atmosphere at 50° C. for 2 hours. The catalyst was filtered off, the solution was evaporated, and the residue was washed with hot water (20 ml) to give the title compound as a white solid (1.306 g, 96%). 1H NMR (DMSO-d6, HMDSO), δ: 2.38-2.64 (2H, m, overlapped with a signal of DMSO), 2.65-2.96 (2H, m); 7.21 (2H, d, J=8.6 Hz); 7.44-8.08 (7H, m); 10.16 (1H, s); 12.09 (1H, s).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([O:13][C:14]([N:16]([C:36]1[C:41]([O:42][CH3:43])=[N:40][C:39]([CH3:44])=[CH:38][N:37]=1)[S:17]([C:20]1[C:21]([C:26]2[CH:31]=[CH:30][C:29]([Si](C)(C)C)=[CH:28][CH:27]=2)=[N:22][CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:18])=[O:15])[CH:10]([CH3:12])[CH3:11]>C(#N)C>[I:1][C:29]1[CH:30]=[CH:31][C:26]([C:21]2[C:20]([S:17]([N:16]([C:14]([O:13][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:15])[C:36]3[C:41]([O:42][CH3:43])=[N:40][C:39]([CH3:44])=[CH:38][N:37]=3)(=[O:19])=[O:18])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:27][CH:28]=1
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc([Si](C)(C)C)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(I)cc1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
N-Iodosuccinimide (0.84 g) was added to a solution of N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-trimethylsilylphenyl)pyridine-3-sulphonamide (1.58 g) in acetonitrile (15 ml) and the reaction mixture was stirred and heated at 65° C. for 17 hours. A further portion of N-iodosuccinimide (50 mg) was added and heating continued for 24 hours, then more N-iodosuccinimide (100 mg) was added and heating continued a further 24 hours. The mixture was cooled and volatile material was removed by evaporation. The residue was purified by chromatography on a silica gel Mega Bond Elut column, eluting with 0-25% ethyl acetate/hexane, followed by trituration with hexane (2×25 ml) to give 2-(4-iodophenyl)-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide as a solid, m.p. 156-158° C.; 1H NMR (CDCl3): 0.7 (d, 6H), 1.7 (m, 1H), 2.5 (s, 3H), 3.8 (d, 2H), 4.0 (s, 3H), 7.4 (d, 2H), 7.5 (dd, 1H), 7.7 (d, 2H), 7.9 (s, 1H), 8.8 (dd, 1H), 8.9 (dd, 1H); mass spectrum (+ve ESP): 583 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][C:5]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:6][CH:7]=1.C([Li])CCC.[CH2:23]([C:25]1[CH:26]=[CH:27][C:28]2[C:38](=[O:39])[C:33]3[N:34]=[C:35]([CH3:37])[O:36][C:32]=3[CH2:31][CH2:30][C:29]=2[CH:40]=1)[CH3:24]>O1CCCC1>[CH3:10][C:9]([CH3:12])([O:8][C:5]1[N:4]=[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]([C:38]2([OH:39])[C:33]3[N:34]=[C:35]([CH3:37])[O:36][C:32]=3[CH2:31][CH2:30][C:29]3[CH:40]=[C:25]([CH2:23][CH3:24])[CH:26]=[CH:27][C:28]2=3)=[CH:7][N:6]=1)[CH3:11]
Reactant: CC(C)(C)Oc1ncc(Br)c(OC(C)(C)C)n1
Reactant: CCc1ccc2c(c1)CCc1oc(C)nc1C2=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc2c(c1)CCc1oc(C)nc1C2(O)c1cnc(OC(C)(C)C)nc1OC(C)(C)C
Reaction time: 0.5 h

Procedure:
A stirred solution of the product from example 1 step (vi) (3.60 g) in tetrahydrofuran (30 ml) at −70° C. was treated dropwise with n-butyllithium (4.75 ml of a 2.5M solution in hexanes) and stirred for 30 minutes. A solution of the product from example 3 step (vi) (2.60 g) in tetrahydrofuran (30 ml) was added dropwise and the reaction stirred at room temperature for 3 hours. The reaction was partitioned between brine and ethyl acetate and the organics dried (MgSO4) and evaporation under reduced pressure gave a brown oil. Purification was by column chromatography eluting with 50% ethyl acetate in isohexane.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])C(=O)[NH:6]2.[OH-:14].[Na+].OO>O>[NH2:6][C:7]1[C:3]([C:4]([OH:13])=[O:14])=[C:2]([CH3:1])[C:10]([CH3:11])=[CH:9][CH:8]=1
Reactant: Cc1ccc2c(c1C)C(=O)C(=O)N2
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: Cc1ccc(N)c(C(=O)O)c1C
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A solution of 4,5-dimethyl-1H-indole-2,3-dione (9.8 g, 0.056 mmol) and sodium hydroxide (8.1 g, 0.2 mol) in water (80 ml) was heated to 85° C., and then 10% aqueous hydrogen peroxide (43 ml) was slowly added. The obtained solution was stirred at 85° C. for 2 hours and then cooled to room temperature and filtered. Sulfuric acid was used for acidification of the filtrate to obtain 6-amino-2,3-dimethylbenzoic acid as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]3[CH:25]=[N:26][N:27]([CH2:29][CH2:30][O:31]C4CCCCO4)[CH:28]=3)[CH:23]=2)[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.Cl>ClCCl.O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[CH:23]=[C:22]([C:24]3[CH:25]=[N:26][N:27]([CH2:29][CH2:30][OH:31])[CH:28]=3)[CH:21]=[N:20][CH:19]=2)[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: Fc1ccccc1-c1cc(-c2cncc(-c3cnn(CCOC4CCCCO4)c3)c2)c2cccnc2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: OCCn1cc(-c2cncc(-c3cc(-c4ccccc4F)nc4ncccc34)c2)cn1
Reaction time: 1 h

Procedure:
A solution of 219 mg (0.44 mmol) 2-(2-fluoro-phenyl)-4-(5-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-pyridin-3-yl)-[1,8]naphthyridine in 7 ml dichloromethane was treated with 0.52 ml of a 4 N solution of hydrochloric acid in dioxane. The reaction mixture was stirred for 60 minutes and the precipitate that had formed was filtered off. The residue was dissolved in water and treated with saturated sodium carbonate solution. The resulting precipitate was filtered off, washed with water and dried under vacuum yielding 2-(4-{5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-pyridin-3-yl}-pyrazol-1-yl)-ethanol as colorless crystals; HPLC-MS: 1.70 min, [M+H] 412.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)[CH3:2].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: C1CNCCN1
Reactant: CCNC(=O)c1ccc(F)cc1
Product: CCNC(=O)c1ccc(N2CCNCC2)cc1
Yield: 77 %

Procedure:
Using N-ethyl-4-fluorobenzamide in the general procedure for nucleophilic aromatic substitution reactions with piperazine (Scheme D), the title compound was obtained (77% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.07 Hz, 3 H) 2.25 (br. s., 1 H) 2.76-2.86 (m, 4 H) 3.09-3.18 (m, 4 H) 3.21-3.28 (m, 2 H) 6.90 (m, J=8.84 Hz, 2 H) 7.67-7.75 (m, 2 H) 8.11 (t, J=5.31 Hz, 1 H). ESI-MS: m/z 234.2 (M+H)+. mp=131.3-134.4° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:15]1[CH:16]=[CH:17][C:18]([N+:30]([O-:32])=[O:31])=[C:19]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:20]=1.[H-].[Na+]>CN(C)C=O>[CH3:29][N:21]([C:19]1[CH:20]=[C:15]([O:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:16]=[CH:17][C:18]=1[N+:30]([O-:32])=[O:31])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26]
Reactant: Oc1ccccc1-c1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2-c2ccccc2)ccc1[N+](=O)[O-]
Yield: 101.1 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 2-phenylphenol (3.5 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (5.6 g), sodium hydride (55 wt. %, 1.08 g) and anhydrous N,N-dimethylformamide (35 ml) and the reaction mixture was purified to give the title compound (8.3 g).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]([F:13])=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:13][C:10]1[CH:11]=[CH:12][C:2]([F:1])=[C:3]2[C:8]([N:18]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5](=[O:7])[C:4]=12)=[O:9]
Reactant: CC(C)CN
Reactant: O=C1OC(=O)c2c(F)ccc(F)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)CN1C(=O)c2c(F)ccc(F)c2C1=O
Temperature: 20 °C

Procedure:
3,6-Difluoro-N-isobutylphthalimide is prepared as described in Example 2, starting with 5.0 g of 3,6-difluorophthalic anhydride, 2.7 cm3 of isobutylamine and a catalytic amount of para-toluenesulfonic acid in 50 cm3 of toluene. The reaction mixture is refluxed for 3 hours. After cooling to a temperature in the region of 20° C., the reaction mixture is filtered and then concentrated to dryness under reduced pressure (2 kPa). The residue is taken up in 50 cm3 of saturated aqueous sodium bicarbonate solution and washed 3 times with 80 cm3 of dichloromethane. The organic extracts are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 6.41 g of 3,6-difluoro-N-isobutylphthalimide are thus obtained in the form of a pale yellow solid. (Rf=0.74, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[N:12]=[C:11]([CH2:13][CH2:14][CH:15]([OH:17])[CH3:16])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH3:18].C([O-])(=O)C.[Na+].C(O)(=O)C>CO.C1COCC1.C([O-])(=O)C.O>[NH2:3][C:4]1[N:12]=[C:11]([CH2:13][CH2:14][CH:15]([OH:17])[CH3:16])[N:10]=[C:9]2[C:5]=1[N:6]=[C:7]([Br:1])[N:8]2[CH3:18]
Reactant: CC(O)CCc1nc(N)c2ncn(C)c2n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(O)CCc1nc(N)c2nc(Br)n(C)c2n1
Reaction time: 0.17 h

Procedure:
Bromine (2.1 ml, 41 mmol) was added dropwise at −14° C. to a solution of 4-(6-amino-9-methyl-9H-purin-2-yl)butan-2-ol (800 mg, 3.60 mmol) in a mixture of MeOH/THF (20 ml, 1/1) and acetate buffer pH=4 (10 ml). The latter was obtained dissolving 4 g of sodium acetate in 100 ml of water and by adjusting to pH 4 through addition of glacial acetic acid. The reaction was stirred at this temperature for 10 minutes and then at RT for 10 minutes. Excess of bromine was quenched by addition of sodium metabisulphite and the reaction was brought to pH 8 by addition of a saturated solution of Na2CO3. The organic solvents were evaporated under reduced pressure, to give a solid that was filtered and used without any further purification.
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.Cl.[CH:24]([N:27]([CH:33]([CH3:35])[CH3:34])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])([CH3:26])[CH3:25].N12CCCN=C1CCCCC2>CN(C)C=O>[CH:33]([N:27]([CH:24]([CH3:26])[CH3:25])[CH2:28][CH2:29][C:30]([O:32][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1)=[O:31])([CH3:35])[CH3:34]
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CC(C)N(CCC(=O)O)C(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)N(CCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1)C(C)C
Yield: 27.7 %

Procedure:
Working as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (6.9 g) in anhydrous dimethylformamide (70 cc), 3-diisopropylaminopropionic acid hydrochloride (4.4 g) and 1,8-diazabicyclo-[5.4.0]undec-7-ene (7.45 g), and after the residue obtained has been recrystallized successively, first in acetonitrile and then in ethanol, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 3-diisopropylaminopropionate (2.7 g), m.p. 135° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:8][C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([F:16])=[CH:11][C:10]=2[Cl:17])[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[Ca+2].[C:23](Cl)(Cl)=[S:24]>C(Cl)CCl.O>[CH3:1][O:2][C:3]([C:5]1([S:8][C:9]2[CH:14]=[C:13]([N:15]=[C:23]=[S:24])[C:12]([F:16])=[CH:11][C:10]=2[Cl:17])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(Sc2cc(N)c(F)cc2Cl)CC1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)C1(Sc2cc(N=C=S)c(F)cc2Cl)CC1
Temperature: 25 °C

Procedure:
While stirring at room temperature, a solution of 5.5 g of 1-(5-amino-2-chloro-4-fluoro-phenylthio)-cyclopropanecarboxylic acid methyl ester in 20 ml of ethylene chloride is added dropwise to a mixture of 3 g of calcium carbonate, 2 ml of thiophosgene in 20 ml of ethylene chloride and 20 ml of water. After stirring for 4 hours at room temperature, the inorganic portion of the reaction mixture is filtered off and the organic phase is dried over calcium chloride and then concentrated by evaporation, yielding 6.3 g of 1-(2-chloro-4-fluoro-5-isothiocyanato-phenylthio)-cyclopropanecarboxylic acid methyl ester having a melting point of from +100° to +101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br[CH2:14][C:15]1[C:27]([F:28])=[CH:26][C:18]([C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[O:20])=[C:17]([F:29])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:11])[F:9])[O:12][CH2:14][C:15]1[C:27]([F:28])=[CH:26][C:18]([C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[O:20])=[C:17]([F:29])[CH:16]=1
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
Reactant: Oc1ccc(C(F)(F)F)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(F)c(COc2ccc(C(F)(F)F)c(Cl)c2)cc1F
Yield: 56.3 %

Procedure:
A solution of 3-chloro-4-(trifluoromethyl)phenol (Preparation 5, 50 mg, 0.26 mmol), 4-(bromomethyl)-2,5-difluoro-N-(methylsulfonyl)benzamide (Preparation 4, 84 mg, 0.26 mmol) and potassium carbonate (71 mg, 0.51 mmol) in dimethyl sulfoxide (5 mL) was stirred at room temperature for 16 hours. A 2M aqueous solution of hydrogen chloride was added to the reaction mixture. The resulting precipitate was filtered, washed with diethyl ether (5 mL) and dried. The material was purified by reverse phase column chromatography (12 g C-18 biotage cartridge; eluents: MeCN+0.1% formic acid, and H2O+0.1% formic acid; Gradient: 30% MeCN, followed by gradient to 100% MeCN, 100% MeCN. Fractions containing product were combined and concentrated in vacuo to afford the title compound as a colourless solid (65 mg, 56%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[F:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[C:35]([CH3:40])[CH:34]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:37][C:36]3[CH:38]=[CH:39][C:33]([F:32])=[CH:34][C:35]=3[CH3:40])=[C:3]([C:16]([N:18]3[CH2:19][CH2:20][C:21]4([C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:25][CH2:24]4)[CH2:22][CH2:23]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1cc(F)ccc1N
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Yield: 92.7 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(spiro[indane-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.08 g, 0.18 mmol) obtained in Example 120, step 2 and 4-fluoro-2-methylaniline (0.034 g, 0.27 mmol), the title compound (0.088 g, 91%) was obtained.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH2:13][CH2:12][N:11]([C:14]([CH2:16][C:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[N:23]3[C:28](=[O:29])[CH:27]=[CH:26][C:25]([C:30]4[C:31]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)=[N:32][N:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=45)=[N:24]3)=[O:15])[CH2:10][CH2:9]2)C=CC=CC=1.C(O)=O.Cl.C(OCC)(=O)C>O>[N:11]1([C:14]([CH2:16][C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=2[N:23]2[C:28](=[O:29])[CH:27]=[CH:26][C:25]([C:30]3[C:31]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[N:32][N:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=34)=[N:24]2)=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: O=C(CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCC1)N1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: O=C(CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCC1)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
The mixture of 3-[2-{2-(4-triphenylmethylpiperazin-1-ylcarbonyl)methyl-1-cyclohexenyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (4.2 g), formic acid (10 ml) and concentrated hydrochloric acid (1.43 ml) was stirred for 2 hours at room temperature. The reaction mixture was poured into a mixture of ethyl acetate (200 ml) and water (100 ml). Aqueous layer was separated, and the pH was adjusted to pH 12.0 with 4N-aqueous sodium hydroxide solution, which was extracted with dichloromethane (300 ml and 150 ml). Organic phase was combined and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel eluting in turn with 5% and 10% methanol in dichloromethane. Fractions containing desired product were collected, and solvent was removed under reduced pressure to give solid, which was recrystallized from ethyl acetate to give 3-[2-{2-(piperazin-1-ylcarbonyl)methyl-1-cyclohexenyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (2.2 g).